Reviewer ’s report  
 
Title:  The effects of prehabilitation versus usual care to reduce postoperative complications in 
high-risk patients with colorectal cancer or dysplasia scheduled for elective colorectal resection: 
study protocol of a r andomized controlled trial  
 
Version: 0 Date: 13 Nov 2017 
 
Reviewer:  Emer  Guinan  
 
Reviewer’s report:  
 
This manuscript describes the protocol for a prehabilitative exercise intervention for patients 
scheduled for colorectal surgery which aims to reduc e incidence of postoperative complications. 
The topic of the manuscript is extremely important in an era of enhanced recovery after surgery 
and increasing focus on the role of exercise prehabilitation to optimise postoperative outcomes.  
 
 
Introduction:  
 
The authors provide a nice overview of the purpose of exercise prehabilitation and cite various 
literature. It would be useful for the authors to describe the challenges of exercise prehabilitation, 
typically related to the short timeframe between diagnosis a nd surgery and how the intervention 
that they propose fits with the current clinical pathway in the Netherlands. The introduction 
should be reviewed for grammatical errors and correct use of terms. For example in paragraph 1, 
line 11 the authors use the te rm 'psychophysiological' which I do not think was intended here.  
 
 
Methods:  
 
The authors aim to reduce incidence of postoperative complications from 50% to 20%, measured 
using the Clavien -Dindo classification. In their sample size calculation, the authors  state that 
current postoperative morbidity post colorectal surgery is 33% but then anticipate a complication 
rate of 50% in the control group. Looking at the publication by Dunne et al., (Reference 28 - 
conference abstract), Dunne et al report preoperativ e improvements in cardiorespiratory fitness 
but do not mention postoperative complication rates. This section needs to be rechecked. 
Furthermore, the reported sample size appears small in comparison with other published work. 
For example the ongoing PREPAR E-ABC trial (SupPoRtive Exercise Programs for Accelerating 
REcovery after major ABdominal Cancer surgery) estimate that they will require 1146 patients  
to detect a 25% reduction in post -operative complications from 55% with exercise 
prehabilitation. The a uthors should double -check the basis for the sample size calculation and 
justify more clearly in the methods section.  
 
The first objective aims to assess changes in preoperative fitness occur with the intervention. It 
should be noted that preoperative fit ness will be measured once in the control arm and twice in 
the intervention arm pre -operatively and therefore analysis of the data pertaining to this objective 
will be limited to a single -arm study design. The authors should justify why they do not repeat a 
pre-operative CPET in the control group pre -surgery in order to test by RCT if the intervention 
leads to an increase in pre -op fitness.  
 
Objective 3 states that patients with a VAT >11 mL/kg/min will not be randomised but will 
continue to be observed po stoperatively. The analysis of this question should be further 
explained in the methods. For example, do the authors plan to use baseline or post -intervention 
CPET data for the intervention group (as the intervention aims to increase fitness)?  
 
Objective 4 aims to investigate the value of a limited geriatric assessment to perform 
preoperative risk stratification. In the methods the authors outline a number of tools that will be 
used to evaluate geriatric assessment. From the methods it appears th at all of this tools will be 
completed at baseline only. Do the authors have concerns that examining baseline data as 
predictors of outcome may be confounded by the effects of the intervention? For example, would 
functional status as measured by the IADL b e influenced by increased aerobic fitness and 
muscular strength?  
 
Objective 5 states that a cost analysis will be completed. The authors describe use of the EQ -5D 
tool to examine health status which is often used in the evaluation of cost effectiveness ho wever 
do not describe other aspects of the cost analysis. This is an important aspect of the study, 
particularly in consideration that we hope for exercise prehabilitation studies to form part of 
standard of care for patients. The authors should include a discussion around the clinical 
feasibility of the proposed protocol in the context of existing clinical pathways.  
 
The exercise intervention described appears reasonable and should elicit therapeutic response. 
The authors propose a novel approach with hig h intensity interval aerobic exercise training, 
resistance exercise training and self -directed home exercise.  
 
Are the metho ds appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the man uscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
None  
 
I agree to the open peer review policy of the journal. I understand that my name will  be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available unde r an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as  confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Reviewer ’s report  
 
Title:  The effects of prehabilitation versus usual care to reduce postoperative complications in 
high-risk patients with colorectal cancer or dysplasia scheduled for elective colorectal resection: 
study protocol of a r andomized controlled trial  
 
Version: 0 Date: 13 Nov 2017 
 
Reviewer:  Emer  Guinan  
 
Reviewer’s report:  
 
This manuscript describes the protocol for a prehabilitative exercise intervention for patients 
scheduled for colorectal surgery which aims to reduc e incidence of postoperative complications. 
The topic of the manuscript is extremely important in an era of enhanced recovery after surgery 
and increasing focus on the role of exercise prehabilitation to optimise postoperative outcomes.  
 
 
Introduction:  
 
The authors provide a nice overview of the purpose of exercise prehabilitation and cite various 
literature. It would be useful for the authors to describe the challenges of exercise prehabilitation, 
typically related to the short timeframe between diagnosis a nd surgery and how the intervention 
that they propose fits with the current clinical pathway in the Netherlands. The introduction 
should be reviewed for grammatical errors and correct use of terms. For example in paragraph 1, 
line 11 the authors use the te rm 'psychophysiological' which I do not think was intended here.  
 
 
Methods:  
 
The authors aim to reduce incidence of postoperative complications from 50% to 20%, measured 
using the Clavien -Dindo classification. In their sample size calculation, the authors  state that 
current postoperative morbidity post colorectal surgery is 33% but then anticipate a complication 
rate of 50% in the control group. Looking at the publication by Dunne et al., (Reference 28 - 
conference abstract), Dunne et al report preoperativ e improvements in cardiorespiratory fitness 
but do not mention postoperative complication rates. This section needs to be rechecked. 
Furthermore, the reported sample size appears small in comparison with other published work. 
For example the ongoing PREPAR E-ABC trial (SupPoRtive Exercise Programs for Accelerating 
REcovery after major ABdominal Cancer surgery) estimate that they will require 1146 patients  
to detect a 25% reduction in post -operative complications from 55% with exercise 
prehabilitation. The a uthors should double -check the basis for the sample size calculation and 
justify more clearly in the methods section.  
 
The first objective aims to assess changes in preoperative fitness occur with the intervention. It 
should be noted that preoperative fit ness will be measured once in the control arm and twice in 
the intervention arm pre -operatively and therefore analysis of the data pertaining to this objective 
will be limited to a single -arm study design. The authors should justify why they do not repeat a 
pre-operative CPET in the control group pre -surgery in order to test by RCT if the intervention 
leads to an increase in pre -op fitness.  
 
Objective 3 states that patients with a VAT >11 mL/kg/min will not be randomised but will 
continue to be observed po stoperatively. The analysis of this question should be further 
explained in the methods. For example, do the authors plan to use baseline or post -intervention 
CPET data for the intervention group (as the intervention aims to increase fitness)?  
 
Objective 4 aims to investigate the value of a limited geriatric assessment to perform 
preoperative risk stratification. In the methods the authors outline a number of tools that will be 
used to evaluate geriatric assessment. From the methods it appears th at all of this tools will be 
completed at baseline only. Do the authors have concerns that examining baseline data as 
predictors of outcome may be confounded by the effects of the intervention? For example, would 
functional status as measured by the IADL b e influenced by increased aerobic fitness and 
muscular strength?  
 
Objective 5 states that a cost analysis will be completed. The authors describe use of the EQ -5D 
tool to examine health status which is often used in the evaluation of cost effectiveness ho wever 
do not describe other aspects of the cost analysis. This is an important aspect of the study, 
particularly in consideration that we hope for exercise prehabilitation studies to form part of 
standard of care for patients. The authors should include a discussion around the clinical 
feasibility of the proposed protocol in the context of existing clinical pathways.  
 
The exercise intervention described appears reasonable and should elicit therapeutic response. 
The authors propose a novel approach with hig h intensity interval aerobic exercise training, 
resistance exercise training and self -directed home exercise.  
 
Are the metho ds appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the man uscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
None  
 
I agree to the open peer review policy of the journal. I understand that my name will  be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available unde r an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as  confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
 
Title:  The effects of prehabilitation versus usual care to reduce postoperative complications in 
high-risk patients with colorectal cancer or dysplasia scheduled for elective colorectal resection: 
study protocol of a r andomized controlled trial  
 
Version: 0 Date: 13 Nov 2017 
 
Reviewer:  Emer  Guinan  
 
Reviewer’s report:  
 
This manuscript describes the protocol for a prehabilitative exercise intervention for patients 
scheduled for colorectal surgery which aims to reduc e incidence of postoperative complications. 
The topic of the manuscript is extremely important in an era of enhanced recovery after surgery 
and increasing focus on the role of exercise prehabilitation to optimise postoperative outcomes.  
 
 
Introduction:  
 
The authors provide a nice overview of the purpose of exercise prehabilitation and cite various 
literature. It would be useful for the authors to describe the challenges of exercise prehabilitation, 
typically related to the short timeframe between diagnosis a nd surgery and how the intervention 
that they propose fits with the current clinical pathway in the Netherlands. The introduction 
should be reviewed for grammatical errors and correct use of terms. For example in paragraph 1, 
line 11 the authors use the te rm 'psychophysiological' which I do not think was intended here.  
 
 
Methods:  
 
The authors aim to reduce incidence of postoperative complications from 50% to 20%, measured 
using the Clavien -Dindo classification. In their sample size calculation, the authors  state that 
current postoperative morbidity post colorectal surgery is 33% but then anticipate a complication 
rate of 50% in the control group. Looking at the publication by Dunne et al., (Reference 28 - 
conference abstract), Dunne et al report preoperativ e improvements in cardiorespiratory fitness 
but do not mention postoperative complication rates. This section needs to be rechecked. 
Furthermore, the reported sample size appears small in comparison with other published work. 
For example the ongoing PREPAR E-ABC trial (SupPoRtive Exercise Programs for Accelerating 
REcovery after major ABdominal Cancer surgery) estimate that they will require 1146 patients  
to detect a 25% reduction in post -operative complications from 55% with exercise 
prehabilitation. The a uthors should double -check the basis for the sample size calculation and 
justify more clearly in the methods section.  
 
The first objective aims to assess changes in preoperative fitness occur with the intervention. It 
should be noted that preoperative fit ness will be measured once in the control arm and twice in 
the intervention arm pre -operatively and therefore analysis of the data pertaining to this objective 
will be limited to a single -arm study design. The authors should justify why they do not repeat a 
pre-operative CPET in the control group pre -surgery in order to test by RCT if the intervention 
leads to an increase in pre -op fitness.  
 
Objective 3 states that patients with a VAT >11 mL/kg/min will not be randomised but will 
continue to be observed po stoperatively. The analysis of this question should be further 
explained in the methods. For example, do the authors plan to use baseline or post -intervention 
CPET data for the intervention group (as the intervention aims to increase fitness)?  
 
Objective 4 aims to investigate the value of a limited geriatric assessment to perform 
preoperative risk stratification. In the methods the authors outline a number of tools that will be 
used to evaluate geriatric assessment. From the methods it appears th at all of this tools will be 
completed at baseline only. Do the authors have concerns that examining baseline data as 
predictors of outcome may be confounded by the effects of the intervention? For example, would 
functional status as measured by the IADL b e influenced by increased aerobic fitness and 
muscular strength?  
 
Objective 5 states that a cost analysis will be completed. The authors describe use of the EQ -5D 
tool to examine health status which is often used in the evaluation of cost effectiveness ho wever 
do not describe other aspects of the cost analysis. This is an important aspect of the study, 
particularly in consideration that we hope for exercise prehabilitation studies to form part of 
standard of care for patients. The authors should include a discussion around the clinical 
feasibility of the proposed protocol in the context of existing clinical pathways.  
 
The exercise intervention described appears reasonable and should elicit therapeutic response. 
The authors propose a novel approach with hig h intensity interval aerobic exercise training, 
resistance exercise training and self -directed home exercise.  
 
Are the metho ds appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
Yes 
 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments to the authors.  
 
Yes 
 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
 
Unable to assess  
 
Are you able to assess any statistics in the manuscript or would you recommend an 
additional statistical review?  
If an additional st atistical review is recommended, please specify what aspects require further 
assessment in your comments to the editors.  
 
I am able to assess the statistics  
 
Quality of written English  
Please indicate the quality of language in the manuscript:  
 
Needs some language corrections before being published  
 
Declaration of competing interests  
Please complete a declaration of competing interests, considering the following questions:  
 
1. Have you in the past five years received reimbursements, fees, funding, or salary from an 
organisation that may in any way gain o r lose financially from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose 
financially from the publication of this manuscript, either now or in the future?  
 
3. Do you hold or are you currently applying for any patents relating to the content of the 
manuscript?  
 
4. Have you received reimbursements, fees, funding, or salary from an organization that 
holds or has applied for patents relating to the content of the man uscript?  
 
5. Do you have any other financial competing interests?  
 
6. Do you have any non -financial competing interests in relation to this paper?  
 
If you can answer no to all of the  above, write 'I declare that I have no competing interests' 
below. If your reply is yes to any, please give details below.  
 
None  
 
I agree to the open peer review policy of the journal. I understand that my name will  be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my report to be made available unde r an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as  confidential comments 
to the editors, which will not be published . 
 
I agree to the open peer review policy of the journal  
assistant