Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a very interesting paper that attempts to address the well-known limitations of RECIST criteria in esophageal squamous cell carcinoma: their poor measurability. To overcome these issue, the authors propose a bidimensional measurement (short and long axis) on contrast-enhanced CT and retrospectively validate the method in 123 patients undergoing neoadjuvant treatment (DCF regimen). The topic is interesting; however, several methodological issues need to be addressed. The main weakness is the lack of an assessment of the reproducibility of CT measurements. Methods

• Please provide details of the CT protocol (including the contrast injection) and specify which contrast phase was used for the measurements. In particular, Figure 1 shows two illustrative measurement images acquired in different contrast phases; this could introduce bias. Please clarify this point and address it in the Discussion and Limitations.
• Please clarify who performed the measurements and how many measurements were taken. Inter-reader agreement is not included in the analysis; this is a major limitation of the study, and I suggest adding it.
• Definition of pathological response: including grade 1b in the high-response group could introduce bias. Please justify this choice (instead of including only grades 2–3) in the Discussion.

  Results

• Please report tumor size on CT (e.g., mean, median, range/IQR).
• Table 4: some hazard ratios and confidence intervals appear internally inconsistent. For example, clinical stage IVa is reported with HR 2.247 but a 95% CI of 0.253–0.783, which does not include the HR. Please verify and correct.
• Please add the median follow-up time, including the number of recurrence and death events.
• Clearly state how overall survival (OS) was calculated (e.g., from treatment initiation, surgery, or diagnosis).

Discussion

• The study population is heterogeneous, including patients with resectable stage II/III disease receiving neoadjuvant chemotherapy and patients with clinical stage IVa locally advanced disease receiving induction chemotherapy. Since subgroup analyses may be underpowered, please discuss this potential source of bias in the Discussion/Limitations.
• The authors state that RECIST had a predictive accuracy of 57.7%, whereas CT-based evaluation had a predictive rate of 82.1%. The method used to calculate these values is not clearly described; please clarify.

Minor comments

• There are several typos (e.g., “TableT4”).
• Figure 2: the text reports an AUC for SRR of 0.873, whereas Figure 2 appears to show 0.866. Please check and ensure consistency.

Author Response

Methods

Comment 1: Please provide details of the CT protocol (including the contrast injection) and specify which contrast phase was used for the measurements. In particular, Figure 1 shows two illustrative measurement images acquired in different contrast phases; this could introduce bias. Please clarify this point and address it in the Discussion and Limitations.

Response 1:

Thank you very much for important comment.

We determined the tumor location comprehensively based on both the early and delayed contrast-enhanced phases.
We will add the following description, including the CT protocol.

Method (Page8, Line4-12): First, the routine unenhanced scans were performed. Subsequently, Contrast medium was administered intravenously at a dose of 1.5 mg/kg body weight. CT examination was acquired at 30 seconds as the early contrast phase and at 120 seconds as the delayed contrast phase. In patients with renal impairment, the dose of contrast medium was adjusted accordingly. Tumor location was determined comprehensively based on differences in enhancement during the early and delayed phases and wall thickness compared with the normal esophageal wall.

Discussion (Page34, Line6-8): Two authors independently performed the measurements of the tumor region on both early and delayed phases of CT, and the reproducibility was generally within an acceptable range

Comment 2: Please clarify who performed the measurements and how many measurements were taken. Inter-reader agreement is not included in the analysis; this is a major limitation of the study, and I suggest adding it.

Response 2:

Thank you very much for important comment. All measurements were performed independently by two authors, and the mean value was calculated. The differences in measurements between observers are an important issue, and this point has been described in both the Methods (Page8, Line17-18) and Discussion sections (Page34, Line 6-8).

Comment 3: Definition of pathological response: including grade 1b in the high-response group could introduce bias. Please justify this choice (instead of including only grades 2–3) in the Discussion.

Response 3:

Thank you very much for important comment. Grade 1b is defined as residual tumor occupying between one-third and two-thirds of the lesion. In addition, partial response (PR) according to the RECIST criteria is defined as a tumor reduction rate of at least 30%, which is consistent with real-world clinical practice. Furthermore, several previous studies with similar designs have also classified Grade 1b as a responder category and demonstrated its association with prognosis. Therefore, in the present study, Grade 1b was included in the responder group. However, the results may differ when only Grade 2 or higher is considered as a response, and this point will be addressed in the Discussion section (Page34, Line10-17).

  Results

Comment 4: Please report tumor size on CT (e.g., mean, median, range/IQR).

Response 4:

Thank you very much for important comment. We added the tumor size in table1

Comment 5: Table 4: some hazard ratios and confidence intervals appear internally inconsistent. For example, clinical stage IVa is reported with HR 2.247 but a 95% CI of 0.253–0.783, which does not include the HR. Please verify and correct.

Response 5:

Thank you very much for pointing out the error. We have corrected it and provided the accurate value (univariate analysis of RECIST and SLRR, multivariate analysis of BMI and cStage).

Comment 6: Please add the median follow-up time, including the number of recurrence and death events.

Response 6:

Thank you very much for important comment. We added the median follow up time, recurrence and death events in the result (Page14, Line11-12).

Comment 7: Clearly state how overall survival (OS) was calculated (e.g., from treatment initiation, surgery, or diagnosis).

Response 7:

Thank you very much for important comment. OS was calculated from treatment (chemotherapy). We added this in the methods (Page10, Line12-13).

Discussion

Comment 8: The study population is heterogeneous, including patients with resectable stage II/III disease receiving neoadjuvant chemotherapy and patients with clinical stage IVa locally advanced disease receiving induction chemotherapy. Since subgroup analyses may be underpowered, please discuss this potential source of bias in the Discussion/Limitations.

Response 8:

Thank you very much for important comment.

This study included both patients with resectable stage II/III disease who received neoadjuvant chemotherapy and patients with clinical stage IVa locally advanced disease who received induction chemotherapy, which may have introduced potential bias due to the heterogeneity of the study population. We added the following statement to the Limitations section.

the study population included patients treated with induction chemotherapy for cStage IVa disease. This may introduce heterogeneity in treatment outcomes, potentially resulting in bias; however, the inclusion of locally advanced cases treated with induction chemotherapy also increases the real-world applicability of this study.

Comment 9: The authors state that RECIST had a predictive accuracy of 57.7%, whereas CT-based evaluation had a predictive rate of 82.1%. The method used to calculate these values is not clearly described; please clarify.

Response 9:

Thank you very much for important pointing out. It indicates the sensitivity for predicting the response to chemotherapy, and this information has been added to the Methods (Page10, Line10-11) and Results sections (Page13, Line12-13).

Minor comments

Comment 10: There are several typos (e.g., “TableT4”).

Response 10:

Thank you very much for pointing out the error. We have corrected it

Comment 11: Figure 2: the text reports an AUC for SRR of 0.873, whereas Figure 2 appears to show 0.866. Please check and ensure consistency.

Response 11:

Thank you very much for pointing out the error. We have corrected it and provided the accurate value.

Reviewer 2 Report

Comments and Suggestions for Authors

Our research colleagues have produced a study aimed at investigating whether two-dimensional computed tomography (CT) measurements predict pathological response and prognosis after neoadjuvant therapy with docetaxel, cisplatin, and 5-fluorouracil in squamous cell carcinoma of the esophagus. The title is well-suited to the study under review, and the abstract provides a good summary of the entire paper. The next section should better define the disease, noting that this condition often brings patients to the doctor for dysphagia and weight loss. Diagnostics is the cornerstone of the oncology process, with its main pillars being imaging and endoscopic and endoscopic ultrasound examinations. This insidious disease can manifest itself in both the proximal and the other two thirds. It can also be multifocal and grow into the submucosa, which is why endoscopic ultrasound and deep biopsy can be two key steps in the diagnostic process. Once the diagnostic workup is complete, the case should be discussed by a multidisciplinary committee and then treated with neoadjuvant therapy and nutritional support. We have nothing to add regarding the materials and methods. These have been excellently described and can be replicated at any high-volume center. We only recommend having a pathologist analyze the resection margins to ensure an R0 procedure. The results, aided by numerous, well-designed explanatory tables with good captions, along with the references, provide a valuable basis for discussion. We ask the authors to also consider minimally invasive surgery (doi.org/10.3390/curroncol32020072, to be read and cited in the references). We also ask the authors to provide the paper's strengths. The conclusions are sound and concrete. Good English, good references. Excellent illustrations, which are essential to the study's overall structure.

Author Response

Comment 1: The next section should better define the disease, noting that this condition often brings patients to the doctor for dysphagia and weight loss. Diagnostics is the cornerstone of the oncology process, with its main pillars being imaging and endoscopic and endoscopic ultrasound examinations.

Response 1:

We appreciate the reviewer for this valuable suggestion. We added the sentence in the introduction (Page4, Line3-5).

Comment 2: We only recommend having a pathologist analyze the resection margins to ensure an R0 procedure.

Response 2:

We appreciate the reviewer for this important suggestion. We added the sentence in the method (Page7, Line15-17).

Comment 3: We ask the authors to also consider minimally invasive surgery (doi.org/10.3390/curroncol32020072, to be read and cited in the references). We also ask the authors to provide the paper's strengths.

Response 3:

Thank you very much for important comment. We added the reference.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have updated the manuscript overall in response to the reviewers’ comments. However, two major issues remain and need to be addresed:

1. The authors have appropriately improved the section describing the CT protocol used for the evaluation; however, they specify only in the Discussion how the measurments were performed ("Two authors independently performed the measurements of the tumor region on both early and delayed phases of CT, ..."). Please specify in the Methods section how many measurements were actually performed, on which phase(s), how the slice was choosen, and how the tumor boundaries were identified. The rationale for this measurement approach should then be discussed in the Discussion section. Since this paper focuses on measurements, ensuring reproducibility is a central aspect of the work.
2. For the same reasons, the sentence “the reproducibility was generally within an acceptable range” (page 13, lines 349–352) is not acceptable as stated, and an inter-reader agreement analysis is required.

Author Response

1. The authors have appropriately improved the section describing the CT protocol used for the evaluation; however, they specify only in the Discussion how the measurments were performed ("Two authors independently performed the measurements of the tumor region on both early and delayed phases of CT, ..."). Please specify in the Methods section how many measurements were actually performed, on which phase(s), how the slice was choosen, and how the tumor boundaries were identified. The rationale for this measurement approach should then be discussed in the Discussion section. Since this paper focuses on measurements, ensuring reproducibility is a central aspect of the work.

Response 1:

Thank you very much for important point out.

In the present study, in accordance with previous reports, tumor regions were defined as areas showing wall thickening compared with the normal wall (specifically, regions with a thickness exceeding 5 mm) or as mass-forming lesions. The longest diameter of the lesion was measured, and the perpendicular diameter was defined as the short axis. These measurements were performed based on a comprehensive assessment of both the early and delayed phases of contrast-enhanced imaging; in some cases, measurements were obtained from either phase depending on image quality and lesion visibility. Two independent readers performed the measurements, each conducting a single assessment.

As pointed out by the reviewer, it is indeed difficult in some cases to objectively and precisely delineate tumor boundaries. Accordingly, the potential for inter-reader variability has been addressed in the Discussion. In addition, detailed results of the inter-reader agreement analysis will be included as described below.

We originally presented representative CT images of tumor size measurements before and after chemotherapy using both early and delayed contrast-enhanced phases, which could potentially mislead readers. To avoid this, we have replaced both images with scans obtained in the early contrast-enhanced phase.

 

The additional text

Materials and Methods (Page8, Line9-15)

・Tumor location was determined comprehensively based on differences in enhancement during the early and delayed phases, wall thickness compared with the normal esophageal wall (esophageal wall thickness exceeding 5 mm on axial CT) and the presence of mass formation. Tumor diameter was measured on the horizontal slice showing the thickest part of the tumor among all slices demonstrating the tumor.

Materials and Methods (Page9, Line2)

・with each investigator conducting one measurement

Discussion (Page34, Line6-14)

・In accordance with previous reports [11,12,14], regions with wall thickening of ≥5 mm on axial CT images were considered tumor lesions, and tumor diameter was measured accordingly. Although this measurement approach is straightforward and easy to implement, it may be susceptible to inter-reader variability. ICCs for pre-chemotherapy tumor diameters demonstrated good reliability, and those for post-chemotherapy tumor diameters demonstrated moderate reliability. Based on these findings, the reproducibility was generally within an acceptable range

 

2. For the same reasons, the sentence “the reproducibility was generally within an acceptable range” (page 13, lines 349–352) is not acceptable as stated, and an inter-reader agreement analysis is required.

Response 2:

Thank you very much for important point out.

Inter-reader agreement for tumor measurements was evaluated using the intraclass correlation coefficient (ICC). The ICCs for the pre-chemotherapy tumor short-axis and long-axis diameters were 0.782 and 0.841, respectively. The ICCs for the post-chemotherapy tumor short-axis and long-axis diameters were 0.715 and 0.741, respectively. We added these in the results.

We added these data in the result.

The additional text

Materials and Methods (Page10, Line9-11)

・Inter-reader agreement between the two investigators was assessed using intraclass correlation coefficient (ICC).

Results (Page12, Line2-8)

・The mean short-axis and long-axis diameters on CT before chemotherapy were 23 mm and 32 mm, respectively. Inter-reader agreement for tumor measurements was evaluated using the ICC. The ICCs for the pre-chemotherapy tumor short-axis and long-axis diameters were 0.782 and 0.841, respectively. The ICCs for the post-chemotherapy tumor short-axis and long-axis diameters were 0.715 and 0.741, respectively.

Reviewer 2 Report

Comments and Suggestions for Authors

The current version of the text under study is an excellent read. We remind the authors that the third line of the introduction emphasizes that a biopsy must also be performed, as this is a starting point for the subsequent process. There are no objections to the rest of the paper. Endorsement

Author Response

Comment 1: The current version of the text under study is an excellent read. We remind the authors that the third line of the introduction emphasizes that a biopsy must also be performed, as this is a starting point for the subsequent process. There are no objections to the rest of the paper. Endorsement

Response 1:

We appreciate the reviewer for this valuable suggestion. We have added a description regarding tissue biopsy in the revised manuscript.