Longitudinal Changes in Nutritional, Inflammatory, and CT-Derived Body Composition Markers During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Nice and intresting work about Longitudinal Changes in Nutritional, Inflammatory, and CT- Derived Body Composition Markers During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer. This work deserves more elements and more detailed informations in the introduction sections. 2.2 sections regarding Nutritional assessment, counseling, and rehabilitation need also more informations.Same comments for 2.4. Follow-up observation.Also add some ct images and comments.Figure 1 is very nice and informative but the authors  have to add more rediological-ct images if availaible. and aslo detailed explanation of them and clinical significance. Table 1 is very informative but please change the presentation adding some graphics.Tables 2 and 3 are informmative but chaotic.too many informations in them.explain them better adding more information and chane the hole presentation of the them.Enlarge figures 2-3-4 and explain them better.Add more elements in the discusiion section.Add more conclusions,add more detailed conclusions,mentioning the new elements of this work.Add more and more recent (2020-2026)references.

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

We sincerely thank the reviewers for their valuable comments and constructive suggestions, which have helped us substantially improve the clarity and quality of our manuscript.

Nice and interesting work about Longitudinal Changes in Nutritional, Inflammatory, and CT- Derived Body Composition Markers During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer. This work deserves more elements and more detailed information in the introduction sections. 2.2 sections regarding Nutritional assessment, counseling, and rehabilitation need also more information.

Response: Thank you for this important comment. Accordingly, we have expanded the Introduction to provide additional background on the diagnostic and treatment pathway for colorectal cancer, multidisciplinary treatment planning, and the importance of nutritional assessment. We have also expanded Section 2.2 to provide further details on nutritional screening, nutritional counseling, and perioperative rehabilitation at our institution. Specifically, we clarified the use of the Malnutrition Universal Screening Tool (MUST), nutritional counseling before discharge, selective post-discharge counseling for patients at high risk of frailty or malnutrition, and perioperative rehabilitation during the surgical hospitalization (page 3, lines 103–113).
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Same comments for 2.4. Follow-up observation.

Response: We further clarified Section 2.4 by stating that the 5-year surveillance program was conducted in accordance with the JSCCR guidelines (page 4, lines 140–144).
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Also add some CT images and comments. Figure 1 is very nice and informative but the authors have to add more radiological images if available. and also detailed explanation of them and clinical significance.

Response: Thank you for this important comment. Accordingly, we have revised the original CT figure to show representative axial CT images obtained preoperatively and 6 months after initiation of adjuvant chemotherapy, thereby illustrating the longitudinal assessment of body composition. Following the addition of the new study flowchart as Figure 1, the original CT figure has been renumbered as Figure 2.
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Table 1 is very informative but please change the presentation adding some graphics. Tables 2 and 3 are informative but chaotic. Too much information in them explain them better adding more information and change the hole presentation of the them. Enlarge figures 2-3-4 and explain them better.

Response: Thank you for this helpful comment. We revised the presentation of the tables and figures to improve readability and facilitate interpretation of the results. For Table 1, we improved the formatting and presentation, as the newly added study flowchart (Figure 1) already provides additional visual information on patient selection and the overall study design. For the original Table 2, we created a new figure presenting Hodges–Lehmann estimates, with 95% CI, of the within-patient changes from the preoperative assessment to follow-up, while the corresponding numerical data were moved to the Supplementary Materials (Tables S1–S3). For the original Table 3, which is now presented as Table 2, we removed the overall-cohort columns and retained only the regimen-stratified comparisons, thereby reducing the amount of information and improving readability. The complete data, including the overall-cohort comparison, are provided in Supplementary Table S4. In addition, the previous Figures 2–4 were reformatted into enlarged two-column layouts to improve the visibility of the Kaplan–Meier curves, numbers at risk, and associated information. The corresponding figure legends and descriptions were also revised for clarity (Figures 1–6, Table 2, Supplementary Tables S1–S4).
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Add more elements in the discussion section. Add more conclusions, add more detailed conclusions, mentioning the new elements of this work. Add more and more recent (2020-2026) references.

Response: Thank you for this helpful comment. We substantially expanded the Discussion and Conclusion to better highlight the main findings and clinical implications of this study. We added further discussion of the potential mechanisms underlying the observed longitudinal changes in nutritional, inflammatory, and body composition markers, the possible prognostic relevance of muscle quality, and the implications for supportive care and future research. We also expanded the Conclusion to more clearly summarize the novel findings of the present study. In addition, we incorporated several recent and relevant references published between 2020 and 2026 to strengthen the Discussion and place our findings in the context of current evidence.

Reviewer 2 Report

Comments and Suggestions for Authors

 The authors have studied Longitudinal Changes in Nutritional, Inflammatory, and CT-Derived Body Composition Markers During Adjuvant Chemotherapy for Stage II/III Colorectal
Cancer and shown that how Adjuvant Chemotherapy several nutritional markers improved and inflammatory markers decreased between the preoperative assessment and 6 months after adjuvant chemotherapy initiation in cancer patients. 

1. Make a graphical representation or diagram to make the study design more clearer. 
2. Figure 1 shows measurement of body composition parameters on an axial CT image. Can author make a figure of several images across the study duration. That will reflect how the composition is changes with the treatment.
3. The data is represented poorly as the statistical data can be presented using graphs or bar diagram. Try to make more figures from the data in tables wherever feasible.
4. What are the pathways involved in the including curative surgery and subsequent adjuvant chemotherapy, which made changes in the nutritional markers improved in patients with Stage II/III colorectal cancer? A pathway diagram or mechanism of action can be made to illustrate this effect.
5. The authors have shown several limitations of this study. But how does author account for those limitations., What are the future perspectives and studies author would like to perform. Any insights on this also help the scientific fraternity in this directions. What kind of research is required in this direction.
6. The author did not mention about the closer supportive care in the conclusion section. Kindly elaborate it with few more lines.

Author Response

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. We look forward to working with you and the reviewers to move this manuscript closer to publication in Cancers.

The authors have studied Longitudinal Changes in Nutritional, Inflammatory, and CT-Derived Body Composition Markers During Adjuvant Chemotherapy for Stage II/III Colorectal Cancer and shown that how Adjuvant Chemotherapy several nutritional markers improved and inflammatory markers decreased between the preoperative assessment and 6 months after adjuvant chemotherapy initiation in cancer patients.

1) Make a graphical representation or diagram to make the study design clearer.

Response: Thank you for this helpful suggestion. In response, we added a new study flowchart as Figure 1 to provide a clearer overview of patient selection and the overall study design.
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2) Figure 1 shows measurement of body composition parameters on an axial CT image. Can author make a figure of several images across the study duration. That will reflect how the composition changes with the treatment.

Response: Thank you for this helpful suggestion. We revised the original CT figure to present representative axial CT images obtained preoperatively and at follow-up, thereby illustrating longitudinal changes in body composition during the treatment course. With the addition of the new study flowchart as Figure 1, the original CT figure has been renumbered as Figure 2.
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3) The data is represented poorly as the statistical data can be presented using graphs or bar diagram. Try to make more figures from the data in tables wherever feasible.

Response: Thank you for this valuable suggestion. Because the original Table 2 contained a large amount of numerical information and was difficult to interpret visually, we converted the longitudinal data into a graphical presentation. The new Figure 3 presents Hodges–Lehmann estimates of within-patient changes with 95% CI for nutritional, inflammatory, and body composition markers from the preoperative assessment to follow-up, allowing the direction and magnitude of these changes to be visualized more clearly. The corresponding numerical data from the original Table 2 were moved to Supplementary Tables S1–S3.
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4) What are the pathways involved in the including curative surgery and subsequent adjuvant chemotherapy, which made changes in the nutritional markers improved in patients with Stage II/III colorectal cancer? A pathway diagram or mechanism of action can be made to illustrate this effect.

Response: Thank you for this insightful comment. Because the present retrospective study did not directly evaluate biological pathways or mechanistic biomarkers, we considered that a mechanistic diagram might imply causal relationships that were not demonstrated by our data. Instead, we expanded the Discussion to describe a plausible mechanism whereby tumor-associated proinflammatory cytokines, including IL-6, IL-1β, and TNF-α, may contribute to appetite suppression and skeletal muscle catabolism, and how removal of the primary tumor may attenuate these inflammatory and catabolic processes (page 12, lines 301–306).
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5) The authors have shown several limitations of this study. But how does author account for those limitations., What are the future perspectives and studies author would like to perform. Any insights on this also help the scientific fraternity in these directions. What kind of research is required in this direction.

Response: Thank you for this important comment. We have expanded the Discussion to describe future research directions aimed at addressing the limitations of the present study. We propose prospective multicenter studies with larger sample sizes and appropriate adjustment for disease Stage and adjuvant treatment regimen. Such studies may help separate the effects of surgery from those of chemotherapy and identify modifiable factors associated with treatment completion and long-term outcomes (page 14, lines 391–398).

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6) The author did not mention about the closer supportive care in the conclusion section. Kindly elaborate it with few more lines.

Response: Thank you for this important comment. We have expanded the Conclusion to clarify that closer supportive care may include continued nutritional counseling and longitudinal body composition monitoring, and to highlight the need for future studies evaluating targeted nutritional and exercise interventions (page 14, lines 411–415).

Reviewer 3 Report

Comments and Suggestions for Authors

Our research colleagues have produced a study whose goal is to evaluate longitudinal changes in nutritional, inflammatory, and body composition markers during adjuvant chemotherapy in colorectal cancer and to explore preoperative factors associated with treatment discontinuation and disease prognosis. The abstract is a good summary of the entire study; we ask researchers to provide the precise meaning of the word "longitudinal," which also appears in the paper's title. The next section introduces the study's subject. We recommend improving the introduction by stating that patients diagnosed with colon cancer, often in the emergency room or sometimes for screening, should undergo diagnostic procedures with imaging and biopsy. With these results, the patient can be referred to a multidisciplinary committee for possible neoadjuvant therapy, and a nutritionist should also be assigned to manage the patient. The concept that every patient with cancer is generally malnourished is absolutely correct, considering the metabolism of the tumor cell. Furthermore, we must consider that digestive tract leukoplasia may also be associated with a possible transit or absorption defect. Otherwise, we agree with what has been written. This is a retrospective, single-center study. The methods were written with extensive data, and the study is replicable in any high-volume department, organized to conduct oncology and tertiary-level surgery. We request that nutritional status assessment criteria (biohumoral, anthropometric, diffraction index, etc.) be added to point 2.2. The tables are well-written, with good and explanatory captions. The statistical analysis does not warrant correction; it is completely understandable and accurate. The results are well described; the patients' BMI and metabolic syndromes were considered; it might be appropriate to write more about this. In any case, the description of the results, along with a selected bibliography, prepares for the discussion. In the latter, we agree with what the authors wrote, but we do not fully agree with the definition of advanced age, the average age of 67 for treated patients. Furthermore, there is a mention of weight, which is not significant in itself, given that patients may experience tissue edema. Furthermore, only a brief mention is made of the postoperative period, but we must carefully consider nutritional conditions for everyone, especially those undergoing surgical treatment. Indeed, although there are methods such as indocyanine green (doi.org/10.3390/gidisord7040076, to be read and cited in the bibliography), which demonstrates vascular vitality for the treated stumps, it cannot guarantee delayed healing and therefore dehiscence around the eighth or tenth postoperative day. The limitations of the study have been clarified, and its strengths can also be highlighted. Excellent English, good bibliography.

Author Response

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. We look forward to working with you and the reviewers to move this manuscript closer to publication in Cancers.

Our research colleagues have produced a study whose goal is to evaluate longitudinal changes in nutritional, inflammatory, and body composition markers during adjuvant chemotherapy in colorectal cancer and to explore preoperative factors associated with treatment discontinuation and disease prognosis. The abstract is a good summary of the entire study; we ask researchers to provide the precise meaning of the word "longitudinal," which also appears in the paper's title.

Response: Thank you for this important comment. We have clarified the precise meaning of “longitudinal” in the Data Collection section. In this study, longitudinal assessment was defined as a within-patient evaluation at two predefined time points: before curative surgery and approximately 6 months after initiation of adjuvant chemotherapy (page 4, lines 146–151).
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The next section introduces the study's subject. We recommend improving the introduction by stating that patients diagnosed with colon cancer, often in the emergency room or sometimes for screening, should undergo diagnostic procedures with imaging and biopsy. With these results, the patient can be referred to a multidisciplinary committee for possible neoadjuvant therapy, and a nutritionist should also be assigned to manage the patient. The concept that every patient with cancer is generally malnourished is absolutely correct, considering the metabolism of the tumor cell. Furthermore, we must consider that digestive tract leukoplasia may also be associated with a possible transit or absorption defect. Otherwise, we agree with what has been written.

Response: Thank you for this insightful comment. Based on this suggestion, we revised the Introduction to briefly describe the diagnostic and treatment pathway for colorectal cancer, including histological diagnosis, appropriate staging, multidisciplinary treatment planning, and nutritional assessment (page 2, lines 61–63).
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This is a retrospective, single-center study. The methods were written with extensive data, and the study is replicable in any high-volume department, organized to conduct oncology and tertiary-level surgery. We request that nutritional status assessment criteria (biohumoral, anthropometric, diffraction index, etc.) be added to point 2.2.

Response: Thank you for this important comment. We have expanded Section 2.2 to provide additional details regarding nutritional assessment at our institution, including routine nutritional screening using the Malnutrition Universal Screening Tool (MUST) at hospital admission. We also clarified the nutritional counseling and perioperative rehabilitation provided during the perioperative period (page 3, lines 103–113).
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The tables are well-written, with good and explanatory captions. The statistical analysis does not warrant correction; it is completely understandable and accurate. The results are well described; the patients' BMI and metabolic syndromes were considered; it might be appropriate to write more about this. In any case, the description of the results, along with a selected bibliography, prepares for the discussion. In the latter, we agree with what the authors wrote, but we do not fully agree with the definition of advanced age, the average age of 67 for treated patients. Furthermore, there is a mention of weight, which is not significant in itself, given that patients may experience tissue edema.

Response: Thank you for these thoughtful comments. Metabolic syndrome was not comprehensively assessed in this retrospective cohort, and we therefore considered that further discussion of this topic would not be sufficiently supported by our data. Regarding age, we agree that a median age of 67 years should not itself be interpreted as advanced age; accordingly, we avoided this terminology and referred to “older age” only in the context of the relative age difference observed in the monotherapy group. We also revised the Discussion to clarify that changes in body weight or BMI do not necessarily parallel changes in skeletal muscle mass, because body weight and BMI do not distinguish skeletal muscle mass from adipose tissue and may also be influenced by fluid retention or edema (page 12, lines 316–330).
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Furthermore, only a brief mention is made of the postoperative period, but we must carefully consider nutritional conditions for everyone, especially those undergoing surgical treatment. Indeed, although there are methods such as indocyanine green (doi.org/10.3390/gidisord7040076, to be read and cited in the bibliography), which demonstrates vascular vitality for the treated stumps, it cannot guarantee delayed healing and therefore dehiscence around the eighth or tenth postoperative day. The limitations of the study have been clarified, and its strengths can also be highlighted. Excellent English, good bibliography.

Response: Thank you for this thoughtful comment. We agree that surgery and postoperative complications may substantially influence nutritional status. Accordingly, we expanded the Discussion to acknowledge that the effects of adjuvant chemotherapy could not be clearly separated from those of the preceding surgery and that gastrointestinal surgery and postoperative complications may adversely affect nutritional status through reduced oral intake, stress-related catabolism, and impaired gastrointestinal function (page 13–14, lines 385–388). We also revised the Discussion to more clearly highlight the longitudinal assessment of nutritional, inflammatory, and CT-derived body composition markers in patients with CRC receiving adjuvant chemotherapy following curative surgery as a strength of the present study (page 12, lines 293–296). We carefully reviewed the suggested reference regarding indocyanine green fluorescence. However, because this study primarily addresses fluorescence-guided intraoperative vascular assessment rather than nutritional, inflammatory, or body composition outcomes, we considered it outside the direct scope of the present study and therefore did not include it in the revised manuscript.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Imporvements in all the sections respect the previous edition

Add more and more detailed conclsions

Add more references and more recent references (2020-2026)

Introductions section and discussion sections need more elements and more documentation

Re look th english language and the engish terms  used

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Reviewer 1:

Improvements in all the sections respect the previous edition.
Add more and more detailed conclusions.

Response: Thank you for this helpful comment. We have further expanded the Conclusions to provide more detailed and clinically oriented interpretations of our findings. Specifically, we added a statement clarifying that preoperative assessment of these markers could help identify patients at higher risk of treatment discontinuation before initiation of oxaliplatin-based doublet therapy, enabling early consideration of supportive interventions (page 14, lines 425–428).
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Add more references and more recent references (2020-2026).

Response: Thank you for this helpful comment. We have added four recent references published between 2023 and 2026, including three published in 2026:

Ref. 12, Nutrients 2026: a study reporting that perioperative HALP score and NLR were associated with severe postoperative morbidity after minimally invasive colorectal surgery.

Ref. 33, Nutrients 2026: a study showing that skeletal muscle loss during chemotherapy was associated with severe treatment-related toxicity and poorer survival in older patients with metastatic CRC.

Ref. 41, Cancers 2026: a study suggesting that impaired muscle quality may have greater prognostic relevance than reduced muscle quantity in upper gastrointestinal tract cancer.

Ref. 46, JAMA Surgery 2023: a multicenter randomized trial demonstrating that multimodal prehabilitation before colorectal cancer surgery reduced severe postoperative complications.

These references were incorporated into the Introduction and Discussion to strengthen the documentation and interpretation of our findings.
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Introductions section and discussion sections need more elements and more documentation

Response: Thank you for this important comment. In the Introduction, we added a sentence explaining the rationale for longitudinal assessment. Because adjuvant chemotherapy is delivered during postoperative recovery and may itself cause anorexia, gastrointestinal toxicity, and muscle loss, these markers may change throughout the treatment course, and a single preoperative assessment may not adequately capture these dynamic changes (page 2, lines 82–85). In the Discussion, we added three elements with supporting documentation: (i) the clinical relevance of chemotherapy-associated muscle loss, which has been associated with severe toxicity and poorer survival (page 12, lines 331–334); (ii) a recent study suggesting that muscle quality may be more prognostically relevant than muscle quantity (page 13, lines 369–371); and (iii) findings from a randomized clinical trial on multimodal prehabilitation, together with discussion of the potential role of exercise-based interventions at different stages of colorectal cancer treatment (page 13, lines 384–388).
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Re look the English language and the English terms used.

Response: Thank you for this comment. We carefully re-examined the English language and terminology throughout the manuscript and made further refinements to improve clarity, consistency, and grammatical accuracy. We also reviewed the use of abbreviations and scientific terminology to ensure consistency throughout the manuscript. All changes are shown using Track Changes in the revised manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

Our colleagues have revised their valuable paper according to the reviewers' recommendations. Many concepts in the methods and discussion of this study have been clarified. An adequate bibliography allows for a good, indeed perfect, understanding of the text. The work is certainly more precise than the previous version. The study is an enjoyable and, above all, informative read. Good English, good bibliography, excellent illustrations. We will therefore support the editor so that this study can be published and thus opened to a wide audience of colleagues who can benefit from it in terms of knowledge and therefore improve their work.

Author Response

Please see the attachment.

Round 3

Reviewer 1 Report

Comments and Suggestions for Authors

.Add more elements in the intoductions and in the discusiion section.Add more conclusions,add more detailed conclusions,mentioning the new elements of this work.Add more and more recent (2020-2026)references.

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Add more elements in the introduction and in the discussion section. Add more conclusions, add more detailed conclusions, mentioning the new elements of this work. Add more and more recent (2020-2026) references.

Response: Thank you for this helpful comment. We have revised the manuscript as follows.

Introduction: We added adipose tissue distribution as a component of body composition and noted that methods for assessing muscle quality vary considerably across studies (page 2, lines 78–80).

Discussion: We added a limitation noting that visceral adiposity was not assessed in the present study, despite its reported association with postoperative complications after colorectal cancer surgery (page 14, lines 402–404).

Conclusions: We added an opening statement highlighting the novel elements of this study, including the longitudinal evaluation of nutritional, inflammatory, and CT-derived body composition markers within the same cohort of patients undergoing curative surgery followed by adjuvant chemotherapy, and the assessment of their associations with treatment discontinuation according to chemotherapy regimen (page 14, lines 416–420).

References: We added two recent systematic reviews, Ref. 20 (Int J Colorectal Dis, 2026) and Ref. 21 (J Cachexia Sarcopenia Muscle, 2024). Overall, 39 of the 49 references in the revised manuscript were published between 2020 and 2026.