Title: Predictors of pathological complete response after total neoadjuvant treatment using short
course radiotherapy for locally advanced rectal cancer
Version: 1 Date: 16 Dec 2024
Reviewer:  Ramakrishnan Ayloor Seshadri
Reviewer's report:
The authors must be commended for their attempt to study the incidence of pathological
complete response after neoadjuvant treatment for rectal cancer and identify the factors
predicting a complete response. The study is interesting because the literature on pathological
complete response after total neoadjuvant treatment, especially using short course radiation and
induction chemotherapy is still evolving. I wish to offer some comments and suggestions which
I hope the authors will address.
The title of the study is quite misleading. The term neoadjuvant chemoradiation usually
indicates long course chemoradiation whereas the patients in this study were treated with total
neoadjuvant treatment (TNT) using short course radiation and either induction or consolidation
chemotherapy. The rest of the manuscript also uses the term neoadjuvant chemoradiation in
multiple places. The authors are requested to replace this term with another appropriate term
like TNT with short course RT or something similar.
How was the decision made to choose one of the two treatment regimens?
The use of induction chemotherapy followed by short course radiation is not standard practice
for rectal cancer and is not backed by evidence. Can the authors explain why they have been
using this regimen?
How many blocks were studied to make sure there is pathological complete response? According
to the UK LOREC (Low Rectal cancer) pathology protocol “Where tumour cells cannot be
found on the first assessment of five blocks of tumour, the whole area of the tumour/scarshould
be embedded. If no tumour cells be seen following assessment of these extra blocks, then
three deeper levels should be taken and examined from each tumour block. If after these
assessments no tumour cells are identified then the tumour should be considered to have
undergone a complete pathological response (TNM stage ypT0)”. Was any such protocol used
before labelling the pathological response as complete? Also consider mentioning if more than
one pathologist was involved in reporting the histological details and if so was there any common
review of the slides to confirm uniformity in reporting a pCR?
Please mention in the methods the definition the authors used for “chemotherapy interruption”.
Please provide range values wherever median value is mentioned and standard deviation
wherever mean is mentioned.
Table 1- please mention if the T and N stages mentioned are clinical (pretreatment) stages
What was the median follow-up duration?
According to Fig.1.a, median survival has not been reached but the text mentions the median
survival as 37 months.
In figures 1b and 1c, the survival curves seem to intersect each other and therefore the log-rank
test should not be used for survival analysis.
The discussion seems unfocussed and the authors need to modify it to a great extent. The
beginning two paragraphs of the discussion repeats what is mentioned in the introduction. It
would be better to start the discussion by summarizing the main findings of the study followed
by comparing the results with other published studies, and then mentioning the strength and
limitations of the study.
Most of the comparisons used in discussion except a few are studies using ling course radiation
without TNT. This is not an appropriate comparison. Eg- Reference 2 and 7 are studies on
patients who have received long course chemoradiation without TNT. Instead, the authors must
compare the results of this study with other studies that have used TNT with short course
radiation. They could still compare their results with those of long course RT without TNT to
see if there are any differences in the incidence of pCR or in factors determining pCR between
these different neoadjuvant treatment regimens, and the context must be clearly mentioned.
The discussion regarding lateral node dissection is out of place in this manuscript and the authors
may consider removing it.
The authors could consider mentioning that the strength of this study lies in the fact that there
is little data on real world outcomes of pCR after TNT using short course RT especially with
induction chemotherapy. At the same time, the small sample size and the retrospective nature of
the study with its inherent limitations should also be mentioned. If the pathological examination
to determine a pCR has not been done in accordance with standard recommendations, it also
must be mentioned as a limitation.
The conclusion in the main text must mention the main outcomes of this study. The conclusion
of the abstract is an apt conclusion of the results of this study and can be modified and used
in the main text also.
Title: Predictors of pathological complete response after total neoadjuvant treatment using short
course radiotherapy for locally advanced rectal cancer
Version: 1 Date: 16 Dec 2024
Reviewer:  Ramakrishnan Ayloor Seshadri
Reviewer's report:
The authors must be commended for their attempt to study the incidence of pathological
complete response after neoadjuvant treatment for rectal cancer and identify the factors
predicting a complete response. The study is interesting because the literature on pathological
complete response after total neoadjuvant treatment, especially using short course radiation and
induction chemotherapy is still evolving. I wish to offer some comments and suggestions which
I hope the authors will address.
The title of the study is quite misleading. The term neoadjuvant chemoradiation usually
indicates long course chemoradiation whereas the patients in this study were treated with total
neoadjuvant treatment (TNT) using short course radiation and either induction or consolidation
chemotherapy. The rest of the manuscript also uses the term neoadjuvant chemoradiation in
multiple places. The authors are requested to replace this term with another appropriate term
like TNT with short course RT or something similar.
How was the decision made to choose one of the two treatment regimens?
The use of induction chemotherapy followed by short course radiation is not standard practice
for rectal cancer and is not backed by evidence. Can the authors explain why they have been
using this regimen?
How many blocks were studied to make sure there is pathological complete response? According
to the UK LOREC (Low Rectal cancer) pathology protocol “Where tumour cells cannot be
found on the first assessment of five blocks of tumour, the whole area of the tumour/scarshould
be embedded. If no tumour cells be seen following assessment of these extra blocks, then
three deeper levels should be taken and examined from each tumour block. If after these
assessments no tumour cells are identified then the tumour should be considered to have
undergone a complete pathological response (TNM stage ypT0)”. Was any such protocol used
before labelling the pathological response as complete? Also consider mentioning if more than
one pathologist was involved in reporting the histological details and if so was there any common
review of the slides to confirm uniformity in reporting a pCR?
Please mention in the methods the definition the authors used for “chemotherapy interruption”.
Please provide range values wherever median value is mentioned and standard deviation
wherever mean is mentioned.
Table 1- please mention if the T and N stages mentioned are clinical (pretreatment) stages
What was the median follow-up duration?
According to Fig.1.a, median survival has not been reached but the text mentions the median
survival as 37 months.
In figures 1b and 1c, the survival curves seem to intersect each other and therefore the log-rank
test should not be used for survival analysis.
The discussion seems unfocussed and the authors need to modify it to a great extent. The
beginning two paragraphs of the discussion repeats what is mentioned in the introduction. It
would be better to start the discussion by summarizing the main findings of the study followed
by comparing the results with other published studies, and then mentioning the strength and
limitations of the study.
Most of the comparisons used in discussion except a few are studies using ling course radiation
without TNT. This is not an appropriate comparison. Eg- Reference 2 and 7 are studies on
patients who have received long course chemoradiation without TNT. Instead, the authors must
compare the results of this study with other studies that have used TNT with short course
radiation. They could still compare their results with those of long course RT without TNT to
see if there are any differences in the incidence of pCR or in factors determining pCR between
these different neoadjuvant treatment regimens, and the context must be clearly mentioned.
The discussion regarding lateral node dissection is out of place in this manuscript and the authors
may consider removing it.
The authors could consider mentioning that the strength of this study lies in the fact that there
is little data on real world outcomes of pCR after TNT using short course RT especially with
induction chemotherapy. At the same time, the small sample size and the retrospective nature of
the study with its inherent limitations should also be mentioned. If the pathological examination
to determine a pCR has not been done in accordance with standard recommendations, it also
must be mentioned as a limitation.
The conclusion in the main text must mention the main outcomes of this study. The conclusion
of the abstract is an apt conclusion of the results of this study and can be modified and used
in the main text also.
Please review this paper.
user
Title: Predictors of pathological complete response after total neoadjuvant treatment using short
course radiotherapy for locally advanced rectal cancer
Version: 1 Date: 16 Dec 2024
Reviewer:  Ramakrishnan Ayloor Seshadri
Reviewer's report:
The authors must be commended for their attempt to study the incidence of pathological
complete response after neoadjuvant treatment for rectal cancer and identify the factors
predicting a complete response. The study is interesting because the literature on pathological
complete response after total neoadjuvant treatment, especially using short course radiation and
induction chemotherapy is still evolving. I wish to offer some comments and suggestions which
I hope the authors will address.
The title of the study is quite misleading. The term neoadjuvant chemoradiation usually
indicates long course chemoradiation whereas the patients in this study were treated with total
neoadjuvant treatment (TNT) using short course radiation and either induction or consolidation
chemotherapy. The rest of the manuscript also uses the term neoadjuvant chemoradiation in
multiple places. The authors are requested to replace this term with another appropriate term
like TNT with short course RT or something similar.
How was the decision made to choose one of the two treatment regimens?
The use of induction chemotherapy followed by short course radiation is not standard practice
for rectal cancer and is not backed by evidence. Can the authors explain why they have been
using this regimen?
How many blocks were studied to make sure there is pathological complete response? According
to the UK LOREC (Low Rectal cancer) pathology protocol “Where tumour cells cannot be
found on the first assessment of five blocks of tumour, the whole area of the tumour/scarshould
be embedded. If no tumour cells be seen following assessment of these extra blocks, then
three deeper levels should be taken and examined from each tumour block. If after these
assessments no tumour cells are identified then the tumour should be considered to have
undergone a complete pathological response (TNM stage ypT0)”. Was any such protocol used
before labelling the pathological response as complete? Also consider mentioning if more than
one pathologist was involved in reporting the histological details and if so was there any common
review of the slides to confirm uniformity in reporting a pCR?
Please mention in the methods the definition the authors used for “chemotherapy interruption”.
Please provide range values wherever median value is mentioned and standard deviation
wherever mean is mentioned.
Table 1- please mention if the T and N stages mentioned are clinical (pretreatment) stages
What was the median follow-up duration?
According to Fig.1.a, median survival has not been reached but the text mentions the median
survival as 37 months.
In figures 1b and 1c, the survival curves seem to intersect each other and therefore the log-rank
test should not be used for survival analysis.
The discussion seems unfocussed and the authors need to modify it to a great extent. The
beginning two paragraphs of the discussion repeats what is mentioned in the introduction. It
would be better to start the discussion by summarizing the main findings of the study followed
by comparing the results with other published studies, and then mentioning the strength and
limitations of the study.
Most of the comparisons used in discussion except a few are studies using ling course radiation
without TNT. This is not an appropriate comparison. Eg- Reference 2 and 7 are studies on
patients who have received long course chemoradiation without TNT. Instead, the authors must
compare the results of this study with other studies that have used TNT with short course
radiation. They could still compare their results with those of long course RT without TNT to
see if there are any differences in the incidence of pCR or in factors determining pCR between
these different neoadjuvant treatment regimens, and the context must be clearly mentioned.
The discussion regarding lateral node dissection is out of place in this manuscript and the authors
may consider removing it.
The authors could consider mentioning that the strength of this study lies in the fact that there
is little data on real world outcomes of pCR after TNT using short course RT especially with
induction chemotherapy. At the same time, the small sample size and the retrospective nature of
the study with its inherent limitations should also be mentioned. If the pathological examination
to determine a pCR has not been done in accordance with standard recommendations, it also
must be mentioned as a limitation.
The conclusion in the main text must mention the main outcomes of this study. The conclusion
of the abstract is an apt conclusion of the results of this study and can be modified and used
in the main text also.
assistant