The Clinical Characteristics of a Stage II Colorectal Cancer T4 Tumor: A Ten-Year Single-Center Research Report

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors analyze in this manuscript the differences in clinico pathological characteristics and long-term survival between patients with colorectal cancer stage T4a and T4b patients. The subject is not new but the authors provide complementary information to current published data. 

The manuscript is well designed and the results are well presented.

Some points that may improve the manuscript:

1. The version available do not have "Abstract".

2. It would be desirable to include a Figure showing a flowchart detailing the selection of patients included and excluded in the study.

3. "Discussion" should be improved. What do they think about the reason of the diferent long-term survival between T4a and T4b patients. Comparison of the results obtained with those from other publications. 

4. The number of patients is low, this fact may have hampered the obtention of clearcut results. This should be mentioned in the limitations of the study.   

Author Response

We are deeply grateful to you for taking the time out of your busy schedule to review our manuscript. Your kind and constructive feedback has truly helped us improve. Below are our point-by-point responses to all of your suggestions.

1.The version available do not have "Abstract".

Thank you so much for your kind reminder. I have uploaded the abstract to the Susy system and have also included it in the manuscript.

2. It would be desirable to include a Figure showing a flowchart detailing the selection of patients included and excluded in the study.

Thank you so much for your invaluable suggestion. We have added a Flow Chart of Patient Selection, now designated as Figure 1.

3. "Discussion" should be improved. What do they think about the reason of the diferent long-term survival between T4a and T4b patients. Comparison of the results obtained with those from other publications. 

Thank you so much for your incredibly valuable suggestion. We have added several new paragraphs in the Discussion section to compare and discuss our findings with other studies. The newly added content has been HIGHLIGHTED IN YELLOW for your review. We kindly ask for your feedback.

4. The number of patients is low, this fact may have hampered the obtention of clearcut results. This should be mentioned in the limitations of the study.   

Following your suggestion, we have added further explanations in the Limitations section. We are truly grateful for your invaluable guidance.

Reviewer 2 Report

Comments and Suggestions for Authors

This article presents a retrospective analysis of data collected from patients at the Taichung Veterans General Hospital between 2010 and 2018. It was prepared with a lack of attention to detail and in disregard of the author's guidelines. It is surprising that the editor did not reject it, given that many of the initial technical requirements for the manuscript were not met. 

Furthermore, this article does not contribute any new insights to this field. The pTNM system was developed as a predictive tool, and its utility in this context has been established in numerous prior studies. Even if the authors restrict their focus to Stage II CRC, this does not guarantee the novelty of the article.

It is with regret that I must recommend rejection of this article.

Title page

- It is unclear where the affiliations of the authors are listed. Despite searching on Scopus, the affiliations could not be found for all authors, except for the last author. It is therefore difficult to confirm the existence of all authors.

- Could you explain why the abstract is absent from the manuscript file?

Introduction

- "Up to now, there have been no articles discussing the differences between Stage II colorectal cancer involving pT4a and pT4b tumors" - On the contrary, there are quite a few articles that focus on pT4 cancers. For example:

1. Bastiaenen, Vivian P., et al. "Risk of metachronous peritoneal metastases in patients with pT4a versus pT4b colon cancer: an international multicentre cohort study." European Journal of Surgical Oncology 47.9 (2021): 2405-2413.

2. Bautista-Saiz, C.; Rivera-Moncada, L.F.; Lino-Silva, L.S.; Pérez-Correa, G.A.; Frías-Fernández, P. Identification of an Objective Cut-Off Point to Define the Clinical Stage T4a in Colon Cancer. Gastroenterol. Insights 2024, 15, 366-374. https://doi.org/10.3390/gastroent15020025

and a bit older

3. Snaebjornsson, P., et al. "pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited." International journal of cancer 135.2 (2014): 467-478.

 

And many, many others. Even though they did not focus entirely on stage II pT4a and 4b tumours, these differences have been discussed and are a popular topic. So to say that this study is unique is just not justified. 

- Line 26-27: is it really that important to name the journal in which this results were published? This should be noted just in the references section. 

- iThenticate indicates, that almost whole introduction was already published elsewhere - here https://journals.lww.com/dcrjournal/citation/2024/06000/meeting_abstracts_from_the_2024_annual_scientific.28.aspx. I am unable to access this document, which precludes me from determining whether the authors are the same or not and whether it constitutes autoplagiarism or not. It is my opinion that the editors should undertake a more detailed examination of this matter.

Generally, the introduction does not provide sufficient insight into the subject matter of this article. 

Materials and methods:

- Why is this section not divided into subsections? It should be.

- Line 40 - the name of "this medical center" is not mentioned before

- The statistical inference description is erroneous. It is evident from the tables that the chi-squared test could not be applied to all the presented variables, including age, BMI, and other continuous variables. Additionally, the name of the multivariate test should be stated. 

Table 1.

All the abbreviations used should be explained. All of the evaluated traits (i.e. BMI, BSA, ECOG test results) must be mentioned for the first time in the Materials and Methods section, not in the Results section.

Table 2. Multivariate analysis usually required a stepwise approach to eliminate all statistically insignificant predictors. Some of them, even if valid in univariate analysis, are not valid in combination with other predictors. The model obtained by the authors includes non-significant predictors that would confound the prediction.

Figures - all the survival curves could be shown in one figure, there is no need to separate them.

Discussion - this section lacks... discussion. There is almost no comparison with the results on similar topics obtained by previous studies. Also, conclusion regarding the adjuvant chemotherapy is not confirmed by the results - where the cancer specific survival analysis shows no statistically significant relations.

These are not all the errors that could be found and described in this manuscript - but I think it's enough to support my decision. Although if it were necessary to point out more errors, I could certainly do so. 

 

 

Author Response

Thank you so much for taking the time out of your busy schedule to review our manuscript. Despite the numerous mistakes in our work that should not have occurred, you showed remarkable patience in pointing out the areas for improvement. Your constructive suggestions and critiques are truly invaluable to us and will serve as a foundation for our growth and improvement. We have worked diligently to revise and enhance this manuscript, and we sincerely hope to receive your guidance once again.

 

Title page

It is unclear where the affiliations of the authors are listed. Despite searching on Scopus, the affiliations could not be found for all authors, except for the last author. It is therefore difficult to confirm the existence of all authors.

Taichung Veterans General Hospital is the only medical center in central Taiwan established by the government, so there must be some misunderstanding. Here is the official website of our hospital: https://www.vghtc.gov.tw/Home/IndexEng. We kindly ask you to review it, and we sincerely thank you for your question.

Could you explain why the abstract is absent from the manuscript file?

I sincerely apologize. Previously, I had only uploaded an abstract on the Susy system. We have now included it in the manuscript. Kindly review it at your convenience, and thank you so much for your understanding.

 

Introduction

"Up to now, there have been no articles discussing the differences between Stage II colorectal cancer involving pT4a and pT4b tumors" - On the contrary, there are quite a few articles that focus on pT4 cancers.

Thank you so much for your kind reminder. We have changed "no" to "few" and included two articles discussing T4N0M0 as references 23 and 24. Additionally, we have incorporated a discussion of these articles in the Discussion section. We sincerely appreciate your guidance.

Line 26-27: is it really that important to name the journal in which this results were published? This should be noted just in the references section.

Thank you so much for your valuable suggestion. We have removed the journal name Diseases of the Colon & Rectum from this section and retained it only in the reference list. We truly appreciate your guidance.

iThenticate indicates, that almost whole introduction was already published elsewhere - here https://journals.lww.com/dcrjournal/citation/2024/06000/meeting_abstracts_from_the_2024_annual_scientific.28.aspx. I am unable to access this document, which precludes me from determining whether the authors are the same or not and whether it constitutes autoplagiarism or not. It is my opinion that the editors should undertake a more detailed examination of this matter.

I sincerely apologize. The ASCRS Meeting Abstracts were indeed submitted by me, so they are exactly the same. However, after being accepted last year, I was unable to attend the 2024 ASCRS Meeting in Baltimore due to scheduling conflicts. As a result, even though the abstract was accepted, I did not complete the registration or payment, and the ePoster was eventually canceled. The only evidence I have is a screenshot of the email, as the webpage is no longer accessible. I am truly sorry for this situation.

 

Materials and methods:

Why is this section not divided into subsections? It should be.

Thank you so much for your kind reminder. This section has now been divided into subsections.

Line 40 - the name of "this medical center" is not mentioned before

Thank you so much for your kind reminder. We have replaced "this medical center" with the name of our hospital, "Taichung Veterans General Hospital." 

The statistical inference description is erroneous. It is evident from the tables that the chi-squared test could not be applied to all the presented variables, including age, BMI, and other continuous variables. Additionally, the name of the multivariate test should be stated. 

Thank you so much for pointing out our mistake. We have corrected it, and we kindly ask for your review once again. 

 

Table 1.

All the abbreviations used should be explained. All of the evaluated traits (i.e. BMI, BSA, ECOG test results) must be mentioned for the first time in the Materials and Methods section, not in the Results section.

Thank you so much for pointing out our mistake. This was our oversight, and we have already made the necessary corrections.

 

Table 2. 

Multivariate analysis usually required a stepwise approach to eliminate all statistically insignificant predictors. Some of them, even if valid in univariate analysis, are not valid in combination with other predictors. The model obtained by the authors includes non-significant predictors that would confound the prediction.

Thank you for your suggestion. We have revised all the Cox regression analyses to use a stepwise procedure. The results show no significant differences compared to the original. We kindly ask for your review.

 

Figures - all the survival curves could be shown in one figure, there is no need to separate them. 

Thank you for your suggestion. I have combined the four survival curve images into a single figure and labeled it as Figure 2. I truly appreciate your guidance.

 

Discussion - this section lacks... discussion. There is almost no comparison with the results on similar topics obtained by previous studies. Also, conclusion regarding the adjuvant chemotherapy is not confirmed by the results - where the cancer specific survival analysis shows no statistically significant relations.

Thank you for your insightful and constructive feedback. After careful review, we have made significant revisions to this section, with all changes highlighted in yellow. We have also updated and added some references for your review.

Lastly, it appears that there is a statistically significant difference in CSS between pT4a and pT4b. We believe that over a 10-year period, CSS can exclude some cases of death due to natural causes. Furthermore, the effect of adjuvant chemotherapy is evident in PFS, as we believe adjuvant chemotherapy most strongly impacts PFS. This is because most colorectal cancer patients tend to experience recurrence within three years. Thank you for pointing this out, which has greatly helped us improve our work.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

First of all – I appreciate the authors’ effort to increase the quality of their manuscript, especially the discussion part. However, despite the changes that have been made, in my opinion this article still lacks novelty and deals with a topic that does not require further confirmatory studies, and as such it should not be published. However, I understand the editorial board's position and would not go against their opinion. In the current review, I'm going to make some detailed comments that can be treated as a minor revision.

- The author's assertion that there are merely "a few" articles on the distinctions between pT4a and pT4b colorectal cancer, as evidenced by the three articles provided as an example, is inaccurate. To refute this claim, I will present additional articles on this subject that address this issue to some extent. 

1.       Bastiaenen, Vivian P., et al. "Risk of metachronous peritoneal metastases in patients with pT4a versus pT4b colon cancer: an international multicentre cohort study." European Journal of Surgical Oncology 47.9 (2021): 2405-2413.

2.       Kumamoto, Tsutomu, et al. "Prognostic risk factors for pT4 colon cancer: A retrospective cohort study." Oncology letters 25.1 (2022): 29.

3.       Baguena, Gloria, et al. "Prognostic impact of pT stage and peritoneal invasion in locally advanced colon cancer." Diseases of the Colon & Rectum 62.6 (2019): 684-693.

4.       Pollheimer, Marion J., et al. "Clinical significance of pT sub-classification in surgical pathology of colorectal cancer." International journal of colorectal disease 25 (2010): 187-196.

5.       Sreekumar, R., et al. "OC-118 Extramural vascular invasion (EMVI) is a better prognostic indicator in PT4 colorectal cancer than pathological subtyping into PT4A and PT4B: clinicopathological analysis of 276 cases." Gut 61.Suppl 2 (2012): A51-A51.

6.       Canney, Aoife L., et al. "Stage II colonic adenocarcinoma: a detailed study of pT4N0 with emphasis on peritoneal involvement and the role of tumour budding." Histopathology 61.3 (2012): 488-496.

7.       Snaebjornsson, P., et al. "pT4 stage II and III colon cancers carry the worst prognosis in a nationwide survival analysis. Shepherd's local peritoneal involvement revisited." International journal of cancer 135.2 (2014): 467-478.

8.       Matsunaga, Keigo, et al. "Prognostic Significance of Enlarged Lymph Nodes in Stage II Colorectal Cancer." Diseases of the Colon & Rectum 66.11 (2023): e1097-e110

9.       Duraes, Leonardo C., et al. "The use of laparoscopy for T4a and T4b colon cancer: are we playing with fire?." Surgical Endoscopy 37.7 (2023): 5679-5686.

10.   Eom, Taeyeong, et al. "Prognostic factors affecting disease-free survival and overall survival in T4 colon cancer." Annals of Coloproctology 37.4 (2021): 259.

 If necessary, I could easily find more. There are many articles on the subject. If the authors need to prove the uniqueness of the subject of this article, they can claim that it's one of the few studies on the population of Taiwan (though not the only one - example here: https://link.springer.com/article/10.1007/s00384-024-04737-1). But as I noticed earlier, the subject is actually very popular.

-          The description of the statistical methods is corrected, but the use of multivariate analysis can be improved. As I can see in Table 2, there are still some predictors that are not statistically significant (p>>0.05). In a stepwise approach, you have to eliminate all the insignificant predictors until all the significant ones remain. The model presented in Table 2 cannot be considered complete.  The same applies to Table 3.

-          Figure 2 - It's much better to have all the survival curves in one place. However, please consider removing insignificant results and leaving only those that are statistically significant.

Author Response

1.If necessary, I could easily find more. There are many articles on the subject. If the authors need to prove the uniqueness of the subject of this article, they can claim that it's one of the few studies on the population of Taiwan (though not the only one - example here: https://link.springer.com/article/10.1007/s00384-024-04737-1). But as I noticed earlier, the subject is actually very popular.

Thank you so much for your valuable suggestions. I have revised the content based on your advice. From your analysis, we understand that there have been numerous studies discussing the differences between T4a and T4b in the past. Therefore, we narrowed the scope to focus on T4N0. However, it is clear from your perspective that this may still lack uniqueness. We will do our best to improve the article's content accordingly.

 

2.The description of the statistical methods is corrected, but the use of multivariate analysis can be improved. As I can see in Table 2, there are still some predictors that are not statistically significant (p>>0.05). In a stepwise approach, you have to eliminate all the insignificant predictors until all the significant ones remain. The model presented in Table 2 cannot be considered complete.  The same applies to Table 3.

Thank you so much for your valuable suggestions. I have revised the statistical section based on your advice. We grouped ECOG into two categories: grade 0–1 as one group and 2–3 as another. Finally, we completed the multivariate analysis using a stepwise approach and retained only the significant results. If there are still any inaccuracies, I would greatly appreciate your further guidance.

 

3.Figure 2 - It's much better to have all the survival curves in one place. However, please consider removing insignificant results and leaving only those that are statistically significant.

Thank you for your valuable suggestions. We have removed the non-significant results with "P=0.086" and "P=0.559." Kindly review the revisions at your convenience.