Bevacizumab in Platinum-Sensitive Recurrent Epithelial Ovarian Cancer: A Risk-Stratified Analysis
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsReview of the Manuscript entitled:
Bevacizumab in Platinum-Sensitive Recurrent Epithelial Ovarian Cancer: A Risk-Stratified Analysis
Dear Editor,
The authors in this research article wanted to compare treatment responses in high and low-risk groups of patients with PSROC and to evaluate the effects of bevacizumab on survival within these risk strata. So, they used patients diagnosed with FIGO stage III and IV EOC who received chemotherapy or chemotherapy plus bevacizumab for platinum-sensitive recurrence. Patients were classified according to risk groups, and their clinicopathological characteristics were compared. Their study suggests that the addition of bevacizumab to treatment for PSROC provides a significant benefit, particularly in patients at high risk. Furthermore, the positive impact of optimal cytoreduction on survival and the varying effect of bevacizumab based on recurrence location suggest that future treatment approaches should be personalized…I think this article can be a promising approach for ovarian cancer treatment. So, it can be acceptable in the journal Pharmaceuticals, but it needs some revisions for improving the quality of the manuscript:
- Page 1, lines 17–18: “This retrospective study included patients diagnosed with FIGO stage III and IV EOC who received chemotherapy or chemotherapy plus bevacizumab for platinum-sensitive recurrence.”
Please define the abbreviation.
- The authors have not clarified the novelty of their work.
- Why did the authors use platinum-sensitive recurrent ovarian cancer? What is the role of the platinum based on its characterization? Please clarify it.
- Have the authors encountered some kinds of platinum doped nanostructure through drug delivery method?
- Please correctly cite the Figure 1 a and Figure 1b. They are not clear. Besides, improve their quality.
- Have the authors observed any other smart elements materials like platinum in literature?
- Figures 2 and Figure 3b were missing.
- Please complete the caption of Table 4.
- The discussion part is well designed.
The abstract is categorized well in different sub-sections. However, the Results sub-section needs to be more illustrated through a short and concise consequence for attracting the reader’s attention.
- Please rephrase the following sentence (page1, lines24–26): “Conclusions: Based on these findings, merging structural features from previous known CSF1R inhibitors might provide the foundation for new and improved drug leads towards this kinase.”
- Page 2, lines 49–51: “However, there are several CSF-1R inhibitors under investigation as therapeutic agents for various disease targets, and some of their chemical structures are represented in Figure 1 [10-15].” Are these structures from literature or optimized molecules by the authors? Please clarify it.
- Page 4, lines 102-105: “Figure 2. (A) The docked conformation of the proposed hybrid molecule (red) exhibits substantial overlap with the ligand (gray) from the published crystal structure (PDB ID: 8CGC). The protein has … Pexidartinib (green)”. Please report the direct linkage or the relate reference for the PDB extracted from Protein Data Bank. Moreover, check it in the whole manuscript for other PDBs.
- Have the authors achieved the structural characterization prediction from isotropic, anisotropic shielding or other nuclear magnetic resonance parameters from reported HNMR and CNMR spectra in supplementary files? Please describe it.
- Did the authors encounter any theoretical results of computational methos from literature for comparison? Please clarify it.
- What can we learn from Figure 4? Please illustrate it. Moreover, the text on the image is not clear.
- It is recommended replacing the section of Materials and Method before the section of Results and Discussion.
- There is no Conclusion section. Please add this section at the end of the manuscript before the References.
- Please re-read the whole manuscript to correct any grammatical errors, mistakes or typos.
- It is recommended that the authors enhance the quality of Figure or schemes in the whole manuscript.
Author Response
Dear Reviewer,
Thank you for your valuable evaluations and constructive feedback. We have made the necessary revisions to our manuscript in accordance with your suggestions, and the relevant sections have been indicated within the text. We believe that your comments have significantly improved the quality of our work.
Once again, we sincerely thank you for your insights and contributions.
Kind regards.
Comments 1: Page 1, lines 17–18: “This retrospective study included patients diagnosed with FIGO stage III and IV EOC who received chemotherapy or chemotherapy plus bevacizumab for platinum-sensitive recurrence.” Please define the abbreviation
Response 1: Dear Reviewer,
In line with your comment regarding the abbreviation on page 1, lines 17–18, we have revised the text to spell out “FIGO” as “International Federation of Gynecology and Obstetrics (FIGO)” at its first mention. Since “epithelial ovarian cancer (EOC)” was already clearly defined at its initial appearance, it was not repeated.
Thank you for your valuable contribution.
Page number: 1 line: 21
Comments 2: The authors have not clarified the novelty of their work.
Response 2: Dear Reviewer,
Thank you for your comment regarding the originality of our study. In response, we have added statements to the abstract, introduction, discussion, and conclusion sections to more clearly highlight our study's contribution to the literature and its original aspects. The added and revised sentences have been highlighted in red for clarity.
Page number: 1 lines: 25-28
Page number: 2 lines: 70-75
Page number: 17 lines: 396-408
Comments 3: Why did the authors use platinum-sensitive recurrent ovarian cancer? What is the role of the platinum based on its characterization? Please clarify it.
Response 3: Dear Reviewer,
The primary reason for selecting patients with platinum-sensitive recurrent ovarian cancer (PSROC) in our study is that platinum-based chemotherapy is still considered a standard and effective treatment option for this patient group. Platinum sensitivity is a key clinical characteristic that determines the patient’s ability to respond to platinum-based therapy and the timing of disease recurrence. Furthermore, this patient population is believed to derive the most potential benefit from bevacizumab treatment.
While subgroup analyses of the ICON7 and GOG-0218 trials, which evaluated the addition of bevacizumab to chemotherapy in treatment-naive patients, classified patients into high- and low-risk groups, such risk stratification has not yet been established in prospective studies involving patients with PSROC. Therefore, our study, which evaluates the efficacy of bevacizumab through a risk-based analysis in PSROC patients, addresses a significant gap in the literature and is expected to contribute to clinical decision-making processes.
Comments 4: Have the authors encountered some kinds of platinum doped nanostructure through drug delivery method?
Response 4: Dear Reviewer,
Given our country's current infrastructure and available resources, studies on drug delivery methods using platinum-based nanostructures are limited. However, we would like to express our willingness to explore research in this field in the future, should appropriate opportunities and collaborations arise.
Comments 5: Please correctly cite the Figure 1 a and Figure 1b. They are not clear. Besides, improve their quality.
Response 5: Dear Reviewer,
Figure 1a and Figure 1b have been revised with appropriate citations in the main text. Additionally, the visual quality of both figures has been enhanced to improve clarity and comprehensibility.
Page number: 6 lines: 168-170
Page number: 6 lines: 171-172
Figure 1a and 1b; Page number: 6-7
Comments 6: Have the authors observed any other innovative elements materials like platinum in literature?
Response 6: Dear Reviewer,
Our study did not include an analysis of drug delivery systems or nanotechnological treatment approaches. Therefore, the use or comparison of other innovative materials similar to platinum falls outside the scope of our research. Our investigation focuses on evaluating the impact of adding bevacizumab on survival outcomes in patients with platinum-sensitive recurrent ovarian cancer, based on clinical risk groups. However, future translational or experimental studies exploring such innovative materials may offer valuable contributions to the literature.
Comments 7: Figures 2 and Figure 3b were missing.
Response 7: Dear Reviewer,
In response to your feedback regarding the missing Figure 2 and Figure 3b, we have added the relevant figures to our manuscript. The omission has been addressed, and we confirm that all figures are now included in the updated version of the file. Thank you for your attention and valuable comments.
Figure 2a ; Page number: 9
Figure 2b ; Page number: 10
Figure 3a ; Page number: 10
Figure 3b ; Page number: 11
Comments 8: Please complete the caption of Table 4.
Response 8: Dear Reviewer,
We have completed the title of Table 4 as suggested and added it to the table. The updated version is included in the revised manuscript file. Thank you for your valuable suggestion.
Page number: 13, line: 248
Comments 9: The discussion section is well designed, and the abstract is well categorized into different sub-sections. However, the Results sub-section needs to be more illustrated with a short and concise consequence to attract the reader’s attention.
Response 9: Dear Reviewer,
Thank you for your valuable comments. As you suggested, the Results subsection has been made more engaging and clear. A concise and focused concluding sentence has been added to enhance reader interest, thereby strengthening the section.
Page number: 4, line: 156-163
Page number: 6, line: 168-170 / 171-172
Page number: 7, line: 177-188
Page number: 9, line: 192-198
Page number: 11, line: 217-230
Page number: 12, line: 234-243
Reviewer 2 Report
Comments and Suggestions for AuthorsThis study aimed to evaluate the effects of bevacizumab use in the treatment of patients diagnosed with PSROC. Based on factors such as clinical stage and residual disease status, authors divided the patients into high- and low-risk groups and compared their treatment responses. Through this comparison, they examined the impact of bevacizumab on treatment efficacy and patient prognosis.
The abstract is not comprehensive. It should be summarized.
Novelty of work is not explained well in the introduction.
There are some recent articles on the same topic published in 2023 and 2024. Please try to relate them also.
Explain the p-value for readers before Table 1.
Kaplan-Meier curves also need explanation in the discussion section for normal readers from all fields.
Author Response
Dear Reviewer,
Thank you for your valuable evaluations and constructive feedback. We have made the necessary revisions to our manuscript in accordance with your suggestions, and the relevant sections have been indicated within the text. We believe that your comments have significantly improved the quality of our work.
Once again, we sincerely thank you for your insights and contributions.
Kind regards.
Comments 1: The abstract is not comprehensive. It should be summarized.
Response 1: Dear Reviewer,
We believe your comment is very important and constructive. Accordingly, we have revised the abstract to make it more comprehensive and concise. In this way, the main findings and objective of our study are now presented more clearly and effectively.
Page number: 1 line: 30-39
Page number: 2 line: 40-46
Comments 2: Novelty of work is not explained well in the introduction.
Response 2: Dear Reviewer,
In line with your valuable comments, a new paragraph has been added to the introduction section to more clearly emphasize the originality of our study. This paragraph states that our work is one of the few studies analyzing the effectiveness of bevacizumab treatment in patients with platinum-sensitive recurrent ovarian cancer based on clinical risk groups and recurrence patterns using real-world data. It also highlights the lack of a comprehensive analysis in the current literature that evaluates these two important variables together. In this way, the scientific novelty and contribution of the study to the field are more clearly demonstrated.
Page number: 3 line: 92-97
Comments 3: There are some recent articles on the same topic published in 2023 and 2024. Please try to relate them also.
Response 3: Dear Reviewer,
References with a potential risk of redundancy have been meticulously re-evaluated to ensure consistency with existing literature and the originality of our work. These comprehensive assessments have further strengthened the scientific quality of our study and its contribution to the literature.
Page number: 20-22 . References 19, 26, 29, 31, 32, and 36 from the initial manuscript have been removed from the study.
Comments 4: Explain the p-value for readers before Table 1.
Response 4: Dear Reviewer,
Before Table 1, the concept of the p-value has been briefly and clearly explained to help readers better understand the statistical results. This addition has made the interpretation of the findings easier.
Page number: 5 line: 169-170
Comments 5: Kaplan-Meier curves also need explanation in the discussion section for normal readers from all fields.
Response 5: Dear Reviewer,
Your comment regarding the Kaplan-Meier curves is highly valuable and constructive. In response, the meaning and interpretation of the Kaplan-Meier analyses have been explained in a more precise and more detailed manner in the discussion section. Additionally, the corresponding figures (e.g., Figure 1a, Figure 2b) have been indicated in parentheses to facilitate easier follow-up for the reader.
Page number: 16 line: 325-344
Reviewer 3 Report
Comments and Suggestions for AuthorsSummary
Bevacizumab added to platinum‑based chemotherapy in PSROC consistently improves PFS but has failed to demonstrate a statistically significant OS benefit in large randomized trials. Real‑world evidence suggests that only patients with high‑risk features derive sustained benefit from bevacizumab in the front‑line setting. The presented study addresses this limitation by applying a comprehensive risk‑stratified design to evaluate bevacizumab’s impact on both PFS and OS. These findings support a more individualized approach, tailoring bevacizumab use to high-risk patients and reinforcing the importance of optimal surgical management.
Below are my suggestions for improvement-
- In Materials and Methods section, the authors mentioned bevacizumab maintenance but does not clearly quantify how many patients continued it, for how long, or its impact. The authors should clarify maintenance use and possibly consider stratifying survival outcomes based on whether maintenance was received.
- The authors provided gBRCAm status, but this information was not analyzed in depth. Molecular predictors such as BRCA and HRD are increasingly recognized as important modulators of treatment response to anti-angiogenic agents like bevacizumab. BRCA and HRD may act as important confounders or effect modifiers in interpreting treatment outcomes. It is recommended that the discussion section expand on the biomarker context to enhance the depth and impact of the study.
- The authors briefly touched on real-world applications, but did not fully develop how their findings could translate into clinical practice. It is recommended to expand the discussion on the potential impact on treatment guidelines and provide specific recommendations for practitioners.
Author Response
Dear Reviewer,
Thank you for your valuable evaluations and constructive feedback. We have made the necessary revisions to our manuscript in accordance with your suggestions, and the relevant sections have been indicated within the text. We believe that your comments have significantly improved the quality of our work.
Once again, we sincerely thank you for your insights and contributions.
Kind regards.
Comments 1: In Materials and Methods section, the authors mentioned bevacizumab maintenance but does not clearly quantify how many patients continued it, for how long, or its impact. The authors should clarify maintenance use and possibly consider stratifying survival outcomes based on whether maintenance was received.
Response 1: Dear Reviewer,
We sincerely thank you for your essential and constructive comments. In line with your suggestion, data regarding maintenance bevacizumab use have been added to Tables 1 and 2. These tables indicate the number of patients who continued maintenance treatment. Additionally, survival analyses have been stratified into separate groups of patients who received maintenance bevacizumab and those who did not. Thus, the potential effects of maintenance therapy are presented more clearly.
Page number: 5, table 1
Page number: 8, table 2
Comments 2: The authors provided gBRCAm status, but this information was not analyzed in depth. Molecular predictors such as BRCA and HRD are increasingly recognized as important modulators of treatment response to anti-angiogenic agents like bevacizumab. BRCA and HRD may act as important confounders or effect modifiers in interpreting treatment outcomes. It is recommended that the discussion section expand on the biomarker context to enhance the depth and impact of the study.
Response 2: Dear Reviewer,
Thank you for your valuable comment. Approximately half of the patients included in our study have unknown BRCA mutation status, and none of the patients underwent homologous recombination deficiency (HRD) analysis. Therefore, we were unable to statistically evaluate the impact of BRCA or HRD status on the response to bevacizumab treatment.
Although PARP inhibitors have become an important part of current treatment algorithms for patients with detected BRCA mutations, access to these agents is not always feasible for every patient in our country due to reimbursement limitations. Consequently, directly analyzing the effect of BRCA mutation on treatment selection is also practically challenging.
For all these reasons, a more detailed analysis of the impact of molecular markers (BRCA/HRD) could not be performed in this study. However, this remains a highly important area of research that should be addressed in future studies conducted in appropriate patient populations. We would certainly be interested in considering your suggestion in such future investigations.
Comments 3: The authors briefly touched on real-world applications, but did not fully develop how their findings could translate into clinical practice. It is recommended to expand the discussion on the potential impact on treatment guidelines and provide specific recommendations for practitioners.
Response 3: Dear Reviewer,
Following your suggestion, the discussion section of our manuscript has been expanded to more thoroughly address the potential implications of our findings for clinical practice, including a broader consideration of their impact on treatment guidelines. Additionally, specific recommendations for clinicians have been included to strengthen our study's contribution to clinical decision-making.
Page number: 17, line: 396-408
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