Review Reports - Long-Term Patient-Reported Outcomes of Hyperbaric Oxygen Therapy for Haematuria Due to Radiation Cystitis Secondary to External Beam Radiotherapy for Pelvic Malignancy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Congratulations to an interesting retrospective study of radiation cystitis treated with hyperbaric oxygen. I have some comments listed below.

It should be clearly stated in the title or in the abstract that the study is a retrospective cohort study.
The numbers presented in the abstract differ from the ones in the result section (e.g. "79 patients underwent HBOT" (row 20), "There were 89 patients who underwent HBOT" (row 93) and Table 1 "Underwent HBOT n=54 (row 102).
Use and define the same expression for a specific group of patients. The expressions “included in the study” and “underwent HBOT” are not clearly defined and seem to refer to the same population in the manuscript, but the groups differ in size in the manuscript.
Only percent (%) is presented and n= is lacking in the abstract for some results. It is unclear if the number 89, 79 or 54 has been used as the devisor to calculate the %. I suggest writing “X of Y patients (Z%)…” to make it clearer.
Missing data is not accounted for. It says on row 83 “Patients were excluded from the study if they did not complete the questionnaire”. As I understand it, all 89 patients who underwent HBOT during the period studies were included in the study. There were 13 dead patients, and 22 patients had missing data (no response). There’s no perfect solution for missing data, so maximizing data collection is crucial and the efforts to do so should be clearly explained. You have used the most common method—complete case analysis—which excludes all incomplete records. This works if few data points are missing, but when many are, it can significantly reduce the dataset and weaken statistical power. The latter is the case here and it would be appropriate to use a method for handling missing data or at least explain why this wasn’t done in the discussion and give the reasons behind this decision.
Row 15 The abbreviation HBOT is introduced in the abstract without explanation. Also, consider using HBO2 as this is the abbreviation recommended by UHMS.
Row 21 It says "95% were male. 94%... for prostate cancer" in the abstract, but in the results (row 96) it says that all male patients had prostate cancer. Please check and correct.
Row 21 "Median age was 74 (69-78)" it would be helpful to write what 69-78 is IQR i.e., 74 (IQR 69-78)
Row 25-27 P-values are given for reduction in GP- and ER-visits and transfusions but no numbers. Please include the underlying data for these p-value calculations. Also, 95% CI (Confidence interval) should normally be calculated and presented to show precision. This applies to all p-values calculated in the manuscript. (e.g. "The mean systolic blood pressure decreased by 12.3 mmHg (95% CI: 9.1 to 15.5 mmHg, p < 0.001) after treatment.")
Row 27 "18 patients (42%)" reported ongoing haematuria. Where does the 42% come from? This is a relatively high number of "non-responders" with sustained haematuria - I think it deserves a comment in the discussion section.
Row 29-30: "No patients reported any severe or ongoing adverse effects". I presume this statement is related to HBO-treatment. Was this data collected from patient records or during the interview?
Row 41 "surround" -> surrounding? and "the bladder" -> the urine bladder?
Please be consistent and use the same expression in the manuscript. Row 41 "radiation cystitis", row 63 "radiation-cystitis" row 68 "radiation-induced cystitis".
Row 42 urologists not Urologists?
Row 48-51: Explains the cause of radiation cystitis; endarteritis and ischemia. I would like to see an expansion of this section, chronic inflammation, fibrosis and neurological dysfunction are also part of the condition and should be mentioned.
The introduction lacks explanation as to why HBO2 would be effective. I would like to se a paragraph explaining the rational for using HBO2 for radiation cystitis.
Row 73-75 It could be clarified that the treatment includes breathing 100% oxygen and with what frequency the treatment was given (once daily Mo-Fr?).
Row 74 Use the SI-unit for pressure, (kPa) and not meters of seawater.
Row 76-79 It says that time from radiation to HBO2 was collected, but no such data is presented.
Row 79 It says that "complications of HBOT was determined using the electronical medical records. on Row 121-124 complications are reported but is in unclear if the data presented are from the medical records or from the interview or both.
Row 90 It says that patient consent was collected, but on row 196 it says that there was no informed consent. Which is true?
Row 96: here the median age is reported (and IQR written out) with one decimal, but in the abstract and in the table, it is without decimals. Please be consistent.
Row 95 22 patients were unable to contact - it could be better described in the methods how many times you tried to reach the patients. Missing data is a huge thing in a retrospective study and must be addressed appropriately.
Row 93 54 patients completed the questionnaire of total 89, and alive 76 (13 dead):
In the abstract row 22-23 it says 53% of the total cohort and 63% of the survivals completed the questionnaire. But 54 of 89 is 61% and 54 of 76 is 71%. Please check and correct.
Row 103-106 The results are presented in a confusing way "median 8/10 (IQR 7/10-10/10)". I suggest making it clear in text that the scale was from 0-10 (?) and present data like this: "median 8 (IQR 7-10)".
Row 110-115 The value given for number of visits to GP and ER lacks time frame and are hard or impossible to evaluate. It would have been much more informative to know how many visits per year. It is likely that the timeframe is different before HBO and after HBO which makes the numbers confusing.
Row 110-118 Median values don't say much with this data. How many blood transfusions were given before HBO and how many after. How many patients required transfusions before and after? Was there any reduction after HBO?
Row 126-130 It says 21 patients reported ongoing haematuria following HBO. Was this ongoing at the interview or was it at one or several occasions after HBO? Is it correct that only 9% (=4?) patients received additional HBO after the first treatment even though 21 patients had reoccurring haematuria? If so, why didn't more patients receive additional HBO? This might be commented on in the discussion.
One of the major limitations of this study is that pre-HBO and post-HBO values were collected at the same time (post HBO). Although it is mentioned, it is not adequately addressed in the discussion.
A lot of space is used to discuss the different scales used to assess effects of HBOT on radiation cystitis. It is said (row 155) that this is a key reason for the heterogeneity of outcomes. I’m not so sure that this is true. There are other reasons for heterogeneity such as demographics, radiation dose, time from radiation to HBO, different HBO-protocols, etc that might be more relevant in the explanation of heterogeneity of results. However, EPIC and SOMA/LENT are validated instruments that have been used in numerous of studies on cystitis (not only including HBO). So, I humbly ask, why did you choose to invent a new score when you (on row 166) point out that a more standardised questionnaire would be better. Can you explain why you didn't use any of the validated tools in the discussion?
Row 208-240 The questionnaire includes question on what symptoms patients experienced (Haematuria, dysuria, frequency and pain), I can’t see that these results are presented.

Comments on the Quality of English Language

I'm dont have English as my primary language, so I refrain from making more detailed comments on the quality of the language, but I make the following remarks:

* Use the same expression in mansucript (e.g. radiation induced, radiation-induced)
* Explain all abbreviations (ED, GP, CTCAE, EORTC, ASTRO etc)
* Use SI-units (e.g. kPa)
* Avoid expression like "very positive", "a large proportion" etc - give more precise figures when possible.

Author Response

Thank you very much for your feedback. It is clear you put in considerable time and effort to help us improve the strength and quality of this paper. We are very appreciative of your efforts. We have addressed the questions for general evaluation, specific comments and the comment on the quality of English language below. We have made my changes in red so they can easily be identified and specified the relevant changed lines for the corresponding comments below.

Questions for general evaluation:

1. Does the introduction provide sufficient background and include all relevant references?

I have made considerable revisions to my introduction. I have added additional information on the pathophysiology of radiation-induced cystitis in likes 56-61. I have added an additional paragraph on the proposed mechanism of HBO2 and the potential adverse effects of HBO2.

2. Is the research design appropriate?

I have not made any changes to the research design, but have elaborated on several parts. In the methods section, I have included the usual protocol at our institution for patients being offered HBO2 in lines 96-99. I have also included more detail on the way the HBO2 is administered and the duration. I have included our definition of patients "not responding" and being excluded in lines 108-109. I have elaborated on the scoring system in line 112 and when the electronic medical records were used in lines 113-114.

3. Are the methods adequately described?

I have explained in the previous question the additions I have made to clearly outline the research design structure. This has also improved the description of the methods.

4. Are the results clearly presented?

I have spent considerable time improving the way I have presented the results. I have ensured that the numbers are consistent in the abstract, main text and table in the way they are presented. I have added the additional data with regards to the other symptoms the patients experienced and included this in figure 2, which provides more evidence of the benefit from HBO2 for this cohort. I have edited my table to include more of the presented data. I have explained more clearly in the paragraph what the percentages are in lines 192-196. I have included confidence intervals in all the data presented.

5. Are the conclusions supported by the results?

Yes. The results have shown a clear clinical benefit from the patient-reported outcomes which is stated in the results.

6. Are all the figures and tables clear and well-presented?

I have improved my table to include more of the data in the results and corrected some of the minor errors. I have included a second figure regarding the symptoms patients experienced pre- and post-HBO2.

Specific comments:

Comment 1: It should be clearly stated in the title or in the abstract that the study is a retrospective cohort study.

Response 1: Thank you for your comment. I have changed line 15 to include that it is a retrospective study. It now reads: "A retrospective cohort study of all consecutive patients who underwent hyperbaric oxygen therapy (HBOT) for radiation cystitis in South Australia from September 2017 – March 20 23 was performed."

Comment 2: The numbers presented in the abstract differ from the ones in the result section (e.g. "79 patients underwent HBOT" (row 20), "There were 89 patients who underwent HBOT" (row 93) and Table 1 "Underwent HBOT n=54 (row 102).

Response 2: Thank you for noting this error. It was 89 total and I have corrected this in line 21. I have changed the table to state that it only includes the 54 patients who completed the questionnaire in line 138.

Comment 3: Use and define the same expression for a specific group of patients. The expressions “included in the study” and “underwent HBOT” are not clearly defined and seem to refer to the same population in the manuscript, but the groups differ in size in the manuscript.

Response 3: We agree with this comment. The initial cohort of 89 patients that had hyperbaric therapy were screened, and only those that completed the questionnaire were included in the study. We have clarified this in the introduction section and the results section. I have also mentioned in the methods that patients are excluded from the study if they did not complete the questionnaire in lines 114-115.

Comment 4: Only percent (%) is presented and n= is lacking in the abstract for some results. It is unclear if the number 89, 79 or 54 has been used as the devisor to calculate the %. I suggest writing “X of Y patients (Z%)…” to make it clearer.

Response 4: My apologies for the confusion. I only included the 54 patients who completed the questionnaire in the statistical analysis, hence there is no missing data.

Comment 5: Missing data is not accounted for. It says on row 83 “Patients were excluded from the study if they did not complete the questionnaire”. As I understand it, all 89 patients who underwent HBOT during the period studies were included in the study. There were 13 dead patients, and 22 patients had missing data (no response). There’s no perfect solution for missing data, so maximizing data collection is crucial and the efforts to do so should be clearly explained. You have used the most common method—complete case analysis—which excludes all incomplete records. This works if few data points are missing, but when many are, it can significantly reduce the dataset and weaken statistical power. The latter is the case here and it would be appropriate to use a method for handling missing data or at least explain why this wasn’t done in the discussion and give the reasons behind this decision.

Response 5: Thanks to the reviewer for this insightful comment. We agree that the missing data is a limitation of this study, but unfortunately these patients were not available for discussion. As the focus of our study was on quality of life, we only performed a complete case analysis. We acknowledge that this introduces an element of selection bias to our study, and that future prospective studies are required to further validate our findings. We have added a sentence to the discussion detailing this limitation and identifying how this could be addressed in future work. This is reflected in lines 263-268 of the discussion in the statement "There are several limitations to this study. Unfortunately, of the 89 patients who underwent HBO2, only 54 patients completed the questionnaire, which was either due to the patient having passed away or being unable to get in contact with the patient. We acknowledge that this may introduce a degree of selection bias to our study, but we believe the data we have provided on quality of life is a valuable addition to the literature, nonetheless."

Comment 6: Row 15 The abbreviation HBOT is introduced in the abstract without explanation. Also, consider using HBO2 as this is the abbreviation recommended by UHMS.

Response 6: Thank you. I have rectified this and changed the acronym.

Comment 7: Row 21 It says "95% were male. 94%... for prostate cancer" in the abstract, but in the results (row 96) it says that all male patients had prostate cancer. Please check and correct.

Response 7: Thank you for this. I can see how this is confusing. I have changed the abstract in lines 21-25. It states initially there are 89 patients but only 54 completed the questionnaire. The median age and gender is on the 54 included patients. It now includes the comment "For those completing the questionnaire" in lines 23-24.

Comment 8: Row 21 "Median age was 74 (69-78)" it would be helpful to write what 69-78 is IQR i.e., 74 (IQR 69-78).

Response 8: Thank you I have made this change.

Comment 9: Row 25-27 P-values are given for reduction in GP- and ER-visits and transfusions but no numbers. Please include the underlying data for these p-value calculations. Also, 95% CI (Confidence interval) should normally be calculated and presented to show precision. This applies to all p-values calculated in the manuscript. (e.g. "The mean systolic blood pressure decreased by 12.3 mmHg (95% CI: 9.1 to 15.5 mmHg, p < 0.001) after treatment.")

Response 9: Thank you for this. I have made some major changes in the way I have presented my results. I have included the average numbers and the total mean reduction with a 95% confidence interval for all the results in the abstract and in the main text.

Comment 10: Row 27 "18 patients (42%)" reported ongoing haematuria. Where does the 42% come from? This is a relatively high number of "non-responders" with sustained haematuria - I think it deserves a comment in the discussion section.

Response 10: Thank you for pointing this out. It has been changed to 39% and explained it is 21 of the 54 included. I have added to the discussion that a"partial response" was experienced by 13% of the patients as they did not require any further intervention. This can be found in lines 200-206.

Comment 11: Row 29-30: "No patients reported any severe or ongoing adverse effects". I presume this statement is related to HBO-treatment. Was this data collected from patient records or during the interview?

Response 11: Thank you I have added to this sentence to explain this in row 33.

Comment 12: Row 41 "surround" -> surrounding? and "the bladder" -> the urine bladder?

Response 12: Thank you I have rectified this.

Comment 13: Please be consistent and use the same expression in the manuscript. Row 41 "radiation cystitis", row 63 "radiation-cystitis" row 68 "radiation-induced cystitis".

Response 13: Thank you I have fixed this throughout the paper so it consistently says "radiation cystitis"

Comment 14: Row 42 urologists not Urologists?

Response 14: Thank you. I have changed this.

Comment 15: Row 48-51: Explains the cause of radiation cystitis; endarteritis and ischemia. I would like to see an expansion of this section, chronic inflammation, fibrosis and neurological dysfunction are also part of the condition and should be mentioned.

Response 15: Thank you. I have added more detail for the pathophysiology of radiation cystitis in lines 56-61.

Comment 16: The introduction lacks explanation as to why HBO2 would be effective. I would like to se a paragraph explaining the rational for using HBO2 for radiation cystitis.

Response 16: Thank you for this. I agree this adds to the context for the introduction. I have included a paragraph in lines 70-75.

Comment 17: Row 73-75 It could be clarified that the treatment includes breathing 100% oxygen and with what frequency the treatment was given (once daily Mo-Fr?).

Response 17: Thank you I have amended this in lines 99-103.

Comment 18: Row 74 Use the SI-unit for pressure, (kPa) and not meters of seawater.

Response 18: Thank you I have changed this to the correct SI unit.

Comment 19: Row 76-79 It says that time from radiation to HBO2 was collected, but no such data is presented.

Response 19: Thank you. I have added this to my results and included it in my table.

Comment 20: Row 79 It says that "complications of HBOT was determined using the electronical medical records. on Row 121-124 complications are reported but is in unclear if the data presented are from the medical records or from the interview or both.

Response 20: Thank you, I can see how this is not presented clearly. I have removed this statement from row 79 that it was taken from the medical records. Below, I have mentioned that patients were asked if they required any additional treatments. In addition to this, we reviewed the medical records to determine if there was any additional treatment required. I have stated this in rows 113-114.

Comment 21: Row 90 It says that patient consent was collected, but on row 196 it says that there was no informed consent. Which is true?

Response 21: Thank you for this comment. Consent was obtained over the phone at the time of the questionnaire. We have amended line 307-308 to address this, this line now reads: "Informed Consent: Formal consent was obtained over the phone at the time the interview was performed."

Comment 22: Row 96: here the median age is reported (and IQR written out) with one decimal, but in the abstract and in the table, it is without decimals. Please be consistent.

Response 22: Thank you I have amended this so that all data is presented to two significant figures.

Comment 23: Row 95 22 patients were unable to contact - it could be better described in the methods how many times you tried to reach the patients. Missing data is a huge thing in a retrospective study and must be addressed appropriately.

Response 23: Thank you. I have added a comment on this in line 108-109.

Comment 24: Row 93 54 patients completed the questionnaire of total 89, and alive 76 (13 dead):
In the abstract row 22-23 it says 53% of the total cohort and 63% of the survivals completed the questionnaire. But 54 of 89 is 61% and 54 of 76 is 71%. Please check and correct.

Response 24: Thank you. I have corrected this in the abstract and included this line in my results.

Comment 25: Row 103-106 The results are presented in a confusing way "median 8/10 (IQR 7/10-10/10)". I suggest making it clear in text that the scale was from 0-10 (?) and present data like this: "median 8 (IQR 7-10)".

Response 25: Thank you. I have added a line in methods explaining this in line 112. I have edited the results as suggested in lines 140-143.

Comment 26: Row 110-115 The value given for number of visits to GP and ER lacks time frame and are hard or impossible to evaluate. It would have been much more informative to know how many visits per year. It is likely that the timeframe is different before HBO and after HBO which makes the numbers confusing.

Response 26: Yes that is a great point. My justification for this is that what I was trying to demonstrate here was the total impact on the healthcare system from radiation cystitis. It would be reasonable to presume that the time of developing symptoms and presenting to the GP and ED would be leading into commencing HBO2. As it was determined from patient-reported outcomes, specific timeframes were difficult. I do have the total time from completing HBO2 and doing the questionnaire, which was 574 days. We acknowledge this is a limitation of our study, but the low total number of GP and ED visits after HBO2 seems to demonstrate a positive response. I have added a statement in my limitations regarding this point in lines 275-283 "It would have also been useful to include a consistent timeframe for the pre and post HBO2 patient-reported outcomes on their GP and ED visits. This is an inherent limitation of the retrospective nature of our study and could be addressed in future by having pre-defined time points to complete the questionnaire. This was included as it was assumed the development of symptoms from radiation cystitis would lead into commencing HBO2 at a reasonably similar timeframe to the duration of time to complete the questionnaire, which was 574 days. The low number of GP and ED visits after HBO2 seems to demonstrate a positive response over a clinically significant period of time."

Comment 27: Row 110-118 Median values don't say much with this data. How many blood transfusions were given before HBO and how many after. How many patients required transfusions before and after? Was there any reduction after HBO?

Response 27: Thank you I have removed the median numbers. I have included the total number of patients requiring transfusions and how many total transfusions given before and afterwards in row 155-156. In an earlier comment, I have also added the mean reduction.

Comment 28: Row 126-130 It says 21 patients reported ongoing haematuria following HBO. Was this ongoing at the interview or was it at one or several occasions after HBO? Is it correct that only 9% (=4?) patients received additional HBO after the first treatment even though 21 patients had reoccurring haematuria? If so, why didn't more patients receive additional HBO? This might be commented on in the discussion.

Response 28: Thank you. This was patients reporting they had intermittent haematuria, so I have added the word 'intermittent' in line 165. I have restructured the results in lines 192-196 so that it more clearly states what the percentages are. It now reads "Five patients had further HBO2 (9%), two had fulguration (4%), three had formalization of the bladder (6%), two had prostatic artery embolization (4%) and give had urinary diversion (9%)." I have also explained that two patients received multiple additional treatments to account for the 17 total additional treatments for 14 total patients. In the discussion section, I had already added the comments about a partial response on a previous comment. I have added in lines 200-206 a comment on the patients who required further treatment which reads: "However, it is important to note that there were seven patients (13%) that did not require any further treatment despite having haematuria, which can be considered a partial response. A partial response rate is still clinically significant for patients if they can avoid using the healthcare system and having more invasive treatment. For patients with significant symptoms after HBO2, a decision as to which further treatment was done would have been decided by the patient and the treating clinician, which was to have further HBO2 in four of the patients."

Comment 29: One of the major limitations of this study is that pre-HBO and post-HBO values were collected at the same time (post HBO). Although it is mentioned, it is not adequately addressed in the discussion.

Response 29: Thanks for this comment. We agree that this is a limitation, and have expanded on this in the discussion in lines 285-286 by saying "The fact that pre-HBO2 and post HBO2 questionnaires were performed at the same time introduces an element of recall bias that could confound the findings of this study."

Comment 30: A lot of space is used to discuss the different scales used to assess effects of HBOT on radiation cystitis. It is said (row 155) that this is a key reason for the heterogeneity of outcomes. I’m not so sure that this is true. There are other reasons for heterogeneity such as demographics, radiation dose, time from radiation to HBO, different HBO-protocols, etc that might be more relevant in the explanation of heterogeneity of results. However, EPIC and SOMA/LENT are validated instruments that have been used in numerous of studies on cystitis (not only including HBO). So, I humbly ask, why did you choose to invent a new score when you (on row 166) point out that a more standardised questionnaire would be better. Can you explain why you didn't use any of the validated tools in the discussion?

Response 30: Thank you for this relevant comment. We agree that further justification for the choice of our questionnaire is required. We made this decision consciously in order to focus on patient centred quality of life outcomes and an assessment of healthcare utilisation. We have therefore added the following paragraph to the discussion in lines 257-262: "Our decision not to use a previously described scoring system was driven by our focus on quality of life and patient centred satisfaction, which we thought was a significant factor that had not previously been thoroughly investigated. Our questionnaire also included a focus on health care utilization in the form of GP and ED visits, which is a novel outcome measure in the setting of radiation cystitis." I have also added a line in the paragraph above in lines 224-226 regarding the other possible factors that may be causing the heterogeneity of results in the other studies: "The heterogeneity may also be attributed to different radiotherapy target zones, radiotherapy dosage, variable HBO2 regimes and timing of administration of HBO2."

Comment 31: Row 208-240 The questionnaire includes question on what symptoms patients experienced (Haematuria, dysuria, frequency and pain), I can’t see that these results are presented.

Response 31: Thank you, this is a great point. I initially did not include it as the main symptoms that patients spoke about was haematuria, but I do agree that it should be included in the paper. I have changed all my comments on "severity of haematuria" to "severity of symptoms" in the paper, which is a more accurate decription. I have included the numerical data in the results for each of these symptoms in lines 143-146. I have also constructed a bar graph for each of these symptoms (Figure 2).

Comments on the quality fo the English language:

I have addressed the points made below regarding the English in the paper. I have ensured that my expression is consistent. "Radiation cystitis" is the only term used in the paper now. I have explained all abbreviations including the Australian terms that are not known internationally like "GP" and "ED". I have changed to the correct SI units. I have avoided the terms like "very" in the paper unless they are appropriate.

Thank you again for all your wonderful feedback.

Reviewer 2 Report

Comments and Suggestions for Authors

see file

Comments for author File: Comments.pdf

Comments on the Quality of English Language

just minor editting

Author Response

Thank you very much for your feedback. We are very appreciative of your efforts. We have made some major changes to the manuscript from your comments and the other reviewers comments which we believe has improved the strength and quality of this paper. We have improved the English throughout. We have addressed the questions for general evaluation, specific comments and the comment on the quality of English language below. We have made my changes in red so they can easily be identified and specified the relevant changed lines for the corresponding comments below.

Questions for general evaluation:

1. Does the introduction provide sufficient background and include all relevant references?

2. Is the research design appropriate?

3. Are the methods adequately described?

I have explained in the previous question the additions I have made to clearly outline the research design structure. This has also improved the description of the methods.

4. Are the results clearly presented?

5. Are the conclusions supported by the results?

Yes. The results have shown a clear clinical benefit from the patient-reported outcomes which is stated in the results.

6. Are all the figures and tables clear and well-presented?

Specific comments:

I agree that the addition of controls would strengthen the results. I have added to my discussion a comment on how a different study design in the future can be done to evaluate these outcomes in lines 291-296.

With regards to the first comment, I have said in my introduction what the incidence is in the literature. For this population, the patients were found by reviewing who has received HBO2 at our institution. Of the 89 patients who had HBO2, the radiotherapy was given at different institutions over the country as either public or private patients. Therefore, it is difficult to determine the total number of patients who received radiotherapy, hence the incidence of radiation-cystitis in this population is not known. There are also many patients who would choose to have other forms of treatment that HBO2, hence would not be captured in this study. We assessed the severity of symptoms prior to HBO2 retrospectively, which we have acknowledged as a limitation in this study in row 285-286. I have specially stated that this should be done prior to HBO2 in our prospective study design in lines 294-295.

With regards to the second comment, I have expanded on my introduction to include more detail about radiation-cystitis. I have added information on the pathophysiology and explained the expected natural history of radiation cystitis without treatment, in lines 56-61 and 70-75. I have also added the potential adverse effects of HBO2 in lines 76-82.

With regards to the third comment, this is an excellent point. In the literature, there is no established acceptable level of radiation cystitis. I have added to my discussion the different potential outcomes of HBO2, including a complete response, partial response and no response. The addition of the population who have a 'partial response' is an interesting group. Whilst not all patients have complete resolution of their symptoms, the reduction in healthcare utilisation and need for anymore invasive treatments is clinically significant. I have added to my discussion that we feel that a reduction in healthcare utilisation, symptoms and anxiety is a significant response. As there is no follow-up investigation that objectively demonstrates that the treatment has worked, we felt a subjective response was more appropriate and clinically significant for practice. This new paragraph is in lines 200-206. I have addressed this comment further in lines 235-241. I have explained that it is difficult to determine the exact degree of physiological response from HBO2, which is why we decided to use a patient-centred subjective scoring system.

I have extended the final paragraph of the discussion to include a prospective study design. I have discussed the implementation of a double-blind crossover study with questionnaires being completed prior and after each treatment. This is in lines 291-296.

Comments on the quality of the English language:

We have made several corrections throughout.

Thank you again for your feedback.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Author

This is a retrospective manuscript about outcomes of hyperbaric oxygen therapy for haematuria due to radiation cystitis secondary to external beam radiotherapy for pelvic malignancy.

1: There are a number of serious errors in the text that need to be corrected. For example, sentences begin with numbers, which should be written in letters.

2: The study methodology and how hyperbaric oxygen was used were not clearly explained.

3: No underlying diseases or surgical history of the patients were reported.

Author Response

Questions for general evaluation:

1. Does the introduction provide sufficient background and include all relevant references?

2. Is the research design appropriate?

3. Are the methods adequately described?

I have explained in the previous question the additions I have made to clearly outline the research design structure. This has also improved the description of the methods.

4. Are the results clearly presented?

5. Are the conclusions supported by the results?

Yes. The results have shown a clear clinical benefit from the patient-reported outcomes which is stated in the results.

6. Are all the figures and tables clear and well-presented?

Specific comments:

Comment 1: There are a number of serious errors in the text that need to be corrected. For example, sentences begin with numbers, which should be written in letters.

Response 1: I have correct all the grammatical errors in the paper. I have reworded several sentences and paragraphs to improve the flow of the paper also.

Comment 2: The study methodology and how hyperbaric oxygen was used were not clearly explained.

Response 2: Thank you for this comment. I agree that the methods was not clearly explained. I have made a number of changes to make the methods section clearer. I have changed lines 88-91 to explain clearly how the HBO2 was administered, which now reads: "Patients in our cohort were all treated with reference to the same protocol which provides for 40 sessions of hyperbaric therapy at 100% oxygen at 10-90-30 meaning 90 minutes of treatment at a pressure of 100.7kPa with 30 minutes of subsequent decompression. The 40 sessions were administered for eight weeks from Monday to Friday."

Additionally, I have made some changes to explain the process of calling patients. I have included the statement "Patients were contacted twice on two separate occasions and were excluded if they did not respond" in lines 97-98. I have described how the symptom severity and anxiety score was used. I have also included that at our institution what is done prior to offering HBO2.

Comment 3: No underlying diseases or surgical history of the patients were reported.

Response 3: Thank you for this point. Unfortunately, this was a difficult issue for us. This patient cohort was determined by looking at patients who received HBO2 at our institution for radiation-cystitis. Unfortunately, we found that the majority of patients had not received their radiotherapy at our institution. For many of the patients, they had received their radiotherapy in the private setting (our institution is a public hospital), and often this was done interstate as well. The vast majority did not have available data so we decided to not include this. I have added this as a limitation to the study in the discussion in lines 268-271.

Comments on the quality of English language:

We have made corrections throughout the paper.

Thank you again for your input.

Reviewer 4 Report

Comments and Suggestions for Authors

This study investigates the long-term analysis of hyperbaric oxygen therapy for hematuria, which is a very interesting topic because hematuria after radiotherapy is a thorny issue without a good treatment plan. To provide a reference for clinical practice, the following problems exist：

1.How did the patient in Figure1 evaluate the degree of hematuria and the degree of anxiety? The method needs to be described clearly.

Is hyperbaric oxygen alone used for the patient with hematuria? Have any other treatment plans been used? It needs to be described clearly.
Did the patient develop any other complications during radiotherapy for PCa and other treatments? Besides hematuria, was there an intestinal fistula? Bladder fistula? The text needs to be described clearly.

Author Response

Thank you very much for your feedback. We are very appreciative of your input. We have made some major changes to the manuscript from your comments and the other reviewers comments which we believe has improved the strength and quality of this paper. We have improved the English throughout. We have addressed the questions for general evaluation, specific comments and the comment on the quality of English language below. We have made my changes in red so they can easily be identified and specified the relevant changed lines for the corresponding comments below.

Questions for general evaluation:

1. Does the introduction provide sufficient background and include all relevant references?

2. Is the research design appropriate?

3. Are the methods adequately described?

I have explained in the previous question the additions I have made to clearly outline the research design structure. This has also improved the description of the methods.

4. Are the results clearly presented?

5. Are the conclusions supported by the results?

Yes. The results have shown a clear clinical benefit from the patient-reported outcomes which is stated in the results.

6. Are all the figures and tables clear and well-presented?

Specific comments:

Comment 1: How did the patient in Figure1 evaluate the degree of hematuria and the degree of anxiety? The method needs to be described clearly.

Response 1: Thank you for this comment. I have added an explanation in my methods section in rows 108-109. During the questionnaire, we asked patients to subjectively rate their symptom severity on a score of 1-10. This figure is a graphical representation of the scores given pre and post HBO2 therapy.

Comment 2: Is hyperbaric oxygen alone used for the patient with hematuria? Have any other treatment plans been used? It needs to be described clearly.

Response 2: Thank you for this comment. In the introduction (lines 62-65), I described some of the other treatment options available. I have acknowledged there is no agreed upon algorithm. In the methods section, I have added what is done at our institution in lines 95-98 which reads: "At our institution, prior to being offered HBO2, all patients underwent clinical evaluation with a triple-phase CT scan and cystoscopy to exclude any other cause of haematuria. If no other cause was found and symptoms due to radiation-cystitis were persistent, patients were offered HBO2."

Comment 3: Did the patient develop any other complications during radiotherapy for PCa and other treatments? Besides hematuria, was there an intestinal fistula? Bladder fistula? The text needs to be described clearly.

Comments on the quality of the English language:

We have made several corrections throughout.

Thank you again for your feedback.

Reviewer 5 Report

Comments and Suggestions for Authors

Dear authors

Thanks for your submission. I read your manuscript and have some suggestions and questions.

1- add a paragraph to your introduction and mention the side effects of HBOT.

2- some mentioned percentages in abstract and manuscript are different.please correct them.

3- as you said at the end of your manuscript, this study had some big limitations that diminish the value of your study, please bold the strengths of your work.

Comments on the Quality of English Language

The manuscript should be reviewed by a native English speaker.

Author Response

Questions for general evaluation:

1. Does the introduction provide sufficient background and include all relevant references?

2. Is the research design appropriate?

3. Are the methods adequately described?

I have explained in the previous question the additions I have made to clearly outline the research design structure. This has also improved the description of the methods.

4. Are the results clearly presented?

5. Are the conclusions supported by the results?

Yes. The results have shown a clear clinical benefit from the patient-reported outcomes which is stated in the results.

6. Are all the figures and tables clear and well-presented?

Specific comments:

Comment 1: Add a paragraph to your introduction and mention the side effects of HBOT.

Response 1: Thank you. I agree that this adds more context and pertinent information for the paper. I have included a paragraph in lines 76-82 describing the potential side effects. This paragraph is included after another paragraph I have added which goes into more detail about how HBO2 treats radiation-induced damage.

Comment 2: Some mentioned percentages in abstract and manuscript are different.please correct them.

Response 2: Thank you I have corrected these. I have made major revisions of how I present my results. I have included more data and improved my table.

Comment 3: As you said at the end of your manuscript, this study had some big limitations that diminish the value of your study, please bold the strengths of your work.

Response 3: Thank you for this comment. I have made several changes to highlight the clinical significance of this paper. I have added multiple paragraphs in the discussion to detail this. Firstly, we have discussed how our paper provides valuable insights into clinically significant outcomes following HBO2. These include specific data on the burden of haematuria and the burden of anxiety. Secondly, we have placed this in the context of reduced health care utilisation by demonstrating how this therapy results in lower numbers of GP and ED visits following implementation of this therapy. Finally, though there are limitations, we present a reasonably large cohort of patients who have had HBO2 in the setting of radiation cystitis, helping to establish a robust evidence base that can be referenced in the future by practitioners considering this therapy, with our data facilitating informed consent discussions with these patients.

I have addressed this specifically with the additional paragraph in lines 235-241 and 257-262.

Comments on the quality of the English language:

We have made several corrections throughout.

Thank you again for your feedback.