Correlation between Lymphocyte-to-Monocyte Ratio (LMR), Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Extramural Vascular Invasion (EMVI) in Locally Advanced Rectal Cancer

Round 1

Reviewer 1 Report (Previous Reviewer 2)

The authors have added considerable new information and also the limitation of interrater reliability. They better articulate the potential importance of the work. They have also added a few tables. If this is acceptable to your journal, I am satisfied if the manuscript is published in its revised form.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

 

It is an interesting study about the relationship of EMVI with LMR, NLR, and PLR in patients with rectal cancer. However, before it can be accepted, several items need to be punctuated:

 

1. How many radiologists evaluated each tumor? There may be interobserver variability, which directly affects the results of the study. How did the authors solve this problem?

2. Why was an intra-rectal coil not used in the MRI to improve the image of each tumor?

3. Was the EMVI evaluated numerically? Or it was only reported as positive or negative. Could this affect the results? 

4. Authors need to cite and discuss this meta-analysis, which is one of the largest on the literature: Siddiqui M, et al. Br J Cancer. 2017 June 6; 116(12): 1513–1519.

Author Response

“It is an interesting study about the relationship of EMVI with LMR, NLR, and PLR in patients with rectal cancer. However, before it can be accepted, several items need to be punctuated:

1. How many radiologists evaluated each tumor? There may be interobserver variability, which directly affects the results of the study. How did the authors solve this problem?”

First of all, thank you very much for reviewing our study and helping us improve it.

The question is very important because the interobserver variability in assessing the status of MRI - EMVI is indeed high (1). We did our best to ensure that this factor did not significantly affect the results of the study. All the MRI scans were evaluated independently by two radiologists with at least ten years of experience in pelvic MRI assessment. In case of disputed results another radiologist was asked to give an opinion and consensus decision was made. We added the missing details on radiological evaluation in the Methods section.

 

“2. Why was an intra-rectal coil not used in the MRI to improve the image of each tumor?”

The MRI acquisition was conducted according to the European Society of Gastrointestinal and Abdominal Radiology (ESGAR) recommendations (2). The MRI was performed with an external surface coil.

 

“3. Was the EMVI evaluated numerically? Or it was only reported as positive or negative. Could this affect the results?” 

Thank you for this question. The status of EMVI in our study was reported as positive or negative. We realize a model of grading of EMVI has been introduced and applied in some studies in order to distinct a group of patients with equivocal status of EMVI (3). However, ESGAR does not recommend using this model in assessment of EMVI. It is not a standard practice in our institution neither. We decided to report the status of EMVI as positive/negative only. Equivocal cases were jointly discussed among experienced team of radiologists. Therefore, in our opinion, the results of the study were not negatively affected by such a simpler presentation.

 

“4. Authors need to cite and discuss this meta-analysis, which is one of the largest on the literature: Siddiqui M, et al. Br J Cancer. 2017 June 6; 116(12): 1513–1519.”

Thank you very much for pointing out this remarkable meta-analysis important to the subject. We have implemented it into the manuscript in the Discussion section as recommended.

Once again, we thank the reviewers for all the comments. We hope we have addressed all the questions and improved the shortcomings of the initial version of the manuscript.

On behalf of the authors,

Corresponding author: Cieszymierz Gawiński

Department of Oncology and Radiotherapy M. Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland

1. Wawelska 15; 02-034 Warsaw, Poland.

e-mail: [email protected]; phone: +48507087597

REFERENCES:

 

1. Inoue A, Sheedy SP, Heiken JP, Mohammadinejad P, Graham RP, Lee HE, et al. MRI-detected extramural venous invasion of rectal cancer: Multimodality performance and implications at baseline imaging and after neoadjuvant therapy. Insights into imaging. 2021;12(1):110.
2. Beets-Tan RGH, Lambregts DMJ, Maas M, Bipat S, Barbaro B, Curvo-Semedo L, et al. Magnetic resonance imaging for clinical management of rectal cancer: Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. European radiology. 2018;28(4):1465-75.
3. Ale Ali H, Kirsch R, Razaz S, Jhaveri A, Thipphavong S, Kennedy ED, et al. Extramural venous invasion in rectal cancer: overview of imaging, histopathology, and clinical implications. Abdominal radiology (New York). 2019;44(1):1-10.

Reviewer 2 Report

The paper is well written and understandable. It is an observational retrospective case series.

EMVI predicts for prognosis but this reviewer is unaware that EMVI status alone is used to inform neoadjuvant or adjuvant treatment decisions. It is an interesting factor, but despite its presence for many years there is no good evidence it can drive decision making. The choice then to correlate blood compound ratios to EMVI should be better justified. I suspect the correlation should be simply with stage, if this has not been extensively done already.

The interrater reliability of expert radiologists to assign EMVI status with MRI is moderate – see work by Gina Brown. This reinforces the importance of our first concern. This should be discussed as a limitation. It would be helpful to correlate EMVI status with pathology findings, stratified by neoadjuvant status.

Only 63 of 231 patients with rectal cancer were eligible. It is not clear if only 63 patients received a pre-neoadjuvant therapy MRI or if the EMVI status was simply not reported in earlier scans. If the latter, physical review of images could provide EMVI status and increase the numbers for analyses.

The low case numbers and numerous tests raise the possibility of Type II errors and data dredging. This should be discussed as a limitation.

Author Response

“The paper is well written and understandable. It is an observational retrospective case series.”

Thank you very much for your time spent on analyzing our study and all the valuable comments.

“EMVI predicts for prognosis but this reviewer is unaware that EMVI status alone is used to inform neoadjuvant or adjuvant treatment decisions. It is an interesting factor, but despite its presence for many years there is no good evidence it can drive decision making. The choice then to correlate blood compound ratios to EMVI should be better justified. I suspect the correlation should be simply with stage, if this has not been extensively done already.”

Thank you for this comment. Indeed, EMVI status alone is not used as an indication for neoadjuvant/adjuvant treatment. However, as stated by the ESMO Clinical Practice Guidelines for management of rectal cancer, it is one of the most important factors which should be taken into consideration in treatment decision-making in locally advanced rectal cancer (1). The risk of distant failures in stage II EMVI-positive tumors corresponds to the EMVI-negative stage III disease (2). MRI- EMVI is a prognostic factor in rectal cancer in terms of both DFS and OS, independent of the stage (3-5). Blood-based parameters such as LMR, NLR and PLR seem to have similar prognostic properties (as proved in the manuscript). We hypothesized that combining MRI-based and blood-based markers may lead to more accurate prognostic assessment of patients (e.g. as a part of risk-scoring models) in the future. In order to investigate it, first, a better understanding of the relation between both kinds of markers should be provided which was the aim of our study. It should be treated as a preliminary research on the subject which is absent in the literature. We hope our study and presented results will lead to further exploration of this important issue.

 

“The interrater reliability of expert radiologists to assign EMVI status with MRI is moderate – see work by Gina Brown. This reinforces the importance of our first concern. This should be discussed as a limitation. It would be helpful to correlate EMVI status with pathology findings, stratified by neoadjuvant status.”

We tried to reduce the interobserver variability in assessing the status of EMVI by the evaluation of each MRI scan independently by two experienced radiologists. Equivocal cases were discussed among broader group of radiologists. However, we realize these measures do not prevent  the occurrence of this problem entirely. We modified the paragraph on the limitations in the Discussion section of the manuscript accordingly. The status of EMVI is not routinely assessed in the pathological specimen (pEMVI) in our institution and could not be evaluated in the study.

However, we collected the available post-surgical pathological results and added an analysis of correlation between the MRI-based status of EMVI and pTNM in the main manuscript and the supplement section providing additional interesting data.

“Only 63 of 231 patients with rectal cancer were eligible. It is not clear if only 63 patients received a pre-neoadjuvant therapy MRI or if the EMVI status was simply not reported in earlier scans. If the latter, physical review of images could provide EMVI status and increase the numbers for analyses. The low case numbers and numerous tests raise the possibility of Type II errors and data dredging. This should be discussed as a limitation.”

We realize the small number of patients eligible for the study is a limitation. We analyzed over 230 patients with locally advanced rectal cancer treated in our institution. A high number of ineligible cases were predominantly due to:

1. a lack of pre-treatment MRI – this concerned mainly patients treated earlier during the analyzed period of time (2016-2021). MRI as a pre-treatment diagnostic procedure was not a commonly used diagnostic modality at that time in our country.
2. a lack of reported status of EMVI on MRI performed outside our institution and unavailable scans to re-assess. – a great majority of analyzed MRI scans had no reported status of EMVI. Whenever possible, such cases were re-assessed by our radiologists and included in the study; however, in some cases the scans were not available.

We comment on this issue in the paragraph concerning limitations in the Discussion section.

However, it is worth noting that as the AUC level for LMR, NLR and PLR was low (close to 0.5), and p-value for those analyses was high ( p = 0.492, p = 0.693 and p = 0.528), it is extremely unlikely the results and conclusions of the study are a matter of a small sample.

 

Once again, we thank the reviewers for all the comments. We hope we have addressed all the questions and improved the shortcomings of the initial version of the manuscript.

On behalf of the authors,

Corresponding author: Cieszymierz Gawiński

Department of Oncology and Radiotherapy M. Skłodowska-Curie National Research Institute of Oncology in Warsaw, Poland

1. Wawelska 15; 02-034 Warsaw, Poland.

e-mail: [email protected]; phone: +48507087597

References

1. Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology. 2017;28(suppl_4):iv22-iv40.

2. Chand M, Bhangu A, Wotherspoon A, Stamp GWH, Swift RI, Chau I, et al. EMVI-positive stage II rectal cancer has similar clinical outcomes as stage III disease following pre-operative chemoradiotherapy. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25(4):858-63.

3. Zhang XY, Wang S, Li XT, Wang YP, Shi YJ, Wang L, et al. MRI of Extramural Venous Invasion in Locally Advanced Rectal Cancer: Relationship to Tumor Recurrence and Overall Survival. Radiology. 2018;289(3):677-85.

4. Gu C, Yang X, Zhang X, Zheng E, Deng X, Hu T, et al. The prognostic significance of MRI-detected extramural venous invasion, mesorectal extension, and lymph node status in clinical T3 mid-low rectal cancer. Scientific Reports. 2019;9(1):12523.

5. Mc Entee PD, Shokuhi P, Rogers AC, Mehigan BJ, McCormick PH, Gillham CM, et al. Extramural venous invasion (EMVI) in colorectal cancer is associated with increased cancer recurrence and cancer-related death. European Journal of Surgical Oncology. 2022;48(7):1638-42.