Review Reports

Round 1

Reviewer 1 Report

General remarks

Mirestean et al. summarized how recently elucidated (HPV)infection- and immune-related, as well as genetic aspects modify the prognosis and clinical outcome measures of HNSCC. The type of the manuscript is obviously a review. Unfortunately, authors did not specify the type of the review (narrative/literature review, scoping review or systematic review). This fact and the method of the selection, evaluation and interpretation should have been included in a “Materials and Methods” section and should also appear in the title of the manuscript. Moreover, in the second sentence of the title of the manuscript authors promise to reevaluate the iso-effect fractionation based on the Linear Quadratic (LQ) model as well as the influence of the “active immune phenotype in head and neck cancer” on the radiotherapy. The approach of the reevaluation and the integration of immune aspects (rather than “Immune phenotype”) in designing the radiotherapy to be applied for different subgroups of patients should also be clearly described in the missing “Materials and Methods” section. Without the well-defined methodology, the aim(s) of the review is/are not quite clear and do not allow firmly stated conclusions as written in the last sentence of the “Abstract” and in “Conclusions”. Sections 2. and 3. do not explain the important question: how exactly “the anti-tumor immune response”, in addition to other factors, such as “dose/fractionation/volume factors”, and “therapeutic sequence” “must” “be included … in the quadratic linear formalism for the adaptation of the a/b ratio in altered fractionation regimens …”. In section 4. authors quite concisely describe hypo-fractionated radiotherapy (HFRT) – mainly for frail patients and in the context of (COVID-19?) pandemics. Unfortunately, the don’t discuss any known or potential influence of immune aspects of HNSCC on the optimization of radiotherapy to be delivered by either conventional r alternative techniques, including HFRT. In summary, the essence of the manuscript is different from what was suggested by the title of the manuscript and the – not clearly described – aims as written in the Abstract and in the Introduction, and does not allow the deduction of quite firmly stated conclusions as written in the Abstract and Conclusions part.

Detailed remarks

The Introduction is too short. Authors should provide a more detailed background information on currently applied radiotherapy methods in HNSCC. How currently respected clinical and biological factors will be considered when designing radiotherapy. The definition and significance of some radiotherapy parameters, such as a/b ratio should be described for the sake of readers who are not engaged in irradiation therapy on a regular basis. Also, “active immune class” of HNSCC should be defined more explicitly.

Section 2., paragraph 1, line 10: “lower values of TP53” – authors should define how they quantify or how they compare “TP53 values”.

Section 2., paragraph 6, lines 6-9: The sentence cannot be easily understood. Again, I would suggest to interpret “radiobiological heterogeneity”, variation of radio-sensitivity during treatment” of HNSCC in the Introduction, in particular in HPV-associated cases.

Three sentences later in the same paragraph authors state: “… the subject of radiosensitivity and favorable response to chemotherapy in the HPV driven HNSCC subgroup remains controversial.” Maybe yes, maybe no. They should explain why they consider that issue controversial, and how this controversy can be solved taking immune aspects of HNSCC into consideration.

In section 3., paragraph one, authors highlight the importance of “6^th R”. However, they fail to discuss, how the interaction of tumor immune components and its irradiation would influence ultimately the applied methods and parameters of radiotherapy.

Grammar and style of the manuscript needs improvement.

Author Response

Dear Reviewer,

Thank you for the analysis and evaluation of the manuscript and for the time and effort allocated for this purpose. We made all the suggested minor corrections including replacing "lower values of TP53" with "expression" and explaining the radiobiological variability of radio-sensitivity. We also completed the manuscript and added paragraphs regarding both hypo-fractionated radiotherapy and the explanation of the linear quadratic model and the expansion of the introduction. We have subdivided a chapter into sub-chapters to make it easier to follow. We resumed the proposed linear quadratic model concept and introduced the new model concept at the end of the manuscript. To make it easier to follow the changes, we marked them in yellow and the inserts in the references were highlighted in red. Also, at the suggestion of another reviewer, we removed the self-citations Hoping that you will appreciate the new version of the manuscript, we are waiting for new suggestions.

Kind regards,

Camil Mirestean 

Reviewer 2 Report

The article "Active immune phenotype in head and neck cancer: Reevaluating the iso-effect fractionation based on the Linear Quadratic (LQ) model" is poorly written. 

It needs to be more readable due to a lack of organization.

In the introduction, the authors should focus on explaining the model well. The introduction part could be more robust and must be improved.

Authors must include a graphical abstract or diagram to clarify their point.

In parts 2 and 3, the information needs to be more organized and easier to read. To make it more clear, add subheadings.

Author Response

Dear Reviewer,

Thank you for the analysis and evaluation of the manuscript and for the time and effort allocated for this purpose. Even if for technical reasons we did not manage to make an abstract graph, we proposed a modified mathematical formalism for the LQ model. We also made the other suggested changes and corrections at the suggestion of the other reviewers. We also completed the manuscript and added paragraphs regarding both hypofractionated radiotherapy and the explanation of the linear quadratic model and the expansion of the introduction. We have subdivided a chapter into sub-chapters to make it easier to follow. We summarized the proposed linear quadratic model concept and introduced the new model concept at the end of the manuscript. To make it easier to follow the changes, we marked them in yellow and the inserts in the references were highlighted in red. Also, at the suggestion of another reviewer, we removed the self-citations. Hoping that you will appreciate the new version of the manuscript, we are waiting for new suggestions.

Kind regards,

Camil Mirestean 

Reviewer 3 Report

Remove the self-citations

Author Response

Dear Reviewer,

Thank you for the analysis and evaluation of the manuscript and for the time and effort allocated for this purpose. We removed the self-citations. We also made the other suggested changes and corrections at the suggestion of the other reviewers. We also completed the manuscript and added paragraphs regarding both hypo-fractionated radiotherapy and the explanation of the linear quadratic model and the expansion of the introduction. We have subdivided a chapter into sub-chapters to make it easier to follow. We summarized the proposed linear quadratic model concept and introduced the new model concept at the end of the manuscript. To make it easier to follow the changes, we marked them in yellow and the inserts in the references were highlighted in red. Hoping that you will appreciate the new version of the manuscript, we are waiting for new suggestions.

Kind regards,

Camil Mirestean