Title: Efficacy and safety of selective internal radiation therapy with yttrium-90 for the treatment
of unresectable hepatocellular carcinoma
Version: 2 Date: 07 Apr 2021
Reviewer's report:
I would like to thank the Editor for giving me the opportunity to revise this interesting
manuscript. The study represents a large series of patients suffering from unresectable HCC and
undergoing Y90 selective internal radiation therapy.
The article is clear enough, although I recommend an English language revision by a native
speaker.
I would like to give some suggestions to improve the quality of the article to permit its
publication.
Major revisions:
1) In the method section the Authors specified that Kaplan-Meier method was adopted to
estimate survival and Cox proportional Hazard model was built to identify independent
predictors of survival. In page 10, line 5 the Authors reported that 53 out of 61 patients died
because of tumor progression. The main concern about the statistical methods used is the
following:
Kaplan-Meier method is the most commonly used time-to-event analysis. However, since not
all the patients died because of cancer I think a survival method that considers the competing
risk (such as the cumulative incidence function – CIF) would be more appropriate. Indeed, as
reported by Austin et al. in 2016 (doi: 10.1161/CIRCULATIONAHA.115.017719), “using the
Kaplan-Meier estimate of the survival function to estimate the incidence function in the presence
of competing risks generally results in upward biases in the estimation of the incidence function”.
Similarly, Subdistribution Hazard model, compared to Cox proportional hazard model, would fit
better in predicting variables independently related to the outcome in the presence of competing
risk.
I understand they represent advanced statistical methods that (unfortunately) are not frequently
used, but their adoption can provide more reliable results. Nevertheless, if the Authors will not
be able to satisfy this request, it will not represent a reason to deem their study unsuitable for
publication.
2) I would suggest the Authors to discuss more in detail the results of the multivariate analysis.
More specifically I would kindly ask the Authors to focus on the HR of the radiologic response
(0.09): such an extremely low value is hard to sustain (it would mean that complete response,
compared to partial response, reduces the risk of death by 91%). Have the Authors assessed
the presence of multicollinearity and overfitting before building the multivariate model? If not
I recommend doing so and specifying it in the methods section.
3) I would also recommend the Authors to discuss the results of the present study taking into
account the findings of two interesting meta-analyses published on this topic (that I suggest
citing):
a. Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma:
systematic review and meta-analyses (doi: 10.18632/oncotarget.11644).
b. Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients: A
systematic review and meta-analysis (doi: 10.4254/wjh.v8.i18.770)
Minor revisions
1) Page 9, line 13: I guess “± 3.5” represents the interquartile range. If so, I suggest reporting
separately 1st and 3rd quartiles;
2) Page 10, line 1: same observation reported at point 1);
Title: Efficacy and safety of selective internal radiation therapy with yttrium-90 for the treatment
of unresectable hepatocellular carcinoma
Version: 2 Date: 07 Apr 2021
Reviewer's report:
I would like to thank the Editor for giving me the opportunity to revise this interesting
manuscript. The study represents a large series of patients suffering from unresectable HCC and
undergoing Y90 selective internal radiation therapy.
The article is clear enough, although I recommend an English language revision by a native
speaker.
I would like to give some suggestions to improve the quality of the article to permit its
publication.
Major revisions:
1) In the method section the Authors specified that Kaplan-Meier method was adopted to
estimate survival and Cox proportional Hazard model was built to identify independent
predictors of survival. In page 10, line 5 the Authors reported that 53 out of 61 patients died
because of tumor progression. The main concern about the statistical methods used is the
following:
Kaplan-Meier method is the most commonly used time-to-event analysis. However, since not
all the patients died because of cancer I think a survival method that considers the competing
risk (such as the cumulative incidence function – CIF) would be more appropriate. Indeed, as
reported by Austin et al. in 2016 (doi: 10.1161/CIRCULATIONAHA.115.017719), “using the
Kaplan-Meier estimate of the survival function to estimate the incidence function in the presence
of competing risks generally results in upward biases in the estimation of the incidence function”.
Similarly, Subdistribution Hazard model, compared to Cox proportional hazard model, would fit
better in predicting variables independently related to the outcome in the presence of competing
risk.
I understand they represent advanced statistical methods that (unfortunately) are not frequently
used, but their adoption can provide more reliable results. Nevertheless, if the Authors will not
be able to satisfy this request, it will not represent a reason to deem their study unsuitable for
publication.
2) I would suggest the Authors to discuss more in detail the results of the multivariate analysis.
More specifically I would kindly ask the Authors to focus on the HR of the radiologic response
(0.09): such an extremely low value is hard to sustain (it would mean that complete response,
compared to partial response, reduces the risk of death by 91%). Have the Authors assessed
the presence of multicollinearity and overfitting before building the multivariate model? If not
I recommend doing so and specifying it in the methods section.
3) I would also recommend the Authors to discuss the results of the present study taking into
account the findings of two interesting meta-analyses published on this topic (that I suggest
citing):
a. Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma:
systematic review and meta-analyses (doi: 10.18632/oncotarget.11644).
b. Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients: A
systematic review and meta-analysis (doi: 10.4254/wjh.v8.i18.770)
Minor revisions
1) Page 9, line 13: I guess “± 3.5” represents the interquartile range. If so, I suggest reporting
separately 1st and 3rd quartiles;
2) Page 10, line 1: same observation reported at point 1);
Please review this paper.
user
Title: Efficacy and safety of selective internal radiation therapy with yttrium-90 for the treatment
of unresectable hepatocellular carcinoma
Version: 2 Date: 07 Apr 2021
Reviewer's report:
I would like to thank the Editor for giving me the opportunity to revise this interesting
manuscript. The study represents a large series of patients suffering from unresectable HCC and
undergoing Y90 selective internal radiation therapy.
The article is clear enough, although I recommend an English language revision by a native
speaker.
I would like to give some suggestions to improve the quality of the article to permit its
publication.
Major revisions:
1) In the method section the Authors specified that Kaplan-Meier method was adopted to
estimate survival and Cox proportional Hazard model was built to identify independent
predictors of survival. In page 10, line 5 the Authors reported that 53 out of 61 patients died
because of tumor progression. The main concern about the statistical methods used is the
following:
Kaplan-Meier method is the most commonly used time-to-event analysis. However, since not
all the patients died because of cancer I think a survival method that considers the competing
risk (such as the cumulative incidence function – CIF) would be more appropriate. Indeed, as
reported by Austin et al. in 2016 (doi: 10.1161/CIRCULATIONAHA.115.017719), “using the
Kaplan-Meier estimate of the survival function to estimate the incidence function in the presence
of competing risks generally results in upward biases in the estimation of the incidence function”.
Similarly, Subdistribution Hazard model, compared to Cox proportional hazard model, would fit
better in predicting variables independently related to the outcome in the presence of competing
risk.
I understand they represent advanced statistical methods that (unfortunately) are not frequently
used, but their adoption can provide more reliable results. Nevertheless, if the Authors will not
be able to satisfy this request, it will not represent a reason to deem their study unsuitable for
publication.
2) I would suggest the Authors to discuss more in detail the results of the multivariate analysis.
More specifically I would kindly ask the Authors to focus on the HR of the radiologic response
(0.09): such an extremely low value is hard to sustain (it would mean that complete response,
compared to partial response, reduces the risk of death by 91%). Have the Authors assessed
the presence of multicollinearity and overfitting before building the multivariate model? If not
I recommend doing so and specifying it in the methods section.
3) I would also recommend the Authors to discuss the results of the present study taking into
account the findings of two interesting meta-analyses published on this topic (that I suggest
citing):
a. Trans-arterial radioembolization in intermediate-advanced hepatocellular carcinoma:
systematic review and meta-analyses (doi: 10.18632/oncotarget.11644).
b. Transarterial radioembolization vs chemoembolization for hepatocarcinoma patients: A
systematic review and meta-analysis (doi: 10.4254/wjh.v8.i18.770)
Minor revisions
1) Page 9, line 13: I guess “± 3.5” represents the interquartile range. If so, I suggest reporting
separately 1st and 3rd quartiles;
2) Page 10, line 1: same observation reported at point 1);
assistant