Hadron Therapy Achievements and Challenges: The CNAO Experience

Round 1

Reviewer 1 Report

The author reports on recent R&D and future plans performed for advanced hadron therapy with many collaborators and clinical research at CNAO. Research topics for next-generation hadron therapy are shared in the world. Many groups have worked on them and CNAO is one of the leading groups.

As an overview, the manuscript contains current topics in hadron therapy, such as IGRT, adaptive therapy and FLASH. However, the topics mentioned in the manuscript are full of subjects at CNAO with European collaborators. I would strongly recommend to modify the title, e.g. "Hadron therapy achievements and challenges at CNAO". In that case, the abstract would also be revised.

The text with respect to all of the subjects is good. Some subjects need to add quantitative descriptions or the purpose of the plan.
In the section of "The third ion source", the performance achieved by its new ion source and/or comparison with existing sources are not clear.
In the section of "Improving delivery technology", I would recommend to clarify the target value of the improved dose rate.
In the section of "Single room for proton therapy", the manuscript presents a plan to install an additional proton therapy apparatus to CNAO, even though the existing CNAO machine can provide the clinical proton beam. It is better to give the purpose why CNAO requires the additional proton machine.

In addition, some minor corrections should be applied, prior to publication.
 
Specific comments 
 
The language could be more precise - please check. e.g.) 
Line 63-65: "Moreover, the higher fraction of ... are processed ..."
Line 225: "The parameters has been ..."
Line 767: "Dosimetric evidence ... need ..."
Line 768: "Trough" --> "Through"

Fig. 1: What is "(a)" located in the bottom right of the figure?

Line 103-104: "can potentially accelerate other ion species" is misleading. Potentially, any PT or CIRT center would be able to accelerate other ion species.

Table 1: Is there the difference in meaning between "4 Bragg peak modulation step" and "5 Range adjustment"?

Table 1: What is the indices "1" in the 2nd column of the row 10, 11, 12, etc.

Line 376-379: The sentence of "In the case of ..." is difficult to understand. Relations of the tracking, additional detector and secondary particles are not clear.

Line 408: Please indicate the meaning of "compliance interval".

Line 684,756,770: Abbreviations, "NTCP","IMPT","CIRT", have been previously defined.

Line 937-939: The sentence of "These data evidence ..." is difficult to understand.

Author Response

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Author Response File: Author Response.PDF

Reviewer 2 Report

GENERAL COMMENTS:

In general the quality of the review is high. There is a good general discussion about the state-of-art regarding the status of hadron therapy currently. The manuscript is well described as well as rigorously detailed and compared with the literature. The only item to be improved is the English, which must be checked in depth. Please check it with an English native speaker or professional human translator.

SPECIFIC comments:

1. since the overall details described in the manuscript are mainly based on the CNAO experience, it must appear in the title explicitly. For example:

   “Hadron Therapy achievements and challenges from the CNAO experience”

   or something like it where it is clarified that it is focused on the CNAO advances and research.

2. please add the reference of Fig. 1 if applicable. It seems that it comes from another source.

3. Line 41: Please add correctly the latin abrevation, for example: “i.e.,” “e.g.,”. Please do the same in the rest of the manuscript.

4. line 59: please define RBE the first time where it appears.

5. pag.4, lines 111-159: although the European ENLIGHT and HITRIplus are interesting networks/projects, this is out of the scope of the paper. Therefore, this part should be removed.

6. Lines 578-583: please add any reference regarding dose average LET

Author Response

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Reviewer 3 Report

The author provides an extensive review on the hardware (development) and clinical application of hadron therapy. The review is well-writen allthough at times can be a bit too lengthly. The author should perhaps be a bit more cautious in clinical conclusions on hadron therapy, as non of the evidence is level I evidence.

Major comment:

-the author should mention and explain the model-based approach (Langendijk, The Netherlands), for example in het head and neck section or in the clinical trials section as an alternative to clinical trials for hadron/proton therapy

 

Author Response

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Round 2

Reviewer 1 Report

The author resubmitted a revised manuscript. It has improved significantly and is ready for publication.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Although the English has been improved in the manuscript, there is not an author's reply-letter of my previous questions. Actually, two of those questions have not been considered, namely:

• please add the reference of Fig. 1 if applicable. It seems that it comes from another source.

  • Please clarify if this figure comes from another source and, if so, add the corresponding reference. Otherwise, clarify if you created that figure.

• pag.4, lines 111-159: although the European ENLIGHT and HITRIplus are interesting networks/projects, this is out of the scope of the paper. Therefore, this part should be removed.

  • Please consider this item. Although this section is interesting, it is out of the scope of the paper. Even though, you can comment in a few sentences in the introduction something related to HITRIplus in case you would like to give visibility to this project into the CNAO framework.

Please, consider these two items and change the manuscript accordingly.

Also, another revision of the English is required.

Author Response

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Reviewer 3 Report

The authors have extensively modified the manuscript and have adopted my suggestion to mention and explain the model based selection approach.

Author Response

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Author Response File: Author Response.pdf