Reviewer’s report
Title: 
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
Version: 
0 
Date: 
30 Dec 2021
Reviewer's report:
The authors presented a protocol summary for the prospective single-arm trial of
90Y radioembolization for patients with unresectable liver-limited hepatocellular
carcinoma. The study would employ personalized dosimetry with minimum
mean tumor dose 150Gy. The protocol includes provisions for sparing some of
the normal parenchyma, and the study would only include patients with adequate
liver function (Child-Pugh A). The manuscript is well written and provide ample
detail regarding the planned study.
Some additional information should be included, as listed below.
Materials and Methods. 
1. Please provide rationale for using 150Gy as the lower limit for tumor absorbed
dose.
2. Page 7, lines 135-138. Please specify target segmental dose for segmental
treatments. Would that dose be 150Gy to the segment (single compartment
model)? Please provide rationale for not using 2-compartment model for all dose
calculations.
3. Page 9, lines 177-184. Please provide rationale for normal liver dose
constraints based on percentage of TLVBSA treated with 90Y microspheres
rather than on percentage of the actual total liver volume.
4. Page 9, lines 194-195. Please provide rationale for only using 3-day
FLEXdose delivery option. The vascular capacity of hepatocellular carcinoma
may vary widely, depending on size and tumor vascularity. Treating with
microspheres closer to the calibration date (more, colder spheres versus fewer,
hotter spheres) may lead to better distribution of the 90Y microspheres
throughout the treatment volume without a detrimental effect on the tumor
absorbed dose.
5. What software would be used to calculate R (patient-specific tumor uptake
ratio)?
6. Page 10, line 213. Patients with HCC treated with liver-directed therapy
usually have follow-up imaging assessments around every 3 months. What is the
rationale for not having any clinical or imaging assessments between 12 and 24
months after SIRT? What if there is a progression event that occurs between 12
and 24 months? The time of the events that occur between 12 and 24 months
would not be captured accurately.
Discussion.
7. Page 14, lines 304-305. As stated earlier in the text, there have been earlier
studies that evaluated the utility of personalized dosimetry for SIRT.
DOORwaY90 would not be the first study to utilize personalized dosimetry
based on patient specific tumor to normal uptake ratio.
Tables.
8. Table 1. There is a potential discrepancy between inclusion and exclusion
criteria in regards to portal vein thrombosis. BCLC stage C disease would
include patients with macrovascular invasion (i.e. portal and/or hepatic vein
tumor thrombus), while exclusion criteria list presence of portal vein thrombosis
as exclusion. Please clarify whether portal vein tumor thrombus, but not "bland"
thrombus is allowed for inclusion in the study.
Publons Reviewer Recognition
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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
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the 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.
I am a recipient of a research grant from Sirtex Medical.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
Reviewer’s report
Title: 
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
Version: 
0 
Date: 
30 Dec 2021
Reviewer's report:
The authors presented a protocol summary for the prospective single-arm trial of
90Y radioembolization for patients with unresectable liver-limited hepatocellular
carcinoma. The study would employ personalized dosimetry with minimum
mean tumor dose 150Gy. The protocol includes provisions for sparing some of
the normal parenchyma, and the study would only include patients with adequate
liver function (Child-Pugh A). The manuscript is well written and provide ample
detail regarding the planned study.
Some additional information should be included, as listed below.
Materials and Methods. 
1. Please provide rationale for using 150Gy as the lower limit for tumor absorbed
dose.
2. Page 7, lines 135-138. Please specify target segmental dose for segmental
treatments. Would that dose be 150Gy to the segment (single compartment
model)? Please provide rationale for not using 2-compartment model for all dose
calculations.
3. Page 9, lines 177-184. Please provide rationale for normal liver dose
constraints based on percentage of TLVBSA treated with 90Y microspheres
rather than on percentage of the actual total liver volume.
4. Page 9, lines 194-195. Please provide rationale for only using 3-day
FLEXdose delivery option. The vascular capacity of hepatocellular carcinoma
may vary widely, depending on size and tumor vascularity. Treating with
microspheres closer to the calibration date (more, colder spheres versus fewer,
hotter spheres) may lead to better distribution of the 90Y microspheres
throughout the treatment volume without a detrimental effect on the tumor
absorbed dose.
5. What software would be used to calculate R (patient-specific tumor uptake
ratio)?
6. Page 10, line 213. Patients with HCC treated with liver-directed therapy
usually have follow-up imaging assessments around every 3 months. What is the
rationale for not having any clinical or imaging assessments between 12 and 24
months after SIRT? What if there is a progression event that occurs between 12
and 24 months? The time of the events that occur between 12 and 24 months
would not be captured accurately.
Discussion.
7. Page 14, lines 304-305. As stated earlier in the text, there have been earlier
studies that evaluated the utility of personalized dosimetry for SIRT.
DOORwaY90 would not be the first study to utilize personalized dosimetry
based on patient specific tumor to normal uptake ratio.
Tables.
8. Table 1. There is a potential discrepancy between inclusion and exclusion
criteria in regards to portal vein thrombosis. BCLC stage C disease would
include patients with macrovascular invasion (i.e. portal and/or hepatic vein
tumor thrombus), while exclusion criteria list presence of portal vein thrombosis
as exclusion. Please clarify whether portal vein tumor thrombus, but not "bland"
thrombus is allowed for inclusion in the study.
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
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the 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.
I am a recipient of a research grant from Sirtex Medical.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
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: 
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
Version: 
0 
Date: 
30 Dec 2021
Reviewer's report:
The authors presented a protocol summary for the prospective single-arm trial of
90Y radioembolization for patients with unresectable liver-limited hepatocellular
carcinoma. The study would employ personalized dosimetry with minimum
mean tumor dose 150Gy. The protocol includes provisions for sparing some of
the normal parenchyma, and the study would only include patients with adequate
liver function (Child-Pugh A). The manuscript is well written and provide ample
detail regarding the planned study.
Some additional information should be included, as listed below.
Materials and Methods. 
1. Please provide rationale for using 150Gy as the lower limit for tumor absorbed
dose.
2. Page 7, lines 135-138. Please specify target segmental dose for segmental
treatments. Would that dose be 150Gy to the segment (single compartment
model)? Please provide rationale for not using 2-compartment model for all dose
calculations.
3. Page 9, lines 177-184. Please provide rationale for normal liver dose
constraints based on percentage of TLVBSA treated with 90Y microspheres
rather than on percentage of the actual total liver volume.
4. Page 9, lines 194-195. Please provide rationale for only using 3-day
FLEXdose delivery option. The vascular capacity of hepatocellular carcinoma
may vary widely, depending on size and tumor vascularity. Treating with
microspheres closer to the calibration date (more, colder spheres versus fewer,
hotter spheres) may lead to better distribution of the 90Y microspheres
throughout the treatment volume without a detrimental effect on the tumor
absorbed dose.
5. What software would be used to calculate R (patient-specific tumor uptake
ratio)?
6. Page 10, line 213. Patients with HCC treated with liver-directed therapy
usually have follow-up imaging assessments around every 3 months. What is the
rationale for not having any clinical or imaging assessments between 12 and 24
months after SIRT? What if there is a progression event that occurs between 12
and 24 months? The time of the events that occur between 12 and 24 months
would not be captured accurately.
Discussion.
7. Page 14, lines 304-305. As stated earlier in the text, there have been earlier
studies that evaluated the utility of personalized dosimetry for SIRT.
DOORwaY90 would not be the first study to utilize personalized dosimetry
based on patient specific tumor to normal uptake ratio.
Tables.
8. Table 1. There is a potential discrepancy between inclusion and exclusion
criteria in regards to portal vein thrombosis. BCLC stage C disease would
include patients with macrovascular invasion (i.e. portal and/or hepatic vein
tumor thrombus), while exclusion criteria list presence of portal vein thrombosis
as exclusion. Please clarify whether portal vein tumor thrombus, but not "bland"
thrombus is allowed for inclusion in the study.
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
from the publication of this manuscript, either now or in the future?
2
. 
Do you hold any stocks or shares in an organisation that may in any way
gain or lose financially from the publication of this manuscript, either now
or in the future?
3
. 
Do you hold or are you currently applying for any patents relating to the
content of the manuscript?
4
. 
Have you received reimbursements, fees, funding, or salary from an
organization that holds or has applied for patents relating to the content of
the 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.
I am a recipient of a research grant from Sirtex Medical.
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?
Yes
Are the methods sufficiently described to allow the study to be repeated?
Yes
Is the use of statistics and treatment of uncertainties appropriate?
Yes
Is the presentation of the work clear?
Yes
Are the images in this manuscript (including electrophoretic gels and blots) free
from apparent manipulation?
Yes
assistant