Title: Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma
Patients in Barcelona Clinic Liver Cancer Stage C (BCLC-C)
Version: 2 Date: 19 Apr 2022
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general.
Although language used is appropriate, I recommend to Editorial staff to check the final version
because I am not a native English speaker.
TITLE
In my opinion the title is not so interesting. Furthermore, I suggest improving it. For example:
Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma Patients
in Barcelona Clinic Liver Cancer Stage C (BCLC-C). If the authors and the editor agree, please
make the title more interesting.
ABSTRACT
The abstract appears moderately clear.
The primary and secondary endpoint were not so clear: please, correct.
Furthermore: the sentence “Median PFS for Group 1 was not reached at 17.3 months mean.”
could be more clear in the context.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular, for example, I
checked “Radioembolization” on MeSH Browser and I did not find this KW. This is important,
in my personal opinion, in order to increase the traceability of this paper (and consequently the
possibility of the Journal to be cited by Readers and Stakeholders). I suggest the check of all
KWs.
SECTION: Introduction
The authors, in my opinion, could improve this section.
Please, could the authors introduce the theme of the association of TARE and Sorafenib
[referring to: Facciorusso A, Paolillo R, Tartaglia N, et al. Efficacy of combined transarterial
radioembolization and sorafenib in the treatment of hepatocarcinoma: A meta-analysis.
Dig Liver Dis. 2022;54(3):316-323. doi:10.1016/j.dld.2021.06.003] and discuss it limitation
according to the mentioned metanalysis.
In the Introduction, could discuss this theme: In China, TACE is still recommended for
the treatment of HCC with portal invasion and improves the survival of these patients
[HepatoBiliary Surg Nutr 2020;9(4):452-463 | http://dx.doi.org/10.21037/hbsn-20-480]. In
my opinion, it is important to report that this experience is different from that of other
hepatological societies [referring to: European Association for the Study of the Liver
(EASL); European Association for the Study of Diabetes (EASD); European Association
for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for
the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402.
doi:10.1016/j.jhep.2015.11.004; ].
It will be interesting if the authors report other important efforts that could provide further
information on the potential use of SIRT with 90Y resin microspheres as first-line therapy
for unresectable HCC [Mahvash A, Chartier S, Turco M, et al. A prospective, multicenter,
open-label, single-arm clinical trial design to evaluate the safety and efficacy of 90Y resin
microspheres for the treatment of unresectable HCC: the DOORwaY90 (Duration Of Objective
Response with arterial Ytrrium-90) study. BMC Gastroenterol. 2022;22(1):151. Published 2022
Mar 28. doi:10.1186/s12876-022-02204-1].
SECTION: M&M
In my opinion it is very difficult to read this section without any explanations about the protocol,
procedures and the evaluation of the treatment response.
In particular, in my opinion, the authors must declare the criteria used to evaluate the
treatment response. Did they used mRECIST? This point is very important, and the authors
must discuss this point. It is well known that the decision on whether a HCC patient is a
responder or progressor after treatments may vary among different radiologists, especially in
case of a non-specifically trained radiologist and, therefore, regardless of the adopted criteria,
patients should be evaluated by experienced radiologists to minimize variability in this critical
instance in a paper that had PFS as an outcome [refer to: Eur Radiol. 2018;28(9):3611-3620.
doi:10.1007/s00330-018-5393-3]. Please, could the Authors report that it is important that
experienced radiologists evaluate imaging, and that one or more experienced radiologists must
evaluated imaging according to mRECIST. Please, cite the aforementioned paper [Eur Radiol.
2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3] and report if the radiologists who
analyse the imaging exams were expert.
During the execution of the TARE procedures there is an amount of absorbed radiant dose, for
operators (interventional radiologists) and for Patients. In my opinion a correct standardization
of the procedures, it is necessary to reduce the number of rays absorbed for both patients and
radiologists in order to reduce the possible stochastic and no-stochastic effects [Med Phys.
2012;39(5):2491-2498. doi:10.1118/1.3702457]. In my opinion, the interventional radiologists
who performed TACE should be necessary expert radiologists in order to reduce the dose in
patients that received these treatments [please, cite the paper: Med Phys. 2012;39(5):2491-2498.
doi:10.1118/1.3702457]. according to the aforementioned paper, could the authors highlight
that the interventional radiologists who performed these procedures will be necessary expert, to
reduce the risks of x-ray exposure?
What does it mean “Combined Tumor Diameter (cm)” in table 1. For example: all the infiltrative
tumors are non target lesion (mRECIST definition): therefore, it is not possible to measure these
lesions. The authors introduced the term combined tumor diameter. Is it the sum of max and min
diameters? Is it the multiplication? For example: in parenthesis, the authors reported (range?
Interquartile? Median? Media?). in group 1, the lesion with 3.2 cm is a lesion with max diameter
of 2 cm + 1.2 cm? did you treat this lesion with TARE?
This point is crucial.
It is difficult to read the paper in the present form. In fact, the authors stated that (in M&M) ON
PAGE 6: Group 2. Portal venous invasion and are ECOG 1-2 and CP B-C without extrahepatic
disease. is This the group 2? In table 2 it was reported that about 40% of patient were in CP
A. WHY this discrepancy?
Moreover: reference number 17: Bolondi et al. analysed the intermediate stage (BCLC C). it is
not clear the link in this section (that evaluate BCLC C).
Vascular invasion: 69/75 are reported in table 1. But the sum of vascular invasion in groups 1,
2 and 3 is 12 + 37 + 6 = 55. ??? Probably, the numbers 6 and 55 are wrong…
Furthermore, it is very interesting that the vast majority of patients in group 3 20/26 have
metastases without macrovascular invasion. Please, could the Authors discuss this point?
SECTION: Results
Results should be re-evaluated after revision o M&M section.
SECTION: Discussion
The authors stated that: “. The rate of tumor vascular invasion in the current trial (81%)”.
However, 69/75 (table 1) = 92%. It is important to read also the discussion after corrections of
the previous sections.
The limitation section should be expandend.
Could the authors discuss this theme: this treatment and these results are related to lesions with
big dimensions (see table 1). In Europe and USA, the surveillance program and also the future
strategy to improve the surveillance program and diagnosis of HCC [Non-enhanced magnetic
resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison with
ultrasound. J Hepatol. 2020;72(4):718-724. doi:10.1016/j.jhep.2019.12.001   -----    Proposal
of a new diagnostic algorithm for hepatocellular carcinoma based on the Japanese guidelines
but adapted to the Western world for patients under surveillance for chronic liver disease. J
Gastroenterol Hepatol. 2016;31(1):69-80. doi:10.1111/jgh.13150], will allow to overcome the
ultrasound limitations. The first consequence will be the detection of more and more lesions in
very early and early stage (small lesions). Could the Authors discuss these themes, and report if
their proposal of using TARE will be effective also for small lesions (the authors could perform
a sub-group analysis to evaluate small lesions)?
SECTION: Conclusion
No major concerns.
Title: Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma
Patients in Barcelona Clinic Liver Cancer Stage C (BCLC-C)
Version: 2 Date: 19 Apr 2022
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general.
Although language used is appropriate, I recommend to Editorial staff to check the final version
because I am not a native English speaker.
TITLE
In my opinion the title is not so interesting. Furthermore, I suggest improving it. For example:
Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma Patients
in Barcelona Clinic Liver Cancer Stage C (BCLC-C). If the authors and the editor agree, please
make the title more interesting.
ABSTRACT
The abstract appears moderately clear.
The primary and secondary endpoint were not so clear: please, correct.
Furthermore: the sentence “Median PFS for Group 1 was not reached at 17.3 months mean.”
could be more clear in the context.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular, for example, I
checked “Radioembolization” on MeSH Browser and I did not find this KW. This is important,
in my personal opinion, in order to increase the traceability of this paper (and consequently the
possibility of the Journal to be cited by Readers and Stakeholders). I suggest the check of all
KWs.
SECTION: Introduction
The authors, in my opinion, could improve this section.
Please, could the authors introduce the theme of the association of TARE and Sorafenib
[referring to: Facciorusso A, Paolillo R, Tartaglia N, et al. Efficacy of combined transarterial
radioembolization and sorafenib in the treatment of hepatocarcinoma: A meta-analysis.
Dig Liver Dis. 2022;54(3):316-323. doi:10.1016/j.dld.2021.06.003] and discuss it limitation
according to the mentioned metanalysis.
In the Introduction, could discuss this theme: In China, TACE is still recommended for
the treatment of HCC with portal invasion and improves the survival of these patients
[HepatoBiliary Surg Nutr 2020;9(4):452-463 | http://dx.doi.org/10.21037/hbsn-20-480]. In
my opinion, it is important to report that this experience is different from that of other
hepatological societies [referring to: European Association for the Study of the Liver
(EASL); European Association for the Study of Diabetes (EASD); European Association
for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for
the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402.
doi:10.1016/j.jhep.2015.11.004; ].
It will be interesting if the authors report other important efforts that could provide further
information on the potential use of SIRT with 90Y resin microspheres as first-line therapy
for unresectable HCC [Mahvash A, Chartier S, Turco M, et al. A prospective, multicenter,
open-label, single-arm clinical trial design to evaluate the safety and efficacy of 90Y resin
microspheres for the treatment of unresectable HCC: the DOORwaY90 (Duration Of Objective
Response with arterial Ytrrium-90) study. BMC Gastroenterol. 2022;22(1):151. Published 2022
Mar 28. doi:10.1186/s12876-022-02204-1].
SECTION: M&M
In my opinion it is very difficult to read this section without any explanations about the protocol,
procedures and the evaluation of the treatment response.
In particular, in my opinion, the authors must declare the criteria used to evaluate the
treatment response. Did they used mRECIST? This point is very important, and the authors
must discuss this point. It is well known that the decision on whether a HCC patient is a
responder or progressor after treatments may vary among different radiologists, especially in
case of a non-specifically trained radiologist and, therefore, regardless of the adopted criteria,
patients should be evaluated by experienced radiologists to minimize variability in this critical
instance in a paper that had PFS as an outcome [refer to: Eur Radiol. 2018;28(9):3611-3620.
doi:10.1007/s00330-018-5393-3]. Please, could the Authors report that it is important that
experienced radiologists evaluate imaging, and that one or more experienced radiologists must
evaluated imaging according to mRECIST. Please, cite the aforementioned paper [Eur Radiol.
2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3] and report if the radiologists who
analyse the imaging exams were expert.
During the execution of the TARE procedures there is an amount of absorbed radiant dose, for
operators (interventional radiologists) and for Patients. In my opinion a correct standardization
of the procedures, it is necessary to reduce the number of rays absorbed for both patients and
radiologists in order to reduce the possible stochastic and no-stochastic effects [Med Phys.
2012;39(5):2491-2498. doi:10.1118/1.3702457]. In my opinion, the interventional radiologists
who performed TACE should be necessary expert radiologists in order to reduce the dose in
patients that received these treatments [please, cite the paper: Med Phys. 2012;39(5):2491-2498.
doi:10.1118/1.3702457]. according to the aforementioned paper, could the authors highlight
that the interventional radiologists who performed these procedures will be necessary expert, to
reduce the risks of x-ray exposure?
What does it mean “Combined Tumor Diameter (cm)” in table 1. For example: all the infiltrative
tumors are non target lesion (mRECIST definition): therefore, it is not possible to measure these
lesions. The authors introduced the term combined tumor diameter. Is it the sum of max and min
diameters? Is it the multiplication? For example: in parenthesis, the authors reported (range?
Interquartile? Median? Media?). in group 1, the lesion with 3.2 cm is a lesion with max diameter
of 2 cm + 1.2 cm? did you treat this lesion with TARE?
This point is crucial.
It is difficult to read the paper in the present form. In fact, the authors stated that (in M&M) ON
PAGE 6: Group 2. Portal venous invasion and are ECOG 1-2 and CP B-C without extrahepatic
disease. is This the group 2? In table 2 it was reported that about 40% of patient were in CP
A. WHY this discrepancy?
Moreover: reference number 17: Bolondi et al. analysed the intermediate stage (BCLC C). it is
not clear the link in this section (that evaluate BCLC C).
Vascular invasion: 69/75 are reported in table 1. But the sum of vascular invasion in groups 1,
2 and 3 is 12 + 37 + 6 = 55. ??? Probably, the numbers 6 and 55 are wrong…
Furthermore, it is very interesting that the vast majority of patients in group 3 20/26 have
metastases without macrovascular invasion. Please, could the Authors discuss this point?
SECTION: Results
Results should be re-evaluated after revision o M&M section.
SECTION: Discussion
The authors stated that: “. The rate of tumor vascular invasion in the current trial (81%)”.
However, 69/75 (table 1) = 92%. It is important to read also the discussion after corrections of
the previous sections.
The limitation section should be expandend.
Could the authors discuss this theme: this treatment and these results are related to lesions with
big dimensions (see table 1). In Europe and USA, the surveillance program and also the future
strategy to improve the surveillance program and diagnosis of HCC [Non-enhanced magnetic
resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison with
ultrasound. J Hepatol. 2020;72(4):718-724. doi:10.1016/j.jhep.2019.12.001   -----    Proposal
of a new diagnostic algorithm for hepatocellular carcinoma based on the Japanese guidelines
but adapted to the Western world for patients under surveillance for chronic liver disease. J
Gastroenterol Hepatol. 2016;31(1):69-80. doi:10.1111/jgh.13150], will allow to overcome the
ultrasound limitations. The first consequence will be the detection of more and more lesions in
very early and early stage (small lesions). Could the Authors discuss these themes, and report if
their proposal of using TARE will be effective also for small lesions (the authors could perform
a sub-group analysis to evaluate small lesions)?
SECTION: Conclusion
No major concerns.
Please review this paper.
user
Title: Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma
Patients in Barcelona Clinic Liver Cancer Stage C (BCLC-C)
Version: 2 Date: 19 Apr 2022
Reviewer's report:
SPECIFIC COMMENTS
This manuscript is pleasurable and flowing, in general.
Although language used is appropriate, I recommend to Editorial staff to check the final version
because I am not a native English speaker.
TITLE
In my opinion the title is not so interesting. Furthermore, I suggest improving it. For example:
Overall Survival and Toxicity of Y90 Radioembolization for Hepatocellular Carcinoma Patients
in Barcelona Clinic Liver Cancer Stage C (BCLC-C). If the authors and the editor agree, please
make the title more interesting.
ABSTRACT
The abstract appears moderately clear.
The primary and secondary endpoint were not so clear: please, correct.
Furthermore: the sentence “Median PFS for Group 1 was not reached at 17.3 months mean.”
could be more clear in the context.
KEYWORDS
Authors did not correctly report all keywords from MeSH Browser. In particular, for example, I
checked “Radioembolization” on MeSH Browser and I did not find this KW. This is important,
in my personal opinion, in order to increase the traceability of this paper (and consequently the
possibility of the Journal to be cited by Readers and Stakeholders). I suggest the check of all
KWs.
SECTION: Introduction
The authors, in my opinion, could improve this section.
Please, could the authors introduce the theme of the association of TARE and Sorafenib
[referring to: Facciorusso A, Paolillo R, Tartaglia N, et al. Efficacy of combined transarterial
radioembolization and sorafenib in the treatment of hepatocarcinoma: A meta-analysis.
Dig Liver Dis. 2022;54(3):316-323. doi:10.1016/j.dld.2021.06.003] and discuss it limitation
according to the mentioned metanalysis.
In the Introduction, could discuss this theme: In China, TACE is still recommended for
the treatment of HCC with portal invasion and improves the survival of these patients
[HepatoBiliary Surg Nutr 2020;9(4):452-463 | http://dx.doi.org/10.21037/hbsn-20-480]. In
my opinion, it is important to report that this experience is different from that of other
hepatological societies [referring to: European Association for the Study of the Liver
(EASL); European Association for the Study of Diabetes (EASD); European Association
for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for
the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64(6):1388-1402.
doi:10.1016/j.jhep.2015.11.004; ].
It will be interesting if the authors report other important efforts that could provide further
information on the potential use of SIRT with 90Y resin microspheres as first-line therapy
for unresectable HCC [Mahvash A, Chartier S, Turco M, et al. A prospective, multicenter,
open-label, single-arm clinical trial design to evaluate the safety and efficacy of 90Y resin
microspheres for the treatment of unresectable HCC: the DOORwaY90 (Duration Of Objective
Response with arterial Ytrrium-90) study. BMC Gastroenterol. 2022;22(1):151. Published 2022
Mar 28. doi:10.1186/s12876-022-02204-1].
SECTION: M&M
In my opinion it is very difficult to read this section without any explanations about the protocol,
procedures and the evaluation of the treatment response.
In particular, in my opinion, the authors must declare the criteria used to evaluate the
treatment response. Did they used mRECIST? This point is very important, and the authors
must discuss this point. It is well known that the decision on whether a HCC patient is a
responder or progressor after treatments may vary among different radiologists, especially in
case of a non-specifically trained radiologist and, therefore, regardless of the adopted criteria,
patients should be evaluated by experienced radiologists to minimize variability in this critical
instance in a paper that had PFS as an outcome [refer to: Eur Radiol. 2018;28(9):3611-3620.
doi:10.1007/s00330-018-5393-3]. Please, could the Authors report that it is important that
experienced radiologists evaluate imaging, and that one or more experienced radiologists must
evaluated imaging according to mRECIST. Please, cite the aforementioned paper [Eur Radiol.
2018;28(9):3611-3620. doi:10.1007/s00330-018-5393-3] and report if the radiologists who
analyse the imaging exams were expert.
During the execution of the TARE procedures there is an amount of absorbed radiant dose, for
operators (interventional radiologists) and for Patients. In my opinion a correct standardization
of the procedures, it is necessary to reduce the number of rays absorbed for both patients and
radiologists in order to reduce the possible stochastic and no-stochastic effects [Med Phys.
2012;39(5):2491-2498. doi:10.1118/1.3702457]. In my opinion, the interventional radiologists
who performed TACE should be necessary expert radiologists in order to reduce the dose in
patients that received these treatments [please, cite the paper: Med Phys. 2012;39(5):2491-2498.
doi:10.1118/1.3702457]. according to the aforementioned paper, could the authors highlight
that the interventional radiologists who performed these procedures will be necessary expert, to
reduce the risks of x-ray exposure?
What does it mean “Combined Tumor Diameter (cm)” in table 1. For example: all the infiltrative
tumors are non target lesion (mRECIST definition): therefore, it is not possible to measure these
lesions. The authors introduced the term combined tumor diameter. Is it the sum of max and min
diameters? Is it the multiplication? For example: in parenthesis, the authors reported (range?
Interquartile? Median? Media?). in group 1, the lesion with 3.2 cm is a lesion with max diameter
of 2 cm + 1.2 cm? did you treat this lesion with TARE?
This point is crucial.
It is difficult to read the paper in the present form. In fact, the authors stated that (in M&M) ON
PAGE 6: Group 2. Portal venous invasion and are ECOG 1-2 and CP B-C without extrahepatic
disease. is This the group 2? In table 2 it was reported that about 40% of patient were in CP
A. WHY this discrepancy?
Moreover: reference number 17: Bolondi et al. analysed the intermediate stage (BCLC C). it is
not clear the link in this section (that evaluate BCLC C).
Vascular invasion: 69/75 are reported in table 1. But the sum of vascular invasion in groups 1,
2 and 3 is 12 + 37 + 6 = 55. ??? Probably, the numbers 6 and 55 are wrong…
Furthermore, it is very interesting that the vast majority of patients in group 3 20/26 have
metastases without macrovascular invasion. Please, could the Authors discuss this point?
SECTION: Results
Results should be re-evaluated after revision o M&M section.
SECTION: Discussion
The authors stated that: “. The rate of tumor vascular invasion in the current trial (81%)”.
However, 69/75 (table 1) = 92%. It is important to read also the discussion after corrections of
the previous sections.
The limitation section should be expandend.
Could the authors discuss this theme: this treatment and these results are related to lesions with
big dimensions (see table 1). In Europe and USA, the surveillance program and also the future
strategy to improve the surveillance program and diagnosis of HCC [Non-enhanced magnetic
resonance imaging as a surveillance tool for hepatocellular carcinoma: Comparison with
ultrasound. J Hepatol. 2020;72(4):718-724. doi:10.1016/j.jhep.2019.12.001   -----    Proposal
of a new diagnostic algorithm for hepatocellular carcinoma based on the Japanese guidelines
but adapted to the Western world for patients under surveillance for chronic liver disease. J
Gastroenterol Hepatol. 2016;31(1):69-80. doi:10.1111/jgh.13150], will allow to overcome the
ultrasound limitations. The first consequence will be the detection of more and more lesions in
very early and early stage (small lesions). Could the Authors discuss these themes, and report if
their proposal of using TARE will be effective also for small lesions (the authors could perform
a sub-group analysis to evaluate small lesions)?
SECTION: Conclusion
No major concerns.
assistant