Reviewer ’s report  
Title: Additional hepatic 166Ho -radioembolization in patie nts with neuroendocrine tumours 
treated with 177Lu -DOTATATE; a single center, interventional, n on-randomized, non -
comparative, open label, phase II study (HEPAR PLUS trial)  
 
Version: 1 Date: 28 Nov 2017  
 
Reviewer: Julius Chapiro  
 
Reviewer's report:  
To the author:  
- Structure:  
o Manuscript is well -structured  
 
- Clinical applicability and relevance:  
o This study is highly relevant as it investigates two relatively new targeted ther apy approaches 
with 166Ho -Radioembolization being a particularly novel technique that enables accurate 
pre-and post -procedural imaging of treatment response on SPECT/CT.  
o Moreover, 166 -Ho imaging on MR may be a future application that offers radiation -free 
imaging for pre -procedural shunt evaluation as well as agent distribution patterns after 
radioembolization and can be easily integrated into the clinical workflow.  
 
- Abstract:  
o In the Abstract - Methods, it is written, that it is a 'two center' study, in the Methods it says 
'single -center'. Please clarify  
o In the Abstract - Methods it is described, that 166HO -RE is received within 12 weeks after 
PRRT. In Methods - Subjects and in Table 3 you tell the RE is within 20 weeks after PRRT.  
 
- Methods:  
o Metho ds and analyses are generally well described and appear standardized and reasonable.  
o For tumor response assessment only RECIST 1.1 was used. However, there are 3D response 
assessment techniques available that are more precise and should have been used in  this 
study, too.  
o Please clarify, if patients with previous treatment are ex - or included. It is only written, that 
all patients have not received conventional treatment options - does this refer to the time of 
recruitment or diagnosis? Were patients wit h additional treatments censored? Please include 
information about previous treatments in the inclusion and exclusion criteria  
o Will patients be excluded, if they get another therapy before the 3 -months follow -up CT?  
o Please describe the patient cohort in detail: Male / Female? Age? Etc.  
o Describe baseline (tumor) characteristics  
 
- Discussion:  
o The discussion relates to current evidence.  
o Mention limitations: e.g. small study cohort, non -comparative, single -center  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments  to the authors.  
No 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical revi ew? 
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I am able to assess the statistics  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
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, f ees, funding, or salary from an 
organisati on that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat 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 declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I  understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my rep ort to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the  editors, which will not be published.  
I agree to the open peer review policy of the journal  
Reviewer ’s report  
Title: Additional hepatic 166Ho -radioembolization in patie nts with neuroendocrine tumours 
treated with 177Lu -DOTATATE; a single center, interventional, n on-randomized, non -
comparative, open label, phase II study (HEPAR PLUS trial)  
 
Version: 1 Date: 28 Nov 2017  
 
Reviewer: Julius Chapiro  
 
Reviewer's report:  
To the author:  
- Structure:  
o Manuscript is well -structured  
 
- Clinical applicability and relevance:  
o This study is highly relevant as it investigates two relatively new targeted ther apy approaches 
with 166Ho -Radioembolization being a particularly novel technique that enables accurate 
pre-and post -procedural imaging of treatment response on SPECT/CT.  
o Moreover, 166 -Ho imaging on MR may be a future application that offers radiation -free 
imaging for pre -procedural shunt evaluation as well as agent distribution patterns after 
radioembolization and can be easily integrated into the clinical workflow.  
 
- Abstract:  
o In the Abstract - Methods, it is written, that it is a 'two center' study, in the Methods it says 
'single -center'. Please clarify  
o In the Abstract - Methods it is described, that 166HO -RE is received within 12 weeks after 
PRRT. In Methods - Subjects and in Table 3 you tell the RE is within 20 weeks after PRRT.  
 
- Methods:  
o Metho ds and analyses are generally well described and appear standardized and reasonable.  
o For tumor response assessment only RECIST 1.1 was used. However, there are 3D response 
assessment techniques available that are more precise and should have been used in  this 
study, too.  
o Please clarify, if patients with previous treatment are ex - or included. It is only written, that 
all patients have not received conventional treatment options - does this refer to the time of 
recruitment or diagnosis? Were patients wit h additional treatments censored? Please include 
information about previous treatments in the inclusion and exclusion criteria  
o Will patients be excluded, if they get another therapy before the 3 -months follow -up CT?  
o Please describe the patient cohort in detail: Male / Female? Age? Etc.  
o Describe baseline (tumor) characteristics  
 
- Discussion:  
o The discussion relates to current evidence.  
o Mention limitations: e.g. small study cohort, non -comparative, single -center  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments  to the authors.  
No 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical revi ew? 
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I am able to assess the statistics  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
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, f ees, funding, or salary from an 
organisati on that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat 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 declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I  understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my rep ort to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the  editors, which will not be published.  
I agree to the open peer review policy of the journal  
Please review this paper.
user
Reviewer ’s report  
Title: Additional hepatic 166Ho -radioembolization in patie nts with neuroendocrine tumours 
treated with 177Lu -DOTATATE; a single center, interventional, n on-randomized, non -
comparative, open label, phase II study (HEPAR PLUS trial)  
 
Version: 1 Date: 28 Nov 2017  
 
Reviewer: Julius Chapiro  
 
Reviewer's report:  
To the author:  
- Structure:  
o Manuscript is well -structured  
 
- Clinical applicability and relevance:  
o This study is highly relevant as it investigates two relatively new targeted ther apy approaches 
with 166Ho -Radioembolization being a particularly novel technique that enables accurate 
pre-and post -procedural imaging of treatment response on SPECT/CT.  
o Moreover, 166 -Ho imaging on MR may be a future application that offers radiation -free 
imaging for pre -procedural shunt evaluation as well as agent distribution patterns after 
radioembolization and can be easily integrated into the clinical workflow.  
 
- Abstract:  
o In the Abstract - Methods, it is written, that it is a 'two center' study, in the Methods it says 
'single -center'. Please clarify  
o In the Abstract - Methods it is described, that 166HO -RE is received within 12 weeks after 
PRRT. In Methods - Subjects and in Table 3 you tell the RE is within 20 weeks after PRRT.  
 
- Methods:  
o Metho ds and analyses are generally well described and appear standardized and reasonable.  
o For tumor response assessment only RECIST 1.1 was used. However, there are 3D response 
assessment techniques available that are more precise and should have been used in  this 
study, too.  
o Please clarify, if patients with previous treatment are ex - or included. It is only written, that 
all patients have not received conventional treatment options - does this refer to the time of 
recruitment or diagnosis? Were patients wit h additional treatments censored? Please include 
information about previous treatments in the inclusion and exclusion criteria  
o Will patients be excluded, if they get another therapy before the 3 -months follow -up CT?  
o Please describe the patient cohort in detail: Male / Female? Age? Etc.  
o Describe baseline (tumor) characteristics  
 
- Discussion:  
o The discussion relates to current evidence.  
o Mention limitations: e.g. small study cohort, non -comparative, single -center  
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
Yes 
Does the work include the necessary controls?  
If not, please specify which controls are required in your comments  to the authors.  
No 
Are the conclusions drawn adequately supported by the data shown?  
If not, please explain in your comments to the authors.  
Yes 
Are you able to assess any statistics in the manus cript or would you recommend an 
additional statistical revi ew? 
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
I am able to assess the statistics  
Quality of written English  
Please indicate the quality of language in the manuscript:  
Acceptable  
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, f ees, funding, or salary from an 
organisati on that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
2. Do you hold any stocks or shares in an organisation t hat 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 declare that I have no competing interests  
 
I agree to the open peer review policy of the journal. I  understand that my name will be included 
on my report to the authors and, if the manuscript is accepted for publication, my named report 
including any attachments I upload will be posted on the website along with the authors' 
responses. I agree for my rep ort to be made available under an Open Access Creative Commons 
CC-BY license ( http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments 
which I do not wish to be included in my named report can be included as confidential comments 
to the  editors, which will not be published.  
I agree to the open peer review policy of the journal  
assistant