Prophylactic Swallowing Exercises in Patients with Laryngeal Cancer Who Underwent Total Laryngectomy—A Randomized Trial

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Swallowing issues after total laryngectomy are a clinically significant topic. Additionally, conducting this research as an RCT adds academic value. However, there are several key issues that need to be addressed and corrected as outlined below.

1. In order for a randomized controlled study to have statistical power, the sample size calculation must be aligned with the research objective. In this study, an RCT was conducted with 92 patients. How was the number of 92 patients determined?

2.Only gender and age were compared between the intervention group and the control group. However, additional information is needed on whether only total laryngectomy was performed, or if total laryngopharyngectomy or total laryngopharyngectomy with cervical esophagectomy were also performed. Additionally, information on the preoperative dietary status in the intervention and control groups is necessary. Poor preoperative nutritional status or low BMI can affect postoperative diet.

3. For better visibility for the readers, it would be advisable to present the Results section as a Table or Figure.

Comments on the Quality of English Language

The English requires minor editing in a few places.

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted file.

Comment 1:  In order for a randomized controlled study to have statistical power, the sample size calculation must be aligned with the research objective. In this study, an RCT was conducted with 92 patients. How was the number of 92 patients determined?

Response 1: Initially to ensure that the study has adequate power to detect a meaningful effect, the sample size had been determined to be at least 100 patients. The study was approved by the Ethics Committee for one year, which should have been sufficient to gather at least 100 patients, but during that period of time only 96 patients gave their informed consent, 1 dropped out during the study and 3 developed a pharyngo-cutaneous fistula so they were excluded from the study. The information was added in the Results section, highlighted. 

Comment 2: Only gender and age were compared between the intervention group and the control group. However, additional information is needed on whether only total laryngectomy was performed, or if total laryngopharyngectomy or total laryngopharyngectomy with cervical esophagectomy were also performed. Additionally, information on the preoperative dietary status in the intervention and control groups is necessary. Poor preoperative nutritional status or low BMI can affect postoperative diet. 

Response 2: Only patients with total laryngectomy were included in the study as it was considered that the patients with total laryngopharyngectomy and/or esophagectomy have a greater degree of swallowing impairment, the time period for which they need a naso-gastric tube or PEG is also higher. Additionaly it isn't determined if the exercises chosen for this study are safe for these types of patients, considering the extent of the surgery these patients may need different, adapted exercises. The information was added in the Materials and Methods section, highlighted. We determined the BMI for patients before surgery and there were no significant differences between the control and the intervention group. I have added the information in the Results section, highlighted.

Comment 3: For better visibility for the readers, it would be advisable to present the Results section as a Table or Figure.

Response 3: I have added a table (Table 1) with the results of the P value for all scores for a better visibility and understanding in the Results section. 

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors :

First of all, you mention the sample size weakly, I do not share this idea. 92 patients is a large sample.

Intuitively, the intervention should be better and you have proven it. But in such a sample it is surprising and needs to be commented:

- no problems with fistula or scarring in the two groups prior to the intervention

- the operations were similar (total laryngectomy associated or not with dissections) this would influence the results ;

I would expect you to talk a little more about why the result was better: wouldn't it be good to speculate on the trophism of the tongue muscles?

Structurally, it would be very good to have tables of evolution of the two groups; table of characteristics of the groups and finally please review table 2, it is strange

I think the work can be published after these revisions and additions in the discussions

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted file.

Comment 1: No problems with fistula or scarring in the two groups prior to the intervention. 

Response1: During the 2 weeks that passed from surgery to the beggining of the intervention, none of the patients developed a fistula. During the intervention period 3 patients developed a pharyngo-cutaneous fistula so we excluded them from the study because they could no longer perform the intervention exercises. The lack of scarring and development of a fistula can be explained by the fact that patients selected for the study didn't receive radiation therapy or chemotherapy before surgery. Also, patients with extensive surgery that required total laryngo-pharyngectomy or a certain degree of esophagectomy were excluded. I have added this information in highlight in the Materials and Methods section.

Comment 2: The operations were similar (total laryngectomy associated or not with dissections) this would influence the results.

Response 2: All surgeries were similar, total laryngectomy with selective neck dissection, I have added this information in highlight in the Materials and Methods section.

Comment 3: I would expect you to talk a little more about why the result was better: wouldn't it be good to speculate on the trophism of the tongue muscles?

Response 3: I have added a highlighted paragraph in the Disscusion section talking about the importance of the trophism of the tongue and how it is improved and maintained with exercises for a good quality swallowing process. 

Comment 4: Structurally, it would be very good to have tables of evolution of the two groups; table of characteristics of the groups and finally please review table 2, it is strange.

Response 4: I have erased Tables 1 and 2 and made a new one (Table 1) which comprises patients characteristics, evolution, the FOIS and PSS H&N scores ranges for both groups at different period of times and also shows P value. It was added in the Results section. 

Reviewer 3 Report

Comments and Suggestions for Authors

The article is very interesting. However, I believe several modifications should be made:

- It is necessary to follow the CONSORT guidelines, which include a randomization diagram for patients.

- Section 2.1 contains text that should be moved to the results section, specifically the second paragraph.

- Tables 1 and 2 are unnecessary and could be integrated into the text. The statistical analysis for sex is irrelevant since it is not an average but a categorical variable.

- Line 265: "As expected, swallowing-related..." Avoid value judgments in the results section. The authors should present the results without personal interpretations.

- Results should be rounded to two decimal places.

- The p-value should not use exponential notation; if the result is 0.000, that is acceptable.

- Were there any losses to follow-up?

- There are missing references throughout the discussion.

- Line 302: "The results of previous research, which has been criticized for methodological flaws, were confirmed." --> What are the references for this statement?

- Perhaps a few words on prehabilitation, the training before surgery, should be added.

- The descriptive analysis of the sample is missing: tumor type, stages, complementary treatment, analytical parameters, anthropometric parameters, type of diet... This represents a significant bias.

- The last paragraph of the discussion and the conclusions are quite similar.

- I see excessive praise from the authors for a study that is mediocre or limited in its variables.

- Subgroup analyses and a multivariate analysis are necessary.

Comments on the Quality of English Language

None

Author Response

Thank you very much for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions/corrections highlighted in the re-submitted file.

Comment 1: It is necessary to follow the CONSORT guidelines, which include a randomization diagram for patients.

Response 1: I have included a flow chart which you can find in the Materials and Methods section.

Comment 2: Section 2.1 contains text that should be moved to the results section, specifically the second paragraph.

Response 2: I have moved the certain paragraph to the Results section.

Comment 3: Tables 1 and 2 are unnecessary and could be integrated into the text. The statistical analysis for sex is irrelevant since it is not an average but a categorical variable.

Response 3: I have erased Tables 1 and 2 and made a new one (Table 1) which you can find in the Results section. 

Comment 4: Line 265: "As expected, swallowing-related..." Avoid value judgments in the results section. The authors should present the results without personal interpretations.

Response 4: I have modified that phrase and also others that had similar value judgments in order to avoid personal interpretations.

Comment 5: Results should be rounded to two decimal places.

Response 5: Results have been rounded to two decimal places.

Comment 6: The p-value should not use exponential notation; if the result is 0.000, that is acceptable.

Response 6: In some cases p-value was very low so the result would have been very long and with lots of 0 which seemed to make the text hard to comprehend for the reader. 

Comment 7: Were there any losses to follow-up?

Response 7: One patient dropped out of the study and three patients developed a pharyngo-cutaneous fistula so they were excluded from the study. There were no losses to the follow-up. I have added this information in highlight in the Materials and Methos section.

Comment 8 and 9: There are missing references throughout the discussion. Line 302: "The results of previous research, which has been criticized for methodological flaws, were confirmed." --> What are the references for this statement?

Response for comments 8 and 9: I have added references number 26, 27, 29, 30, 32, 33, which you can find in highlight in the Discussion section. Line 302 has been erased. 

Comment 10: Perhaps a few words on prehabilitation, the training before surgery, should be added.

Response 10: The patients didn't receive any training before surgery.

Comment 11: The descriptive analysis of the sample is missing: tumor type, stages, complementary treatment, analytical parameters, anthropometric parameters, type of diet... This represents a significant bias.

Response 11: I have specified the type of the tumor and stages in the Materials and Methods section, highlighted and also the BMI and other characteristics of the patients in Table 1 in the Results section.

Comment 12: The last paragraph of the discussion and the conclusions are quite similar.

Response 12: I have erased the conclusion because it was indeed similar to the last part of the Discussion section and therefore was derisory. 

Comment 13 and 14: I see excessive praise from the authors for a study that is mediocre or limited in its variables. Subgroup analyses and a multivariate analysis are necessary.

Response 13 and 14: I changed the phrases that were subjective and avoided personal judgments, also added in the Discussion section in highlight certain aspects and flaws in the study that may have increased it's bias. 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The statistical techniques for sample size calculation for the RCT are still insufficient, but other aspects have been well addressed.

Author Response

Thank you again for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comment: The statistical techniques for sample size calculation for the RCT are still insufficient, but other aspects have been well addressed.

Response: I have given details about the sample size calculation in the Materials and Methods section in highlight. I will also paste them here for ease.

The objective was to compare the mean outcomes of a treatment group and a control group with the effect size being the expected difference in means between the treatment and control groups. The significance level (α) as commonly was set at 0.05 and the probability of correctly rejecting the null hypothesis when it is false was set at 0.80. With a total sample size of 96 (48 per group), the effect size that can be detected with 80% power at a 5% significance level, given a standard deviation of 10 units, is approximately 5.71 units. As the effect size that we were aiming to detect was larger than 5.71, a sample size of 96 patients (48 per group) was considered sufficient. 

Reviewer 2 Report

Comments and Suggestions for Authors

There was a significant improvement in the writing, but some minor changes, in my understanding

1. Figure 1 needs captions

2. The objective of the work as well as the conclusion need to be highlighted

3. The swallowing exercises are methods; take them to this chapter

After these minor changes, I believe it will be released for publication

Author Response

Thank you again for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comment 1: Figure 1 needs captions.

Response 1: The captions was added.

Comment 2: The objective of the work as well as the conclusion need to be highlighted.

Response 2: The objective has been highlighted in the Materials and Methods section and a conclusion was added at the end of the text.

Comment 3: The swallowing exercises are methods; take them to this chapter.

Response 3: The description of the swallowing exercises has been moved to the Materials and Methods section.

Reviewer 3 Report

Comments and Suggestions for Authors

- The results section of a clinical trial abstract must contain some numerical values.

- I find it curious that organ preservation treatment is only considered in stage 3 when the patient cannot undergo surgery. Is there any reason for this?

- How was the randomization process conducted?

- In the methodology, sub-sections should be used to explain the different processes: intervention, control group, and variable measurement. This will improve the readability and understanding of the text.

- Loss to follow-up should be included in the results section.

- A sub-section on surgical technique is missing: total laryngectomy with or without preservation of the hyoid and musculature, type of neck dissection, placement of a voice prosthesis, type of pharyngeal suturing, etc.

- In the statistical analysis sub-section, it is necessary to specify the type of studies used. Means should be expressed with standard deviation.

- Sentences in English should not start with a number (line 277).

- The improvement in Table 1 is noticeable. I recommend avoiding the use of colors in the cells.

- The section on FOIS and the other scales doesn't make sense. What is intended to be expressed in each cell? You could categorize the variable and present the number of patients in each score range of the scale. You could also present the mean score of each scale in the different groups. Statistical advice is needed.

- The differences in distribution between groups can be obtained: tumor stage control vs. intervention.

- I repeat, p-values should be reported with three decimal places. If the result is, for example, 0.0000000000000000000000124, it should be expressed as <0.000.

- There is still no descriptive analysis of the sample.

- There is still no multivariate analysis of the sample or a justification for its absence.

- If there was follow-up, how many patients required subsequent radiotherapy? Are there any differences in swallowing function among them?

- The paragraph on line 338 is interesting, but are there no peer-reviewed scientific articles that have previously evaluated this type of exercise? Are we relying on an abstract from a meeting?

- Line 350 mentions the use of PEG, but this is the first mention of this aspect in the text. Were these data not collected?

- Deleting the last paragraph because it was repeated does not mean the text should not have a conclusions section.

There is still work to be done, and statistical knowledge is still lacking.

Comments on the Quality of English Language

Need revision

Author Response

Thank you again for taking the time to review this manuscript. Please find the detailed responses below and the corresponding revisions highlighted in the re-submitted files.

Comment 1: The results section of a clinical trial abstract must contain some numerical values.

Response 1: The Results section of the Abstract was modified. 

Comment 2: I find it curious that organ preservation treatment is only considered in stage 3 when the patient cannot undergo surgery. Is there any reason for this?

Response 2: This is not the only case where organ peservation treatment is consiered for stage 3 tumors, but the study focused only on patients that underwent surgery as the exercises were established only for patients after surgery. Therefore, we did not go into details about patients who followed organ preservation treatments as they were excluded from the study. 

Comment 3: How was the randomization process conducted?

Response 3: The objective was to assess the efficacy of prophylactic swallowing exercises on swallowing function in patients undergoing total laryngectomy for laryngeal cancer. 
Participants: 96 adults. Please see the first paragraph of the Materials and Methods section.

Recruitment:

- Patients with laryngeal cancer that presented in Coltea Clinical Hospital, that were eligible for surgery and gave their consent.

Baseline Assessment:

 - Each participant undergoes a baseline assessment to determine if they can perform the exercises and also complete the questionnaires. 

Randomization:

- Simple randomization using a computer-generated random number sequence.

Blinding:

- Both participants and researchers are blinded to group assignments to reduce bias.

Intervention:

- Participants receive their assigned treatment for a predetermined duration.

Follow-Up:

- After the intervention period, participants complete the questionnaires.

Data Analysis:

- Analyze the data to compare outcomes between the two groups using P value.

Reporting:

- Results are reported, including any adverse effects and the overall effectiveness.

Please also see Flow Chart 1.

Comment 4:  In the methodology, sub-sections should be used to explain the different processes: intervention, control group, and variable measurement. This will improve the readability and understanding of the text.

Response 4: Please find the corresponding revision highlighted in the Materials andd Methods section.

Comment 5: Loss to follow-up should be included in the results section.

Response 5: Please find the corresponding revision highlighted in the Results section.

Comment 6: A sub-section on surgical technique is missing: total laryngectomy with or without preservation of the hyoid and musculature, type of neck dissection, placement of a voice prosthesis, type of pharyngeal suturing, etc.

Response 6: The decision not to include detailed discussions on aspects such as total laryngectomy with or without hyoid preservation, neck dissection types, voice prosthesis placement, and pharyngeal suturing was primarily based on the focus and scope of our study. Our research aimed to concentrate on the result of the swallowing exercises on patients who underwent surgery, which led us to streamline the manuscript to highlight those key areas. We believed that including extensive surgical techniques might detract from our primary objectives and could overwhelm the reader with details that, while important, were outside the core focus of our findings. We do recognize the importance of surgical techniques in influencing swallowing outcomes and acknowledge that including this information could enhance the manuscript’s clarity and context. 

Comment 7:  In the statistical analysis sub-section, it is necessary to specify the type of studies used. Means should be expressed with standard deviation.

Response 7: Please find the revision in the Statistical analysis sub-section and Table 1.

Comment 8: Sentences in English should not start with a number (line 277).

Response 8: I have modified the sentence.

Comment 9: The improvement in Table 1 is noticeable. I recommend avoiding the use of colors in the cells.

Response 9: I have modified Table 1. 

Comment 10: The section on FOIS and the other scales doesn't make sense. What is intended to be expressed in each cell? You could categorize the variable and present the number of patients in each score range of the scale. You could also present the mean score of each scale in the different groups. Statistical advice is needed.

Response 10: The above mentioned sections are meant to show that the range of the scales increased in the intervention group at 3, 6, 9 and 12 months compared to the control group and also highlight the P value which shows a difference that is statistically significant between the control and the intervention group for all scales at 3, 6, 9 and 12 months.

Comment 11: The differences in distribution between groups can be obtained: tumor stage control vs. intervention.

Response 11: Please find the revision in Table 1.

Comment 12: I repeat, p-values should be reported with three decimal places. If the result is, for example, 0.0000000000000000000000124, it should be expressed as <0.000.

Response 12: I have made this change.

Comment 13:  There is still no descriptive analysis of the sample.

Response 13: Please find the revision in the Materials and Methods section, Sub-section Descriptive Analysis.

Comment 14: There is still no multivariate analysis of the sample or a justification for its absence.

Response 14: The trial employed a robust randomization process that ensured balanced baseline characteristics across groups. As a result, we found that the need for controlling confounding variables was minimized, making univariate analyses sufficient to assess the primary outcomes. The principal aim of the research was to assess the impact of the prophylactic swallowing exercises. We did not need to investigate more than one predictor at the same time because our study was built specifically to target this outcome. Our study included a small sample size. A higher sample size is usually needed for multivariate analysis in order to guarantee accurate estimates and sufficient statistical power. In this instance, we chose to concentrate on more straightforward analyses that were suitable for the sample size in order to preserve the integrity of our findings. When presenting our results, we tried to be as clear and simple as possible. We thought that publishing univariate analysis would give readers clearer insights without the possible complexity and misunderstanding generated by multivariate modeling, given the nature of the intervention and its results. We found that although multivariate analysis can yield insightful results in a variety of settings, univariate analysis was more suitable for our goals in this RCT due to its design, sample size, and emphasis on important outcomes. Further studies with bigger sample numbers might delve deeper into these connections. 

Comment 15:  If there was follow-up, how many patients required subsequent radiotherapy? Are there any differences in swallowing function among them?

Response 15: Yes, there was a follow-up phase in our study. In particular, several individuals needed radiation treatment after the intervention. Nevertheless, we concluded that the information about the number of patients undergoing radiation therapy and any variations in swallowing function among those patients was unrelated to the main goal of our investigation. Rather than concentrating on the long-term care of problems or subsequent therapies, our main objective was to evaluate the intervention's effects. Because of the possibility that it may confuse the interpretation of our key findings and detract from the main research questions we set out to answer, we decided not to include this follow-up data in our analysis. 

Comment 16: The paragraph on line 338 is interesting, but are there no peer-reviewed scientific articles that have previously evaluated this type of exercise? Are we relying on an abstract from a meeting?

Response 16: All exercises were chosen because they were evaluated in peer reviewed scientific articles and were proven to be effective for these types of patients as it can be seen in all references, I just considered that the information from that abstract was worth mentioning. 

Comment 17: Line 350 mentions the use of PEG, but this is the first mention of this aspect in the text. Were these data not collected?

Response 17: The use of PEG is part of the FOIS scale (Figure 7, scores from 1 to 3 include tube dependent feeding), most of the patients had at first responses from 1 to 3 (which you can find in Table 2). 

Comment 18: Deleting the last paragraph because it was repeated does not mean the text should not have a conclusions section.

Response 18: A new conclusion was added. 

Round 3

Reviewer 2 Report

Comments and Suggestions for Authors

the work got better with the corrections; I think that only the photograph of the laryngectomy ,that is not adequate, could be removed and then, I think that the publication will be released

Author Response

Thank you for taking the time to review the manuscript. 

At the editor's suggestion I modified the figure with some anatomical landmarks and also added some comments about the anatomical structures that are mostly involved in swallowing.