Reviewer’s report
Title: 
Drug-Related Adverse Events Potentially Predict the Efficacy of Apatinib
on Advanced Hepatocellular Carcinoma
Version: 
1 
Date: 
19 Jul 2022
Reviewer's report:
"PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: response
1.Apatinib has not been approved globally in advanced HCC. The impact of this
study may be less significant.
comment to issue: Apatinib is a highly selective tyrosine kinase inhibitor of
VEGFR-2, which is the main target of lenvatinib and sorafenib—the first-line
treatment of HCC. And in China, apatinib has been recommended for HCC
according to guidelines for treating HCC. In addition, our previous study has
found that the pattern of proteinuria induced by other VEGFR-2 inhibitors is
similar to that of apatinib[1]. Therefore, the conclusion of our study is
generalizable.
My comment: So, apatinib is not approved for its use in hepatocellular
carcinoma in China. To suggest that the pattern of proteinuria of apatinib is
similar to other VEGF inhibitors as 
an argument that 'the conclusion is
generalizable" is simply flawed
2.This is a retrospective study but not a clinical trial. It is not suitable to mention
it as a trial in line 96 of page 6.
comment to issue: Thank you very much for your professional suggestion. We
fully agree with you and we have replaced trial with study. (Line 98, page 7).
My comment well done 
3.As mentioned by the authors, HTN was excluded from the analysis in this
study, because their previous work has explored the effect of HTN. However, it
is strange to exclude one kind of AE and perform a new study to analyze other
AEs.
comment to issue: Thank you very much for your comment. Initially, we
thoroughly analyzed the role of TKI-induced HTN in predicting the efficacy of
TKIs on HCC. With further data mining and the increasing number of HCC
patients whose treatment was affected by TKI inducedproteinuria, we started to
focus on proteinuria and decided to conduct a further
and comprehensive analysis of all adverse events caused by TKIs. Considering
thatthe analysis of HTN has been made before, there will be duplicate results if it
is notexcluded in this study, we therefore diluted the content of HTN in the
conclusion.
My comment this a fair point . 
4.The longer treatment duration, the occurrence of any AEs were more likely.
The associations of these AEs with PFS or OS may just be associations.
Prediction was a very strong word. The conclusion should be toned down.
comment to issue: Thank you very much for your suggestion. Our next work will
pay more attention to therelationship between the time that AEs occur and
prognosis of HCC. In this manuscript, we replaced predictor by potential
predictor.
My comment 
well done 
5.About the inclusion criteria, in line 87 of page 6, is it correct for CCr
≤40mL/min ? Thank you very much for your reminder, the right inclusion
criteria is "CCr ≥40mL/min".
comment to issue: We have corrected this error. (Line 89, page 6).
My comment 
well done 
6.In page 6, the inclusion criteria allowed systemic therapy ≤1, but the first
exclusion criteria was ""systemic anti-cancer therapy"".
comment to issue: Thank you very much for your comment. The exclusion
criteria we want to state is that ""received systemic anti-cancer therapy within 28
days prior to entry into the study"".
7.Since this is a retrospective study, it is hard to believe that every patient could
receive regular tumor assessment every 8 weeks, as mentioned in lines 111 and
112 in page 7.
comment to issue: Thank you very much for your professional comment. We
performed a careful data check and confirmed that the time scale of follow-up
was 8-12 weeks. We have modified this error. (Line 110, page 7).
8.As shown in Table S1-3, the baseline data before PSM were not so different
between subgroups. Using PSM in this study was not very necessary.
comment to issue: Thank you for your valuable suggestion, our purpose of
performing PSM is to better exclude the impacts of some factors such as the
initial drug dose on the results.
My comments: The authors use propensity score matching , a very popular
method of preprocessing data for causal inference. While this may balance
observed baseline covariates between groups, propensity score analyses have the
limitation that remaining unmeasured confounding variables may still be present,
thus leading to biased results. I am not certain whether I agree that the purpose of
the propensity score matching 
is to " exclude the impacts of some factors" The
reviewer is right that if the distribution of confounders between groups is well
balanced (to increase between group comparability) propensity match scoring is
not necessary. .
9.A Fig 2C should be provided for comparison of PFS in non-diarrhea and
diarrhea patients.
comment to issue: We sincerely thank you for this comment and agree with your
suggestion. We have provided it as Fig 2c. (Line 167-168, page 15).
My comment: changes have been incorporated 
10.The subgroup analysis in page 18 was not very relevant. It is difficult to
explain the findings.
comment to issue: We sincerely appreciate your comments and completely agree
with your suggestion. We have removed the relevant part.
My comment: changes have been incorporated 
11.The DISCUSSION part had too much elaboration and the logic was not very
clear. 
comment to issue: Thank you very much for pointing out our problem. We have
made the modification.
12.English editing is still needed.
comment to issue: Thank you very much for your professionally suggestiong, we
have performed the English editing.
My comment: I do not see in the manuscript where this has been done. Although
this is a generic comment, the answer by the authors (with typos) leaves some
room for doubt. 
Reviewer 2: 
Minor points to be addressed by the authors:
1.In the abstract background section a sentence concerning advanced HCC is
more proper. What the authors provide in their background is the aim of the
study and is repeated later on.
comment to issue: Thank you for your valuable suggestion, and we have made
the modification. Content of manuscript: "Hepatocellular carcinoma (HCC) is
the fourth leading cause of cancer-related deaths worldwide every year, and most
HCC patients are diagnosed with advanced disease and can only receive
systemic treatment. TKIs are the most important components of the systemic
treatment of HCC and have both good efficacy and adverse events (AEs)."(Line
32-35, page 2-3).
My comment: changes have been incorporated 
2.I would propose moving the paragraph ""In summary, among all the adverse
events caused by apatinib in the....."" into the conclusions section as it is more
appropriate.
comment to issue: 
We sincerely appreciate your comments and completely agree
with your suggestion. We have moved this part into the conclusions section.
(Line 246-249, page 21).
My comment: changes have been incorporated 
3.Add a reference after ""Over 70% of HCC patients are diagnosed as advanced
disease that resection or transplantation are not suitable."" ie. PMID 34405284
comment to issue: 
Thank you very much for your professional suggestion. We
have added this paper into
reference.(Line 59, page 4
My comment: changes have been incorporated
REQUESTED REVISIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full
ADDITIONAL REQUESTS/SUGGESTIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full"
Publons Reviewer Recognition
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
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Are the methods sufficiently described to allow the study to be repeated?
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Is the use of statistics and treatment of uncertainties appropriate?
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Is the presentation of the work clear?
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Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
Drug-Related Adverse Events Potentially Predict the Efficacy of Apatinib
on Advanced Hepatocellular Carcinoma
Version: 
1 
Date: 
19 Jul 2022
Reviewer's report:
"PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: response
1.Apatinib has not been approved globally in advanced HCC. The impact of this
study may be less significant.
comment to issue: Apatinib is a highly selective tyrosine kinase inhibitor of
VEGFR-2, which is the main target of lenvatinib and sorafenib—the first-line
treatment of HCC. And in China, apatinib has been recommended for HCC
according to guidelines for treating HCC. In addition, our previous study has
found that the pattern of proteinuria induced by other VEGFR-2 inhibitors is
similar to that of apatinib[1]. Therefore, the conclusion of our study is
generalizable.
My comment: So, apatinib is not approved for its use in hepatocellular
carcinoma in China. To suggest that the pattern of proteinuria of apatinib is
similar to other VEGF inhibitors as 
an argument that 'the conclusion is
generalizable" is simply flawed
2.This is a retrospective study but not a clinical trial. It is not suitable to mention
it as a trial in line 96 of page 6.
comment to issue: Thank you very much for your professional suggestion. We
fully agree with you and we have replaced trial with study. (Line 98, page 7).
My comment well done 
3.As mentioned by the authors, HTN was excluded from the analysis in this
study, because their previous work has explored the effect of HTN. However, it
is strange to exclude one kind of AE and perform a new study to analyze other
AEs.
comment to issue: Thank you very much for your comment. Initially, we
thoroughly analyzed the role of TKI-induced HTN in predicting the efficacy of
TKIs on HCC. With further data mining and the increasing number of HCC
patients whose treatment was affected by TKI inducedproteinuria, we started to
focus on proteinuria and decided to conduct a further
and comprehensive analysis of all adverse events caused by TKIs. Considering
thatthe analysis of HTN has been made before, there will be duplicate results if it
is notexcluded in this study, we therefore diluted the content of HTN in the
conclusion.
My comment this a fair point . 
4.The longer treatment duration, the occurrence of any AEs were more likely.
The associations of these AEs with PFS or OS may just be associations.
Prediction was a very strong word. The conclusion should be toned down.
comment to issue: Thank you very much for your suggestion. Our next work will
pay more attention to therelationship between the time that AEs occur and
prognosis of HCC. In this manuscript, we replaced predictor by potential
predictor.
My comment 
well done 
5.About the inclusion criteria, in line 87 of page 6, is it correct for CCr
≤40mL/min ? Thank you very much for your reminder, the right inclusion
criteria is "CCr ≥40mL/min".
comment to issue: We have corrected this error. (Line 89, page 6).
My comment 
well done 
6.In page 6, the inclusion criteria allowed systemic therapy ≤1, but the first
exclusion criteria was ""systemic anti-cancer therapy"".
comment to issue: Thank you very much for your comment. The exclusion
criteria we want to state is that ""received systemic anti-cancer therapy within 28
days prior to entry into the study"".
7.Since this is a retrospective study, it is hard to believe that every patient could
receive regular tumor assessment every 8 weeks, as mentioned in lines 111 and
112 in page 7.
comment to issue: Thank you very much for your professional comment. We
performed a careful data check and confirmed that the time scale of follow-up
was 8-12 weeks. We have modified this error. (Line 110, page 7).
8.As shown in Table S1-3, the baseline data before PSM were not so different
between subgroups. Using PSM in this study was not very necessary.
comment to issue: Thank you for your valuable suggestion, our purpose of
performing PSM is to better exclude the impacts of some factors such as the
initial drug dose on the results.
My comments: The authors use propensity score matching , a very popular
method of preprocessing data for causal inference. While this may balance
observed baseline covariates between groups, propensity score analyses have the
limitation that remaining unmeasured confounding variables may still be present,
thus leading to biased results. I am not certain whether I agree that the purpose of
the propensity score matching 
is to " exclude the impacts of some factors" The
reviewer is right that if the distribution of confounders between groups is well
balanced (to increase between group comparability) propensity match scoring is
not necessary. .
9.A Fig 2C should be provided for comparison of PFS in non-diarrhea and
diarrhea patients.
comment to issue: We sincerely thank you for this comment and agree with your
suggestion. We have provided it as Fig 2c. (Line 167-168, page 15).
My comment: changes have been incorporated 
10.The subgroup analysis in page 18 was not very relevant. It is difficult to
explain the findings.
comment to issue: We sincerely appreciate your comments and completely agree
with your suggestion. We have removed the relevant part.
My comment: changes have been incorporated 
11.The DISCUSSION part had too much elaboration and the logic was not very
clear. 
comment to issue: Thank you very much for pointing out our problem. We have
made the modification.
12.English editing is still needed.
comment to issue: Thank you very much for your professionally suggestiong, we
have performed the English editing.
My comment: I do not see in the manuscript where this has been done. Although
this is a generic comment, the answer by the authors (with typos) leaves some
room for doubt. 
Reviewer 2: 
Minor points to be addressed by the authors:
1.In the abstract background section a sentence concerning advanced HCC is
more proper. What the authors provide in their background is the aim of the
study and is repeated later on.
comment to issue: Thank you for your valuable suggestion, and we have made
the modification. Content of manuscript: "Hepatocellular carcinoma (HCC) is
the fourth leading cause of cancer-related deaths worldwide every year, and most
HCC patients are diagnosed with advanced disease and can only receive
systemic treatment. TKIs are the most important components of the systemic
treatment of HCC and have both good efficacy and adverse events (AEs)."(Line
32-35, page 2-3).
My comment: changes have been incorporated 
2.I would propose moving the paragraph ""In summary, among all the adverse
events caused by apatinib in the....."" into the conclusions section as it is more
appropriate.
comment to issue: 
We sincerely appreciate your comments and completely agree
with your suggestion. We have moved this part into the conclusions section.
(Line 246-249, page 21).
My comment: changes have been incorporated 
3.Add a reference after ""Over 70% of HCC patients are diagnosed as advanced
disease that resection or transplantation are not suitable."" ie. PMID 34405284
comment to issue: 
Thank you very much for your professional suggestion. We
have added this paper into
reference.(Line 59, page 4
My comment: changes have been incorporated
REQUESTED REVISIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full
ADDITIONAL REQUESTS/SUGGESTIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full"
Publons Reviewer Recognition
. Springer Nature can send verification of this
review directly to Publons (a subsidiary of Clarivate Analytics). If you would
like to take advantage of this service, please click on the “Yes” option below.
Your name, email address, title of the reviewed manuscript, name of the journal,
and date of your review submission (the “Review Data”) will then be transmitted
to Publons after the final decision on the manuscript has been made. If you have
already registered at Publons, they will notify you of the receipt of this review
and update your profile 
as per your settings and their policy. If you are not
registered with Publons, you will receive an email from them asking you to
register in order for them to be able to recognize your review on your new
profile page. Publons may use the Review Data to generate derivative metadata
for the benefit of Publons and you as a reviewer, carefully considering the
sensitivity of such information. For example, Publons may verify your record as
a reviewer by updating your profile published on its webservice if you have
registered for such service or help editors to identify candidate reviewers. Please
find the details of processing in Publons’ privacy policy
https://publons.com/about/terms
No
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 or lose financially
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If you can answer no to all of the above, write 'I declare that I have no competing
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This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
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recommendation.
Reviewer Publication Consent.
 I agree for my report to be made available
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Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
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No
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Please review this paper.
user
Reviewer’s report
Title: 
Drug-Related Adverse Events Potentially Predict the Efficacy of Apatinib
on Advanced Hepatocellular Carcinoma
Version: 
1 
Date: 
19 Jul 2022
Reviewer's report:
"PEER REVIEWER ASSESSMENTS: 
OBJECTIVE - Full research articles: is there a clear objective that addresses one
or several testable research questions? (Brief or other article types: is there a
clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols)
appropriate for the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with sufficient
technical rigor to allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results
reasonable and not overstated?
No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your
concerns sufficiently for you to now recommend the work as a technically sound
contribution? If not, can further revisions be made to make the work technically
sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS: 
GENERAL COMMENTS: response
1.Apatinib has not been approved globally in advanced HCC. The impact of this
study may be less significant.
comment to issue: Apatinib is a highly selective tyrosine kinase inhibitor of
VEGFR-2, which is the main target of lenvatinib and sorafenib—the first-line
treatment of HCC. And in China, apatinib has been recommended for HCC
according to guidelines for treating HCC. In addition, our previous study has
found that the pattern of proteinuria induced by other VEGFR-2 inhibitors is
similar to that of apatinib[1]. Therefore, the conclusion of our study is
generalizable.
My comment: So, apatinib is not approved for its use in hepatocellular
carcinoma in China. To suggest that the pattern of proteinuria of apatinib is
similar to other VEGF inhibitors as 
an argument that 'the conclusion is
generalizable" is simply flawed
2.This is a retrospective study but not a clinical trial. It is not suitable to mention
it as a trial in line 96 of page 6.
comment to issue: Thank you very much for your professional suggestion. We
fully agree with you and we have replaced trial with study. (Line 98, page 7).
My comment well done 
3.As mentioned by the authors, HTN was excluded from the analysis in this
study, because their previous work has explored the effect of HTN. However, it
is strange to exclude one kind of AE and perform a new study to analyze other
AEs.
comment to issue: Thank you very much for your comment. Initially, we
thoroughly analyzed the role of TKI-induced HTN in predicting the efficacy of
TKIs on HCC. With further data mining and the increasing number of HCC
patients whose treatment was affected by TKI inducedproteinuria, we started to
focus on proteinuria and decided to conduct a further
and comprehensive analysis of all adverse events caused by TKIs. Considering
thatthe analysis of HTN has been made before, there will be duplicate results if it
is notexcluded in this study, we therefore diluted the content of HTN in the
conclusion.
My comment this a fair point . 
4.The longer treatment duration, the occurrence of any AEs were more likely.
The associations of these AEs with PFS or OS may just be associations.
Prediction was a very strong word. The conclusion should be toned down.
comment to issue: Thank you very much for your suggestion. Our next work will
pay more attention to therelationship between the time that AEs occur and
prognosis of HCC. In this manuscript, we replaced predictor by potential
predictor.
My comment 
well done 
5.About the inclusion criteria, in line 87 of page 6, is it correct for CCr
≤40mL/min ? Thank you very much for your reminder, the right inclusion
criteria is "CCr ≥40mL/min".
comment to issue: We have corrected this error. (Line 89, page 6).
My comment 
well done 
6.In page 6, the inclusion criteria allowed systemic therapy ≤1, but the first
exclusion criteria was ""systemic anti-cancer therapy"".
comment to issue: Thank you very much for your comment. The exclusion
criteria we want to state is that ""received systemic anti-cancer therapy within 28
days prior to entry into the study"".
7.Since this is a retrospective study, it is hard to believe that every patient could
receive regular tumor assessment every 8 weeks, as mentioned in lines 111 and
112 in page 7.
comment to issue: Thank you very much for your professional comment. We
performed a careful data check and confirmed that the time scale of follow-up
was 8-12 weeks. We have modified this error. (Line 110, page 7).
8.As shown in Table S1-3, the baseline data before PSM were not so different
between subgroups. Using PSM in this study was not very necessary.
comment to issue: Thank you for your valuable suggestion, our purpose of
performing PSM is to better exclude the impacts of some factors such as the
initial drug dose on the results.
My comments: The authors use propensity score matching , a very popular
method of preprocessing data for causal inference. While this may balance
observed baseline covariates between groups, propensity score analyses have the
limitation that remaining unmeasured confounding variables may still be present,
thus leading to biased results. I am not certain whether I agree that the purpose of
the propensity score matching 
is to " exclude the impacts of some factors" The
reviewer is right that if the distribution of confounders between groups is well
balanced (to increase between group comparability) propensity match scoring is
not necessary. .
9.A Fig 2C should be provided for comparison of PFS in non-diarrhea and
diarrhea patients.
comment to issue: We sincerely thank you for this comment and agree with your
suggestion. We have provided it as Fig 2c. (Line 167-168, page 15).
My comment: changes have been incorporated 
10.The subgroup analysis in page 18 was not very relevant. It is difficult to
explain the findings.
comment to issue: We sincerely appreciate your comments and completely agree
with your suggestion. We have removed the relevant part.
My comment: changes have been incorporated 
11.The DISCUSSION part had too much elaboration and the logic was not very
clear. 
comment to issue: Thank you very much for pointing out our problem. We have
made the modification.
12.English editing is still needed.
comment to issue: Thank you very much for your professionally suggestiong, we
have performed the English editing.
My comment: I do not see in the manuscript where this has been done. Although
this is a generic comment, the answer by the authors (with typos) leaves some
room for doubt. 
Reviewer 2: 
Minor points to be addressed by the authors:
1.In the abstract background section a sentence concerning advanced HCC is
more proper. What the authors provide in their background is the aim of the
study and is repeated later on.
comment to issue: Thank you for your valuable suggestion, and we have made
the modification. Content of manuscript: "Hepatocellular carcinoma (HCC) is
the fourth leading cause of cancer-related deaths worldwide every year, and most
HCC patients are diagnosed with advanced disease and can only receive
systemic treatment. TKIs are the most important components of the systemic
treatment of HCC and have both good efficacy and adverse events (AEs)."(Line
32-35, page 2-3).
My comment: changes have been incorporated 
2.I would propose moving the paragraph ""In summary, among all the adverse
events caused by apatinib in the....."" into the conclusions section as it is more
appropriate.
comment to issue: 
We sincerely appreciate your comments and completely agree
with your suggestion. We have moved this part into the conclusions section.
(Line 246-249, page 21).
My comment: changes have been incorporated 
3.Add a reference after ""Over 70% of HCC patients are diagnosed as advanced
disease that resection or transplantation are not suitable."" ie. PMID 34405284
comment to issue: 
Thank you very much for your professional suggestion. We
have added this paper into
reference.(Line 59, page 4
My comment: changes have been incorporated
REQUESTED REVISIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full
ADDITIONAL REQUESTS/SUGGESTIONS: 
This study describes apatinib related adverse events as predictors of efficacy in
hepatocellular carcinoma. 
Apatinib is a tyrosine kinase inhibitor that selectively
inhibits the vascular endothelial growth factor receptor-2. Apatinib (HengRui
Pharmaceutical Co, Ltd, Lianyungang, People's Republic of China), is a novel
small molecule tyrosine kinase inhibitor which was approved in China in 2014
and has been approved as a standard third line treatment for advanced gastric
cancer in China. Apatinib is being 
used in the treatment of advanced
hepatocellular carcinoma , but its efficacy has not been systematically evaluated.
The authors selected 207 patients with locally advanced unresectable or
metastatic hepatocellular carcinoma who were treated with apatinib.
The authors found that adverse effects predicted overall survival. Specifical
hand-foot syndrome, proteinuria, and diarrhea predicted better survival and
progression free survival was better in patients with hand-foot syndrome 
and
proteinuria 
I appreciate the effort that went into this study, and unearthing the data from the
files. However, it is and remains a retrospective study and from a single center
(albeit an expert center). These are limitations 
that really are important from a
methodological perspective. In order to be able to change practice, studies need
to be prospective and from multiple centers. I realize that this is difficult to
change now, but as a community we need to focus on rigorous studies that are
able to make a difference for us as clinicians. 
The authors have to be commended for the use of the STROBE guideline. 
I think it would be helpful for the reader to have insight in the regulatory
framework of apatinib. Is it approved for use in hepatocellular carcinoma inside
and outside mainland China? 
As I understand, large randomized controlled trials
(phase III) are still needed to explore the efficacy and safety of apatinib for the
indication of advanced hepatocellular carcinoma.
The findings apparently contradict with another study in a large cohort of
hepatocellular carcinoma. There, patients who developed 
diarrhoea under
sorafenib had a dismal disease course with earlier death from hepatocellular
carcinoma. doi: 10.1002/ueg2.12111 
It would help to contrast these findings 
I seek for a biological plausibility of these findings. Can the authors offer the
reader a clinical reasoning as to why these wide range of adverse events lead to a
better prognosis. 
Could the authors comment whether the doses of apatinib taken by patients were
correlated with any of the outcomes of the study. The authors use starting dose
of 500 mg as a variable but it has been reported that in hepatocellular carcinoma
dosages of apatinib are much lower (250 mg) than for indications such as gastric
and breast cancer.
https://www.frontiersin.org/articles/10.3389/fphar.2022.894016/full"
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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 or 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
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Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the manuscript?
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.
This reviewer has been recruited by a partner organization, Research Square.
Reviewers with declared or apparent competing interests are not utilized for
these reviews. This reviewer has agreed to publication of their comments online
under a Creative Commons Attribution License attributed to Research Square
and was paid a small honorarium for completing the review within a specified
timeframe. Honoraria for reviews such as this are paid regardless of the reviewer
recommendation.
Reviewer Publication Consent.
 I agree for my report to be made available
under an Open Access Creative Commons CC-BY License (
http://creativecommons.org/licenses/by/4.0
) if this manuscript is accepted for
publication. Any comments that I do not wish to be included in the published
report have been included as confidential comments to the editor, which will not
be published.
If you are not happy for us to publish this report, please contact the
editorial office before completing the review.
If you wish, you can include your
name in your published report. Please note you must decide whether to include
your name at the start of the process and confirm this decision whenever
prompted. If you change your decision later, we will not be able to publish your
name.
I agree to the terms of the CC-BY 4.0 license; please 
do not
 publish my name
with my report. (default)
Is the study design appropriate to answer the research question (including the use
of appropriate controls), and are the conclusions supported by the evidence
presented?
No
Are the methods sufficiently described to allow the study to be repeated?
No
Is the use of statistics and treatment of uncertainties appropriate?
No
Is the presentation of the work clear?
No
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
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