Estimation of Dose Enhancement for Inhomogeneous Distribution of Nanoparticles: A Monte Carlo Study

Round 1

Reviewer 1 Report

The paper is well written and the experimental approach is on average comprehensively described. The final conclusions are supported by the results and rightly affirm that further studies are requested to evaluate the clinical effects of such an approach. 
Just a few comments that you can take into consideration before the publication:

- row99: it is not clear for me what do you mean for 'studying the size or shape of the NPs'. Perhaps do you refer to the effects of these properties on the enhancement effects?

- rows 149-151: A graphical sketch could help to better understand to the reader the technique used to determine the depth DEF

- rows 254:  I presume that also a significant amount of direct and compton scattered gamma rays deposit their energy in the healty tissues. Will these topics deeply studied in future papers if a clinical approach of this technique has to be considered?

- row 261-263: The meaning is a repetition of what is written in 245-247.

Author Response

Please find enclosed the response to the reviewer comments

Author Response File: Author Response.pdf

Reviewer 2 Report

The present manuscript studies macroscopic NP dose enhancement under X-ray irradiation of different energies, while taking into account that due to tumour vascularization problems, the NP distribution in the tumour (and thus, dose enhancement) could be highly inhomogeneous. Results are well justified and presented in a generally very clear and tidy manner and a range of conditions (beam energy, NP concentration, NP material) is investigated. Some modifications are recommended for improvement before publication, as follows. In particular, the discussion section is currently needs more attention to be strengthened.

abstract; this manuscript uses a continuum concentration of the metal in question as if "dissolved" in the water/tissue. While I agree that for photon radiation, the present macroscopic description and the code used this is a valid approach to deal with a distribution of nanoparticles, the word nanoparticle could be misleading. I recommend the authors add a more specific mention that the "particles" are not discrete but a uniform material concentration, in the abstract.

Introduction, l.40; a contiguous organ at risk should always be spared, not only if "functionally" related to the tumor

Introduction, l.45; until now, they are much studied but not (yet) very used except in first trails, please rephrase.

p.2, l.74; why was the phantom volume chosen with the specific dimensions (quite elongated)?

p.3, l.96; "overestimate the dose in some cases", thanks for this remark which is sometimes neglected. I guess this is due to the absence of self-absorption in the mixture technique? Can you provide a comment for the readership?

p.3, l.122; the authors state that the highest concentration is only for comparison. For fairness, a clear statement about the realistic maximum concentration (non-toxic for patients), or typical experimental concentrations, is needed. I'm not sure about the other metals, but e.g. for Au the generally accepted concentration is 1%(w/w), corresponding to the present lowest 10mg/g.

p.4, l.162; ".. it can be noted that, ..., the enhancement gradient is steeper." I'm not very convinced; the largest difference (from proportional behaviour) between concentrations I see is the assymmetric behaviour across the tumour at the lowest energy - but that would mean an effective dose reduction downstream of the target which means an advantage for conformality. Please add further explanation/arguments or consider modifying.

p.6, l.185; how sensitive are the results to the depth of the target volume? please discuss.

Figures 2,3,4; The DEF depth curves would be better appreciated with the vertical axes adapted to the maximum effect at each energy. In the present shape, panels (c) and (d) are not too useful. The decimal points on the vertical axis labels can be removed (also in fig.5).

p.7, l.203; "This is due to water having the highest electronic density than any NPs mixtures used in this study." do the authors mean per mass (due to the higher neutron content of the heavier materials)? The electron density per volume is surely larger for the much more compact metals. PLease clarify.

Figure 5; in the right part, for better visual clarity the vertical axis should be limited to approximately the range covered by the data.

Figure 7; in the right part, for better visual clarity the vertical axis should be limited to the maximum % contribution that actully occurs, ~40%.

p.10, l.243; maybe I missed it, but I cannot find a definition of epsilon; please check.

p.11, l.257; what total dose is meant here, or putting it differently, what is kept constant? the fluence? (at surface?) This is hard to understand for spanning 2-3 orders of magnitude. please clarify, also in caption of fig. 7.

Discussion; the first paragraph is a useful background/current-state summary but should be moved to the introduction. On the other hand, a comparison of the results found with other similar published applications is missing - at least partially as far as available and similar effects were studied. This is to ensure that the present results are quantitatively consistent with existing work. Since various materials and energies are included in the present manuscript, some overlaps can surely be found. Please add. Other points that could be addressed for a more comprehensive overall picture are e.g.:
Monoenergetic energies are chosen for this study. Can the authors give an extrapolative outlook how the results would look like for typical X-ray tube photon spectra or what the main differences would be?
In application scenarios it is often assumed that the NPs are injected directly into the tumour mass. In this case, the present model (assumed NP distribution) would not be realistic; please add a comment.
In view of the results, is there any recommendation/reflection regarding the fractionation scheme for NP-enhanced therapy of hypoxic tumours? (I'm thinking about shrinkage and reoxygenation, maybe the DEF distribution would move across the tumour in the course of treatment...) Likewise, do you anticipate an impact on planning margins due to the slightly dose-enhanced contiguous NT?

Author Response

Please find enclosed the response to the reviewer comments

Author Response File: Author Response.pdf