MRI and PET Alterations in Adult Skull Base Tumors: A Narrative Review of Proton Versus Photon Radiotherapy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

Please refer to the attached "Comments to the Author" PDF file for detailed comments on the manuscript.

Thank you.

Comments for author File: Comments.pdf

Author Response

Reviewer 1 – Comment 1: Abstract reformulation

Comment: “Abstract (line 17–18): Radiotherapy is an essential component for the treatment of skull skull‑base tumours.”

Response: We sincerely thank the Reviewer for this constructive comment.  We corrected this typographical duplication and revised the sentence for clarity.

Location in revised manuscript: Page 1, Line 17.

Reviewer 1 – Comment 2: Abstract acronym (ASL)

Comment: “Abstract (line 31): Please spell ‘ASL’ in full and put its acronym in a bracket.”

Response: We are grateful for this helpful suggestion, which has strengthened the manuscript.  To keep the Abstract concise and to avoid introducing additional acronyms, we removed the explicit list of advanced MRI techniques from the Abstract. The Abstract now refers generically to ‘advanced MRI imaging’ and ‘amino-acid PET’.

Location in revised manuscript: Page 1, Lines 34–36.

Reviewer 1 – Comment 3: Abstract acronyms (RIBI and PET)

Comment: “Please use ‘RIBI’ and ‘PET’ as the acronyms have already been introduced.”

Response: We appreciate the Reviewer’s careful reading and thoughtful remark.  We revised the Abstract to consistently use acronyms after their first definition (RIBI and PET).

Location in revised manuscript: Page 1, Lines 17–20 (RIBI) and Lines 35–36 (PET).

Reviewer 1 – Comment 4: Abstract wording (‘fluorodeoxyglucose’)

Comment: “Use lowercase for ‘Fluorodeoxyglucose’ as it is not a proper noun.”

Response: We thank the Reviewer for this valuable observation and have revised the text accordingly.  The term was removed from the Abstract. Where relevant elsewhere, we use the correct lowercase form (fluorodeoxyglucose; FDG).

Location in revised manuscript: Abstract—Page 1, Lines 34–36; Abbreviations—Page 20, Line 664.

Reviewer 1 – Comment 5: Introduction redundancy

Comment: “Please delete the repetitive sentences… (lines 64–67).”

Response: We appreciate this important point and have clarified the manuscript as suggested.  We condensed the Introduction and removed redundant/repetitive phrasing to improve readability and flow while preserving the key message regarding rarity, complexity, and the need for highly conformal radiotherapy.

Location in revised manuscript: Page 2, Lines 46–58.

Reviewer 1 – Comment 6: Acronym (‘CT’)

Comment: “Introduction (line 147): Please spell ‘CT’ in full and put its acronym in a bracket.”

Response: We are thankful for this insightful comment, which improved the clarity of our work.  We spelled out computed tomography at first mention and retained the acronym thereafter.

Location in revised manuscript: Page 3, Line 102.

Reviewer 1 – Comment 7: Research questions / aims

Comment: “The manuscript would benefit from a clearer articulation of the research questions guiding the study… Please identify the questions that would be answered from the review.”

Response: We sincerely thank the Reviewer for this constructive comment.  We added explicit research questions at the end of the Introduction to clarify the objectives of this narrative review and to guide the structure of the subsequent sections.

Location in revised manuscript: Page 3, Lines 106–114.

Reviewer 1 – Comment 8: Significance of the review

Comment: “Please explain why this narrative review is needed and how it contributes to our current understanding of the topic.”

Response: We are grateful for this helpful suggestion, which has strengthened the manuscript.  We strengthened the Introduction by adding a statement of significance, emphasizing the increasing frequency of post-treatment imaging changes in the era of proton therapy, heterogeneity of terminology, and the clinical consequences of misclassification (unnecessary interventions or inappropriate treatment changes).

Location in revised manuscript: Page 3, Lines 115–117.

Reviewer 1 – Comment 9: Methods (publication year range)

Comment: “Please provide the range of publication years of the studies that were included in the review.”

Response: We appreciate the Reviewer’s careful reading and thoughtful remark.  We added the publication year range of the included literature in the Literature Search Strategy subsection.

Location in revised manuscript: Page 3, Lines 124–126.

Reviewer 1 – Comment 10: Methods (inclusion/exclusion criteria)

Comment: “Please provide the study’s inclusion and exclusion criteria.”

Response: We thank the Reviewer for this valuable observation and have revised the text accordingly.  We added an explicit ‘Study Selection and Inclusion Criteria’ subsection detailing population, intervention, and outcomes of interest, and we explicitly state exclusion criteria.

Location in revised manuscript: Pages 3–4, Lines 136–153.

Reviewer 2 Report

Comments and Suggestions for Authors

Congratulations on the very interesting article.
The radiation treatment and retreatment of brain tumors is a major challenge for the radiation oncologist. The use of various radiotherapy methods (photons and protons) can help reduce radiation toxicity. The greatest challenge is distinguishing true progression from pseudoprogression, and radiomics, MR, and PET FET or MET are essential for retreatment. I'll cite an article that also addresses this topic on brain tumors and should be cited in the introduction or discussion (PMID: 35447948). This need is even greater in cases of pediatric tumors such as DIPG (PMID: 37891817).
Congratulations again.

Author Response

Response to Reviewer 2

Reviewer 2 – Comment 1: Additional references (PMID: 35447948; PMID: 37891817)

Comment: The reviewer suggested adding references on radiomics/MRI/PET for progression vs pseudoprogression and the relevance to pediatric tumors (DIPG).

Response: We are thankful for this insightful comment, which improved the clarity of our work.  We incorporated the suggested references into the Introduction (advanced MRI, amino-acid PET and radiomics for distinguishing treatment effect from progression, particularly in re-irradiation) and into the Discussion/Future Research section (highlighting the greater challenge in pediatric tumors such as DIPG).

Location in revised manuscript: Introduction—Pages 2–3, Lines 86–89; Discussion/Future research—Page 19, Lines 621–624.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

This review summarizes post-radiotherapy imaging findings of skull-base tumors on MRI and PET. The topic is clinically relevant and could be useful for practice. Here’s my detailed comments:

1.In line 86, you state that proton-based therapy for chordoma requires 60–74 Gy, and then you repeat a very similar statement again in line 98 (“Adult patients often require high doses (60–74 Gy_RBE) for chordomas”). Please remove the redundancy or merge these two sentences.

2.Around line 117, you mention (as an example) that radiotherapy for pituitary adenoma rarely causes temporal lobe injury but may cause optic nerve enhancement. The above paragraph is discussing how anatomy relates to post-radiotherapy changes. This pituitary example is location-related as well fit better in that paragraph.

3.The section around lines 103–119 is a useful MRI-based summary of post-radiotherapy changes across different skull-base tumors. This content would be good from a skull-base anatomy schematic or a table for clearer presentation. Also, it is currently placed in the Introduction, which is already very long, 11 paragraphs. Most content reads like results/summary conclusions appears in the Introduction, which is not the purpose of an introduction. Introduction should be concise, 3–4 paragraphs, mainly sets the background and scope.

4.Lines 120–130 focus on skull-base regions involving the nasal cavity and paranasal sinuses. This is also location-based information. Consolidating all location/anatomy-related content into one coherent section in the main text.

5.For a narrative review, you typically do not need to separate the paper into “Methods” and “Results” as in an original study. The main section headings should be organized around key arguments.

6.In the “Results” section lines 185–251, the text is mostly a direct descriptive listing of findings from prior papers. A review should synthesize and distill the literature rather than repeat it. Consider summarizing these findings in tables and rewrite the text to provide a clear take-home structure.

7.In the meningioma section (line 272), the manuscript states “caution is needed when planning.” Please clarify what this specifically means. This phrasing is too generic—any radiotherapy planning requires caution. You mention that “high-dose volumes and prior irradiation increase risk,” but you do not define what “high-dose” means in the meningioma context. As a review, you should summarize practical dose/risk concepts more clearly.

Similar issues appear throughout the manuscript. Many sections read like copied summaries of individual studies without meaningful thininks, and tables/figures that could help summarize patterns are largely missing. Overall, the manuscript does not yet meet the expected standard for a basic review article.

Author Response

Response to Reviewer 3

Reviewer 3 – Comment 1: Redundant chordoma dose statement

Comment: “You state that proton-based therapy for chordoma requires 60–74 Gy, and then repeat a similar statement later. Please remove redundancy or merge.”

Response: We appreciate this important point and have clarified the manuscript as suggested.  We removed redundancy and retained a single concise statement. We also corrected the dose range to reflect typical high-dose prescriptions for chordoma (70–74 Gy[RBE]).

Location in revised manuscript: Page 2, Lines 67–71.

Reviewer 3– Comment 2: Pituitary adenoma example (location-related)

Comment: “The pituitary adenoma example… is location-related and would fit better in the anatomy/location paragraph.”

Response: We are thankful for this insightful comment, which improved the clarity of our work.  We moved and consolidated the pituitary/optic apparatus discussion into the dedicated pituitary adenoma/craniopharyngioma subsection and summarized location-dependent imaging pitfalls in the anatomy-based table.

Location in revised manuscript: Page 8, Lines 360–367 and Table 4 (Page 15, Line 536).

Reviewer 3 – Comment 3: Long Introduction / need for anatomy table

Comment: “The MRI-based summary… would be clearer as an anatomy schematic or table and should not be placed in an already long Introduction.”

Response: We sincerely thank the Reviewer for this constructive comment.  We condensed and refocused the Introduction, and we integrated the anatomy/location-driven synthesis into the Results and tabular summaries to provide a clearer take-home structure.

Location in revised manuscript: Introduction—Pages 2–3, Lines 45–120; anatomy/location summary—Table 4 (Page 15, Line 536).

Reviewer 3– Comment 4: Consolidate skull-base anatomy content

Comment: “Consolidate all location/anatomy-related content into one coherent section.”

Response: We are grateful for this helpful suggestion, which has strengthened the manuscript.  We consolidated key location/anatomy-dependent imaging pitfalls into Table 4 to avoid dispersing location-based details across multiple sections.

Location in revised manuscript: Table 4 (Page 15, Line 536).

Reviewer 3 – Comment 5: Narrative review structure (Methods/Results)

Comment: “For a narrative review, you typically do not need to separate the paper into ‘Methods’ and ‘Results’…”

Response: We appreciate the Reviewer’s careful reading and thoughtful remark.  We retained a concise Materials and Methods section to ensure reproducibility (as requested by the Editor), and we reorganized the Results into argument-based subsections (terminology, pathophysiology, MRI patterns, tumor-specific sections, dosimetric predictors, and advanced imaging).

Location in revised manuscript: Pages 3–4, Lines 121–160 (Methods) and Pages 4–11, Lines 166–512 (Results subsections).

Reviewer 3 – Comment 6: Synthesis and tabular summaries

Comment: “The Results section is mostly a descriptive listing… Consider summarizing findings in tables and rewrite to provide a clear take-home structure.”

Response: We thank the Reviewer for this valuable observation and have revised the text accordingly.  We revised the Results to emphasize synthesis and added/expanded summary tables to distill key incidence estimates, dose–volume predictors, and practical imaging pitfalls.

Location in revised manuscript: Section 3.5.2 (Page 9, Lines 392–406), Table 1 (Page 12, Lines 520–524), and Table 4 (Page 15, Line 536).

Reviewer 3 – Comment 7: ‘Caution’ and definition of ‘high dose’ in meningioma

Comment: “In the meningioma section… clarify what ‘caution’ means and define what ‘high-dose’ means in the meningioma context.”

Response: We appreciate this important point and have clarified the manuscript as suggested.  We removed vague wording and instead define relevant ‘high-dose’ concepts using dose–volume metrics reported in skull-base proton/photon cohorts (e.g., focal hot-spots such as V67Gy and broader high-dose burden such as D1%). These quantitative thresholds are presented as cohort-derived guidance rather than absolute rules.

Location in revised manuscript: Meningioma subsection—Page 8, Lines 353–359; Dose–volume definitions—Page 9, Lines 392–406; Discussion caveats—Page 18, Lines 590–601.