Personalized Prehabilitation Improves Tolerance to Chemotherapy in Patients with Oesophageal Cancer

Round 1

Reviewer 1 Report

It is a  well organized study addressing the beneficial effect of the incorporation of a rehabilitation program in advance of a chemotherapy course. The metabolic dysregulations of chemotherapy seems to be prevented somehow from exercise. However I have some concerns that follow:

Comment 1: You state in the discussion section about a similar project that was carried out in England and published (reference 18) and thus I am wondering why to have an analogous project presented. You have used in your study retrospective observatory methods for data collection and we need information about the effect of the rehab program in the causative mechanisms of the adverse reactions of the chemotherapy that may lead to a diminished quality of life. Thus in order your work not to match to the previous published I would suggest to include in your manuscript results chapter all relevant statistical evaluations  in regard of the rehab effect on eventual functional specific impairments or demographic parameters that may influence the completion or not of the chemotherapy course. These are factors either related to the disease or to chemotherapy as an adverse reaction that the rehab program successfully intervened.

Comment 2: The study participation is very low for safe conclusions and the power of the study calculations are not referred anywhere in the text. Thus I recommend to the authors to comment it in the limitations of the study.

Comment 3: In lines 67-68 I feel that something is missing in the sentence.

Author Response

Comment: It is a  well organized study addressing the beneficial effect of the incorporation of a rehabilitation program in advance of a chemotherapy course. The metabolic dysregulations of chemotherapy seems to be prevented somehow from exercise. However I have some concerns that follow:

Authors’ response: We would like to thank the reviewer for their comments.

Comment 1: You state in the discussion section about a similar project that was carried out in England and published (reference 18) and thus I am wondering why to have an analogous project presented. You have used in your study retrospective observatory methods for data collection and we need information about the effect of the rehab program in the causative mechanisms of the adverse reactions of the chemotherapy that may lead to a diminished quality of life. Thus in order your work not to match to the previous published I would suggest to include in your manuscript results chapter all relevant statistical evaluations  in regard of the rehab effect on eventual functional specific impairments or demographic parameters that may influence the completion or not of the chemotherapy course. These are factors either related to the disease or to chemotherapy as an adverse reaction that the rehab program successfully intervened.

Authors’ response: Thank you for the comments.

Ref 18 is important because it corroborates our finding of increased tolerance to neo-adjuvant chemotherapy in the prehabilitation group.

We have added further variables to the univariate and multivariate analysis in TABLE 3. In multivariate analysis, only prehabilitation was an independent factor associated with completion of chemotherapy. The findings are discussed in the results section.

Comment 2: The study participation is very low for safe conclusions and the power of the study calculations are not referred anywhere in the text. Thus I recommend to the authors to comment it in the limitations of the study. 

Authors’ response: This is recognised as a limitation in the discussion section.

Comment 3: In lines 67-68 I feel that something is missing in the sentence.

Authors’ response: We have edited these lines to make them clearer to read and understand.

Reviewer 2 Report

Well written manuscript addressing the effect of prehabilitation programmes on tolerance to chemotherapy. I only have few remarks

Introduction:

Please elaborate a bit in more detail on the Karnofsky score and prehabilitation programmes

Results

Whilst the chemotherapy using EOX and ECX is relatively similar between the vase and control group, "other" (table 1) can include a lot of things. Authors should make clear that their results are not influenced by large differences in treatment protocols. 

Discussion

Please elaborate a bit more on the limited sample size, and potential influences of two different institutes as case group and control group. Could this be a likely cause of bias?

Author Response

Comment: Well written manuscript addressing the effect of prehabilitation programmes on tolerance to chemotherapy. I only have few remarks

Authors’ response: We would like to thank the reviewer for their kind comments.

Comment: Introduction: Please elaborate a bit in more detail on the Karnofsky score and prehabilitation programmes

Authors’ response: In accordance to the above-mentioned comments, details on the Karnofsky score and prehabilitation programmes have been added to the Methods section.

Comment: Results Whilst the chemotherapy using EOX and ECX is relatively similar between the vase and control group, "other" (table 1) can include a lot of things. Authors should make clear that their results are not influenced by large differences in treatment protocols. 

Authors’ response: EOX and ECX were the most commonly used chemotherapy regimens. Both centres followed the same protocols. ‘Other’ includes FLOT and variations of EOX and ECX based on  individualization of therapy for clinical reasons for e.g. cardiac disease.

Comment: Discussion Please elaborate a bit more on the limited sample size, and potential influences of two different institutes as case group and control group. Could this be a likely cause of bias?

Authors’ response: This has been recognised as a limitation

Reviewer 3 Report

This manuscript describes the tolerance effect of prehabilitation on NAC in surgical esophageal patients, but I have some comments to the author.

Comment 1. P<0.05 is generally used in tests of statistical significance, and P<0.05 was also used in the previous report by the authors (cited ref. 17). But why is “P ≤ 0.05” used in this manuscript?

Comment 2. It is surprising that the control group, which originally showed a higher Karnofsky score, had a lower NAC tolerance. What was the Karnofsky score after NAC in both groups?

Comment 3. The authors say, “prehabilitation has a positive impact on the tolerance of NAC in oesophageal cancer patients,” but exclude patients such as those who failed to complete prehabilitation. Doesn't that mean we chose better patients during NAC?

Comment 4. I don't quite understand Table 3. Why is "Standard error" emphasized? What is the confidence interval for "95% C.I."? Is it the confidence interval for the standard error? ? ?

If you show the results of multiple logistic regression analysis, wouldn't it be easier to understand if you show the odds ratio and its 95% C.I.?

Comment 5. The description on Page 4 “…acute renal failure (2 patients, 2%) and cardiovascular events (1 patient, 1%)” does not have a period, but does this sentence end here?

Comment 6. Based on these results, I think it would be simplistic to conclude that the presence or absence of prehabilitation alone affects the NAC completion rate. I think that the factors included in prehabilitation should be examined in more detail.

Author Response

This manuscript describes the tolerance effect of prehabilitation on NAC in surgical esophageal patients, but I have some comments to the author.

Comment 1. P<0.05 is generally used in tests of statistical significance, and P<0.05 was also used in the previous report by the authors (cited ref. 17). But why is “P ≤ 0.05” used in this manuscript?

Authors’ response: A p-value <0.05 is considered as a statistically significant result. We apologise for the typo.

Comment 2. It is surprising that the control group, which originally showed a higher Karnofsky score, had a lower NAC tolerance. What was the Karnofsky score after NAC in both groups?

Authors’ response: As per routine clinical practice, Karnofsky score is only assessed at the beginning as part of the treatment eligibility assessment process.

Comment 3. The authors say, “prehabilitation has a positive impact on the tolerance of NAC in oesophageal cancer patients,” but exclude patients such as those who failed to complete prehabilitation. Doesn't that mean we chose better patients during NAC?

 Authors’ response: Figure 1 depicts the flowchart of the present study. Only patients that were lost to follow-up or experienced a disease progression were excluded from the present study. As per the study protocol, we only included patients who went on to have surgery and thus completed the whole treatment pathway. Patients who were excluded were the ones where prehabilitation was stopped due to the change in treatment pathway due to disease progression.

Comment 4. I don't quite understand Table 3. Why is "Standard error" emphasized? What is the confidence interval for "95% C.I."? Is it the confidence interval for the standard error? ? ?

If you show the results of multiple logistic regression analysis, wouldn't it be easier to understand if you show the odds ratio and its 95% C.I.?

Authors’ response: Table 3 has been modified. We have used 95% C.I. now

Comment 5. The description on Page 4 “…acute renal failure (2 patients, 2%) and cardiovascular events (1 patient, 1%)” does not have a period, but does this sentence end here?

Authors’ response: amendment made

Comment 6. Based on these results, I think it would be simplistic to conclude that the presence or absence of prehabilitation alone affects the NAC completion rate. I think that the factors included in prehabilitation should be examined in more detail.

Authors’ response: In response to this, we have now included univariate analysis of several variables that can affect the completion of chemotherapy in TABLE 3. On multivariate analysis, prehabilitation was the only independent factor associated with completion of chemotherapy. The findings are discussing in the Results section.

Round 2

Reviewer 3 Report

I feel like I didn't get enough answers to my previous comments, so I'll comment again.

Comment 1. The authors state that “prehabilitation has a positive impact on her NAC tolerance in patients with esophageal cancer,” but exclude patients such as those who failed to complete prehabilitation. It was said that patients whose treatment route was changed due to disease progression were included in that, but if you add these 8 patients who dropped out to the prelihabilitation group 47 patients, it will be a total of 55 patients. Eight out of 55 (14.5%) dropped out, but I find it strange that the author states, “prehabilitation has a positive impact on the tolerance of NAC in oesophageal cancer patients,”

Comment 2. The author said that Table 3 was revised, but why is "standard error" emphasized? Isn't it easier? Incidentally, the authors' previous paper (reference 17) shows the odds ratio and its 95% CI.

Author Response

Comment 1. The authors state that “prehabilitation has a positive impact on her NAC tolerance in patients with esophageal cancer,” but exclude patients such as those who failed to complete prehabilitation. It was said that patients whose treatment route was changed due to disease progression were included in that, but if you add these 8 patients who dropped out to the prelihabilitation group 47 patients, it will be a total of 55 patients. Eight out of 55 (14.5%) dropped out, but I find it strange that the author states, “prehabilitation has a positive impact on the tolerance of NAC in oesophageal cancer patients,”

Author response- Just to clarify, these patients did not drop out of the prehabilitation programme. The programme was intentionally withdrawn when their treatment plan was changed due to disease progression. This is for a number of reasons. Firstly, patients are in a different state of mind when their treatment plan is changed. Secondly, some of them would have been admitted due to worsening symptoms due to disease progression. There are always some patients who will progress during chemotherapy. In these patients the disease burden is probably so high to start with that prehabilitation is unlikely to impact on cancer progression. The primary aim of this study is tolerance to neo-adjuvant chemotherapy.

We have reported our results according to the study protocol, which stated that we only included those patients who completed the entire treatment pathway consisting of neo-adjuvant chemotherapy followed by surgery. We did not include the 8 patients because their programme was intentionally stopped. They did not voluntarily drop out.

Our statement “prehabilitation has a positive impact on the tolerance of NAC in oesophageal cancer patients,” is based on the findings of the impact of prehabilitation on the primary study outcome- ‘completion of the full chemotherapy/chemoradiotherapy course as per protocol’.

Comment 2. The author said that Table 3 was revised, but why is "standard error" emphasized? Isn't it easier? Incidentally, the authors' previous paper (reference 17) shows the odds ratio and its 95% CI.

Author response- In table 3 standard error column has been replaced by Odds Ratio as suggested.

Author Response File: Author Response.docx

Round 3

Reviewer 3 Report

Thank you for sending the revised manuscript. I saw the manuscript of the 3rd. revised version. I think the Table 3 has been corrected enough.