Review Reports - Chemoprevention in Skin Cancer: What Advice?

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review provides a good and balanced overview of chemoprevention in skin cancer; the definition of chemoprevention used in the introduction is well framed. The authors appropriately acknowledge the associated difficulties in assessing chemopreventive strategies, which strengthens the context of the review.

Comments:

For improved clarity and completeness, the number of patients included in each clinical trial should be added to the summary table.
A brief paragraph on ingenol mebutate would be valuable for completeness, given its historical relevance in this field.
Minor corrections are required, including the nomenclature of xeroderma pigmentosum in the Endonuclease V section
There is likely a wrong reference at L.637
If laser-based approaches are discussed, consideration should also be given to including superficial radiotherapy (Grenz rays) and liquid nitrogen as relevant physical modalities.
Imiquimod is discussed with both formulations, 5-fluorouracil should as well
The sunscreen section would benefit from inclusion of the study by Thomson et al. (NEJM 1993; doi:10.1056/NEJM199310143291602).
While the sections on SPF and UVA determination are informative, it may be out of topic for chemoprevention
As Jansen’s paper is cited, the authors could consider adding some comparative discussions between topical chemopreventive agents to further enhance the clinical utility

Author Response

Comments Reviewer 1:

For improved clarity and completeness, the number of patients included in each clinical trial should be added to the summary table.

Response: Thank you very much for your comment. Kindly notice that we provided a column in Table 1 (page 3 of the manuscript) with the number of patients included in each clinical trial

A brief paragraph on ingenol mebutate would be valuable for completeness, given its historical relevance in this field.

Response: Thank you for pointing this out. A paragraph on ingenol mebutate has been added (now section 3.4, page 16)

Minor corrections are required, including the nomenclature of xeroderma pigmentosum in the Endonuclease V section

Response: We thank the reviewer for this comment. Please notice that we have corrected the nomenclature of xeroderma pigmentosum in the Endonuclease V section (page 23, lines 766, 770)

There is likely a wrong reference at L.637

Response: Thank you for pointing this out. We have reviewed the reference (now line 863, page 26)

If laser-based approaches are discussed, consideration should also be given to including superficial radiotherapy (Grenz rays) and liquid nitrogen as relevant physical modalities.

Response: We thank the reviewer for the proposal. We did not include liquid nitrogen in our review as we focused on field treatments and not targeted therapies.

Regarding superficial radiotherapy, it was not included as radiation based therapies have been excluded from chemoprevention as they can potentially increase the risk of secondary cancers. They are indeed mostly reserved for older patients and avoided in the immunosuppressed.

Imiquimod is discussed with both formulations, 5-fluorouracil should as well

Response: Thank you very much for pointing this out. We have included both formulations of 5-FU (page 12, lines 370-372, 379-385, and 390-393)

The sunscreen section would benefit from inclusion of the study by Thomson et al. (NEJM 1993; doi:10.1056/NEJM199310143291602).

Response: We thank the reviewer for this comment. The reference has been added (page 27, line 879-885)

While the sections on SPF and UVA determination are informative, it may be out of topic for chemoprevention

Response Thank you for pointing this out. The sections have been deleted.

As Jansen’s paper is cited, the authors could consider adding some comparative discussions between topical chemopreventive agents to further enhance the clinical utility

Response: Thank you very much for this comment. A section has been added to discuss between topical chemopreventive agents (now section 3.8, page 20-21)

Reviewer 2 Report

Comments and Suggestions for Authors

The paper revises the studies focused on chemoprevention in skin cancers and various tools medicine has to work in that direction. The research work is comprehensive an clearly presented, in a fluent style.

I have the following observations:

the title should reflect the focus on skin cancer; in the current form, it seems to refer to all types of cancer, in general
the methodology of research in terms of article selection, inclusion criteria, databases search, etc. should be introduced
in Table 1: I did not understand why are the adverse effects mentioned in the first column, in the row that further mentions different parameters? maybe there is a mistake the authors failed to see before submitting?
the classification in section 2 mentions active compounds with 1 exception: point 2.4 where there is a mechanism of action - it should be replaced with "compounds that inhibit the arachidonic....." for a more fluent style
limitations of the study should be introduced
future directions are rather poorly discussed
for all active compounds and therapies, schemes should be introduced for the mechanism of action, it is a huge support for the reader to see a graphical representation instead/added to plain text.

Comments on the Quality of English Language

The paper should be checked for typos and English topic and style.

Author Response

the title should reflect the focus on skin cancer; in the current form, it seems to refer to all types of cancer, in general

Response: Thank you very much for your comment. We have modified the title to focus on skin cancer

the methodology of research in terms of article selection, inclusion criteria, databases search, etc. should be introduced

Response: Thank you very much for pointing this out. Please notice that the methodology has been introduced (page 2, lines 63-79)

in Table 1: I did not understand why are the adverse effects mentioned in the first column, in the row that further mentions different parameters? maybe there is a mistake the authors failed to see before submitting?

Response: Thank the reviewer for pointing this out. This was indeed incorrectly placed in the table during the editing. The table has now been corrected and the paragraph moved back to the text in the manuscript (page 7, Table 1).

the classification in section 2 mentions active compounds with 1 exception: point 2.4 where there is a mechanism of action - it should be replaced with "compounds that inhibit the arachidonic....." for a more fluent style

Response: Thank you very much for pointing this out. The title of the section has been replaced by “Compounds that inhibit the arachidonic acid pathway” (page 9, line 259)

limitations of the study should be introduced

Response: Thank you very much for pointing this out. Limitations have been introduced (page 28, lines 955-957)

future directions are rather poorly discussed

Response: Thank you very much for pointing this out. Future conclusions have been reviewed and extended (pages 28-29, lines 962-964, and 973-976)

for all active compounds and therapies, schemes should be introduced for the mechanism of action, it is a huge support for the reader to see a graphical representation instead/added to plain text.

Response: Thank you very much for pointing this out. Graphical representations have been added in the manuscript at the beginning of each compound and therapy

The paper should be checked for typos and English topic and style.

Response: Thank you very much for your comment. The paper has been checked professionally for typos and English topic and style (corrections marked on the text)

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have revised the article according to the reviewers' suggestions and can be published in its current form.