Pooled Analysis of Trabectedin Efficacy in Myxoid/Round Cell Liposarcoma from Three Prospective Clinical Trials

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “POOLED ANALYSIS OF TRABECTEDIN EFFICACY IN MYXOID/ROUND CELL LIPOSARCOMA FROM THREE PROSPECTIVE CLINICAL TRIALS” has undergone a thorough evaluation, indicating the necessity for several detailed analyses prior to its submission for peer review.

To enhance the introduction, it is vital to provide a more comprehensive overview of the statistics associated with myxoid/round cell liposarcoma (MRCLS). This overview should include precise regional data that will provide critical context and underscore the significance of the research within the broader field of MRCLS studies. The authors are encouraged to elaborate on the role of Trabectedin in cancer treatment, particularly by focusing on its mechanisms of action, prior clinical outcomes, and its current standing in therapeutic practice.

In addition, the manuscript would greatly benefit from the inclusion of a detailed flow diagram illustrating the patient selection process in the pooled analysis. This diagram should effectively depict each stage of the selection process while clearly outlining both inclusion and exclusion criteria. Such a visual representation will enhance the study's transparency, enabling readers to better understand the methodological framework used throughout the investigation.

Concerning the statistical methods employed, the manuscript necessitates a comprehensive overview of the analytical techniques used in the study. Each statistical test should be meticulously justified, including the theoretical foundations that support its application. This clarity will enhance the study's overall credibility and facilitate a deeper understanding of the data analysis process among readers.

Furthermore, the conclusions indicated in the manuscript are relatively concise and warrant further elaboration. A more extensive examination of how these findings relate to the existing body of research would enrich the conclusions drawn and elucidate their implications for clinical practice and future research.

Moreover, the manuscript's reference list is currently limited. The authors are strongly advised to expand their literature review by incorporating a wider array of scholarly sources. A broader reference list will not only enhance the credibility of the research but also contextualize the findings within the wider discourse on MRCLS and the efficacy of Trabectedin.

Given that the authors have integrated data from three clinical trials, it is essential to include a discussion of both the study's merits and limitations. This discussion should highlight the strengths of the pooled analysis, such as the increased statistical power and the potential for broader generalizations, while also addressing any limitations related to trial heterogeneity, sample sizes, or variations in treatment protocols.

Finally, the manuscript should include a comprehensive list of all abbreviations used throughout the text, accompanied by clear definitions on first mention. This practice will significantly improve the manuscript's overall readability and comprehension, ensuring that the intended messages are accessible to a diverse audience, including those who may not be familiar with the specialized terminology in the field.

Author Response

Reviewer Comment # 1: To enhance the introduction, it is vital to provide a more comprehensive overview of the statistics associated with myxoid/round cell liposarcoma (MRCLS). This overview should include precise regional data that will provide critical context and underscore the significance of the research within the broader field of MRCLS studies. The authors are encouraged to elaborate on the role of Trabectedin in cancer treatment, particularly by focusing on its mechanisms of action, prior clinical outcomes, and its current standing in therapeutic practice.

Authors’ response to reviewer comment #1: The introduction has been updated to include the incidence of MRCLS, as well as prognostic factors, recurrence, survival on recurrence, and the treatment paradigm. The information on trabectedin MoA and potential roles and location in the treatment of MRCLS has also been expanded.

Reviewer Comment # 2: In addition, the manuscript would greatly benefit from the inclusion of a detailed flow diagram illustrating the patient selection process in the pooled analysis. This diagram should effectively depict each stage of the selection process while clearly outlining both inclusion and exclusion criteria. Such a visual representation will enhance the study's transparency, enabling readers to better understand the methodological framework used throughout the investigation.

Authors’ response to reviewer comment #2: The current flow diagram and inclusion criteria diagram (figures 1 and 2) have been updated.

Reviewer Comment #3: Concerning the statistical methods employed, the manuscript necessitates a comprehensive overview of the analytical techniques used in the study. Each statistical test should be meticulously justified, including the theoretical foundations that support its application. This clarity will enhance the study's overall credibility and facilitate a deeper understanding of the data analysis process among readers.

Authors’ Response to reviewer comment #3: The methods have been updated to describe the response and time to event endpoints. These have been defined and are standard definitions used to assess response and time to event endpoints. RECIST v1.1 criteria the accepted response criteria standard. Additionally, the methodology used has been justified, and appropriate references added.

Reviewer Comment # 4: Furthermore, the conclusions indicated in the manuscript are relatively concise and warrant further elaboration. A more extensive examination of how these findings relate to the existing body of research would enrich the conclusions drawn and elucidate their implications for clinical practice and future research.

Authors’ Response to reviewer comment #4: The conclusions have been updated and expanded.

Reviewer Comment # 5: Moreover, the manuscript's reference list is currently limited. The authors are strongly advised to expand their literature review by incorporating a wider array of scholarly sources. A broader reference list will not only enhance the credibility of the research but also contextualize the findings within the wider discourse on MRCLS and the efficacy of Trabectedin.

Authors’ Response to reviewer comment #5: The literature references have been expanded.

Reviewer comment # 6: Given that the authors have integrated data from three clinical trials, it is essential to include a discussion of both the study's merits and limitations. This discussion should highlight the strengths of the pooled analysis, such as the increased statistical power and the potential for broader generalizations, while also addressing any limitations related to trial heterogeneity, sample sizes, or variations in treatment protocols.

Authors’ Response to review comment #6: The last paragraph of the discussion was extensively expanded to highlight the study’s merits and limitations.

Reviewer Comment # 7: Finally, the manuscript should include a comprehensive list of all abbreviations used throughout the text, accompanied by clear definitions on first mention. This practice will significantly improve the manuscript's overall readability and comprehension, ensuring that the intended messages are accessible to a diverse audience, including those who may not be familiar with the specialized terminology in the field.

Authors’ response to reviewer comment # 7: Most abbreviations have now been removed. Abbreviations kept include myxoid/round cell liposarcoma (MRCLS) and confidence interval (CI). A list of abbreviations was added to the end of the document. 

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript. The topic is clinically relevant, and the pooled analysis of trabectedin efficacy in myxoid/round cell liposarcoma may provide a useful benchmark for future studies. However, the manuscript requires substantial revision in terms of language, formatting, and adherence to journal style before it can be considered for publication.

Major points:

1. Journal formatting should be revised throughout the manuscript. In particular, abbreviations should generally be avoided in the title and abstract. Abbreviations should be introduced in full at first mention in the main manuscript and only then used subsequently.
2. The English language requires substantial editing. There are multiple grammatical issues, awkward sentence constructions, punctuation problems, inconsistent capitalization, and typographical errors throughout the text. Careful language revision by a fluent English speaker or professional editing service is recommended.
3. The title and abstract should be revised for clarity and style. The abstract currently contains several non-standard abbreviations, formatting inconsistencies, and sentences that should be rephrased for clarity. Outcome definitions should be presented more clearly and in a more standard scientific format.
4. Methods section requires clearer and more precise reporting. The description of inclusion criteria, study selection, and trial flow should be rewritten for clarity. Some sentences are difficult to follow and should be simplified. Outcome definitions should be stated explicitly and consistently. Statistical methods are generally appropriate but should be described more precisely.
5. Results presentation should be improved. Numerical reporting, confidence interval formatting, and terminology should be standardized throughout. Some sentences in the Results section require punctuation or restructuring to improve readability.
6. Figures and tables should be reformatted according to journal requirements. It would be preferable to separate figures, figure legends, tables, and table legends into dedicated sections rather than embedding them directly in the main text. Figure and table captions should also be revised for style and consistency.
7. Terminology and abbreviations should be used consistently. Terms such as ORR, OS, DOR/DoR, SOC/SoC, MRCLS, and histologic subtype names should be standardized throughout the manuscript.
8. Several specific textual corrections are needed throughout the manuscript. These include typographical errors, spacing problems, statistical formatting issues, and multiple sentences that should be rewritten for clearer scientific expression.

Overall, the manuscript addresses an interesting clinical question and may be suitable for publication after major revision, particularly focused on language editing, journal formatting, clarification of the Methods section, and improvement in the presentation of figures, tables, and results.

All suggested edits and corrections have been incorporated directly into the manuscript and are highlighted in red for clarity.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

The English language requires revision to improve clarity, grammar, and overall readability throughout the manuscript.

Author Response

Reviewer comment # 1: Journal formatting should be revised throughout the manuscript. In particular, abbreviations should generally be avoided in the title and abstract. Abbreviations should be introduced in full at first mention in the main manuscript and only then used subsequently.

Authors’ response to reviewer comment #1: Abbreviations have mostly been removed; when included, they are defined at first introduction. Abbreviations have been removed from the title and abstract, and the manuscript and all tables and figures have been formatted to journal style in line with the Author Guidelines.

Reviewer comment # 2: The English language requires substantial editing. There are multiple grammatical issues, awkward sentence constructions, punctuation problems, inconsistent capitalization, and typographical errors throughout the text. Careful language revision by a fluent English speaker or professional editing service is recommended.

Authors’ Response to reviewer comment #2: All language, grammar, and punctuation have been checked and revised throughout the manuscript, tables and figures.

 Reviewer comment # 3: The title and abstract should be revised for clarity and style. The abstract currently contains several non-standard abbreviations, formatting inconsistencies, and sentences that should be rephrased for clarity. Outcome definitions should be presented more clearly and in a more standard scientific format.

 Authors’ response to reviewer comment #3: The abstract has been reviewed and is in line with Author Guidelines and previously published articles in Cancers.

Reviewer comment # 4: Methods section requires clearer and more precise reporting. The description of inclusion criteria, study selection, and trial flow should be rewritten for clarity. Some sentences are difficult to follow and should be simplified. Outcome definitions should be stated explicitly and consistently. Statistical methods are generally appropriate but should be described more precisely.

Authors’ Response to reviewer comment #4: Thank you for your suggestions. The methods section has been rewritten to improve the trial flow, study selection and inclusion, and exclusion criteria, as well as outcome definitions and description of statistical methods.

Reviewer comment # 5: Results presentation should be improved. Numerical reporting, confidence interval formatting, and terminology should be standardized throughout. Some sentences in the Results section require punctuation or restructuring to improve readability.

Authors’ Response to reviewer comment #5: The Results section has been revised and improved as per the recommendations made by Reviewer 2.

Reviewer comment # 6: Figures and tables should be reformatted according to journal requirements. It would be preferable to separate figures, figure legends, tables, and table legends into dedicated sections rather than embedding them directly in the main text. Figure and table captions should also be revised for style and consistency.

Authors’ Response to reviewer comment #6: As per Author Guidelines, all figures, figures legends, table, and table legends should be embedded directly in the main text. The original submitted manuscript had these as a separate section. However, Cancers requests these to be embedded in the main text. The figures, tables, and legends have been updated and edited per the Author Guidelines.

Reviewer comment # 7: Terminology and abbreviations should be used consistently. Terms such as ORR, OS, DOR/DoR, SOC/SoC, MRCLS, and histologic subtype names should be standardized throughout the manuscript.

Authors’ Response to reviewer comment #7: Most abbreviations have now been removed (please see previous response to Reviewer # 1) and all text/terminology has been standardized throughout the manuscript.

Reviewer comment # 8: Several specific textual corrections are needed throughout the manuscript. These include typographical errors, spacing problems, statistical formatting issues, and multiple sentences that should be rewritten for clearer scientific expression.

Authors’ Response to reviewer comment #8: These have now been corrected.

Overall, the manuscript addresses an interesting clinical question and may be suitable for publication after major revision, particularly focused on language editing, journal formatting, clarification of the Methods section, and improvement in the presentation of figures, tables, and results.

All suggested edits and corrections have been incorporated directly into the manuscript and are highlighted in red for clarity.

Reviewer 3 Report

Comments and Suggestions for Authors

This study presents a pooled analysis of three prospective clinical trials evaluating the efficacy of trabectedin in patients with MRCLS. The results establish a benchmark for trabectedin outcomes in this rare sarcoma subtype.

The manuscript looks like well written and organized. The authors have presented an interesting topic in the field of oncology. The paper should be considered after major revisions.

• The authors should expand discussion on biological rationale for increased trabectedin sensitivity in MRCLS (such as translocation-related biology).
• The authors should compare results more critically with other prospective datasets and emerging therapies. On this point, in the introduction or discussion, the authors should describe The biological role of CDK4 amplification, particularly in well-differentiated/dedifferentiated liposarcomas and its evolution as a therapeutic target. The following references should be included in the manuscript: “doi: 10.1007/s12094-025-03989-9”, “doi: 10.1186/s40164-024-00540-4” and “doi: 10.1016/j.critrevonc.2020.103029”.
• Minor concerns: standardize terminology (such as, MRCLS vs myxoid/round cell liposarcoma), ensure all acronyms are defined at first use.

Author Response

Reviewer comment # 1: The authors should expand discussion on biological rationale for increased trabectedin sensitivity in MRCLS (such as translocation-related biology).

Authors’ Response: Thank you for the suggestion. The introduction has been expanded to discuss the increased sensitivity of MRCLS to trabectedin.

Reviewer comment # 2: The authors should compare results more critically with other prospective datasets and emerging therapies. On this point, in the introduction or discussion, the authors should describe the biological role of CDK4 amplification, particularly in well-differentiated/de-differentiated liposarcomas and its evolution as a therapeutic target. The following references should be included in the manuscript: “doi: 10.1007/s12094-025-03989-9”, “doi: 10.1186/s40164-024-00540-4” and “doi: 10.1016/j.critrevonc.2020.103029”.

Authors’ Response: The main focus of this manuscript is trabectedin in myxoid liposarcoma (MRCLS), which is genetically distinct from well- differentiated/de-differentiated liposarcoma. CDK4 amplification and MDM2 amplification are hallmarks of well-differentiated and de-differentiated liposarcoma, whereas myxoid/round cell liposarcoma is defined by DDIT3 fusions and does not have CDK4 amplification. CDK4 amplification, as well as CDK4 inhibitors, have no role whatsoever in the treatment of myxoid liposarcoma. Their role is limited to well- differentiated/de-differentiated liposarcomas alone. So, the indicated references are not applicable to this analysis or this manuscript. Phase III randomized trials are possible for well- differentiated/de-differentiated liposarcoma given the incidence of that disease. The same is not true for MRCLS. The two are not comparable situations. So, we have not included these references, as they are not applicable for this manuscript.

Reviewer comment # 3: Minor concerns: standardize terminology (such as, MRCLS vs myxoid/round cell liposarcoma), ensure all acronyms are defined at first use.

Author Response: These errors have now been corrected, all terminology standardized, and abbreviations removed except as in response to Reviewer #1 and Reviewer #2 (points 7 and 7).

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been accepted for publication, the authors made significant revision based on reviewer comments. 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is now acceptable for publication