Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

One of the main limitations of the article is the small sample size, which is partly attributable to the rarity of the disease.

On the other hand, the mean follow-up of 96 months represents a major strength of the study, reinforcing the findings and supporting their long-term robustness.

The sections comparing the study results with surgical treatments should be expanded, providing a more detailed discussion of the advantages and disadvantages of each treatment option, with reference to the largest patient cohorts reported in the literature.

Similarly, greater emphasis should be placed on the preoperative follow-up period, which is essential for understanding the natural history of the disease. In cases of very slow-growing tumors, a “wait-and-scan” strategy may represent an appropriate management option, whereas documented tumor growth would favor active treatment. Different considerations apply to younger patients, who should be treated regardless.

Furthermore, the use of a universally recognized classification system, such as the Modified Fisch and Mattox classification, is mandatory to better define the relationship between the disease and surrounding neural and vascular structures, as well as bone erosion and intradural extension.

In Table 1, patient number two is reported as having a right internal auditory canal paraganglioma; however, the cells of origin of paragangliomas are not present within the internal auditory canal. This raises the possibility that the tumor may instead have originated from the jugular bulb or the middle ear with subsequent extension into the internal auditory canal, or that the lesion may be attributable to a different histological entity.

Finally, cases are described as inoperable without clearly defining the criteria for inoperability; recent literature has addressed the surgical feasibility of so-called “inoperable” paragangliomas, and these studies should be cited and discussed. 

Author Response

One of the main limitations of the article is the small sample size, which is partly attributable to the rarity of the disease.

On the other hand, the mean follow-up of 96 months represents a major strength of the study, reinforcing the findings and supporting their long-term robustness.

The sections comparing the study results with surgical treatments should be expanded, providing a more detailed discussion of the advantages and disadvantages of each treatment option, with reference to the largest patient cohorts reported in the literature.

Response: Four paragraphs and six references have been added to the introduction section for this topic.

Similarly, greater emphasis should be placed on the preoperative follow-up period, which is essential for understanding the natural history of the disease. In cases of very slow-growing tumors, a “wait-and-scan” strategy may represent an appropriate management option, whereas documented tumor growth would favor active treatment. Different considerations apply to younger patients, who should be treated regardless.

Response: One paragraphs and  two references have been added to the introduction section for this topic.

Furthermore, the use of a universally recognized classification system, such as the Modified Fisch and Mattox classification, is mandatory to better define the relationship between the disease and surrounding neural and vascular structures, as well as bone erosion and intradural extension.

Response: One paragraphs and  one reference have been added to the introduction section for Fisch classification.

In Table 1, patient number two is reported as having a right internal auditory canal paraganglioma; however, the cells of origin of paragangliomas are not present within the internal auditory canal. This raises the possibility that the tumor may instead have originated from the jugular bulb or the middle ear with subsequent extension into the internal auditory canal, or that the lesion may be attributable to a different histological entity.

Response: The tumor was jugulotympanic origin with extension into the internal auditory canal. expression added

Finally, cases are described as inoperable without clearly defining the criteria for inoperability; recent literature has addressed the surgical feasibility of so-called “inoperable” paragangliomas, and these studies should be cited and discussed. 

Response I found two separate major studies on this topic. I've included them in the discussion along with their references.

Reviewer 2 Report

Comments and Suggestions for Authors

Introduction

The Introduction is interesting and well written, providing a detailed description of the pathology. However, it is overly extensive and addresses topics that are not described in the methodology or results sections. As this study is primarily focused on radiotherapy and imaging-based response, I suggest that the Introduction be more clearly oriented toward these aspects.

Methodology

The authors do not include hearing loss and tinnitus, which are part of the natural course of the disease, given that the cochlea is involved in the treatment of paragangliomas. Therefore, I suggest including an analysis distinguishing whether auditory damage is secondary to the treatment per se or to tumor progression; this distinction should be clearly described in the methodology.

Results

The results are interesting; however, several points should be considered:

1. The authors should clearly define the term “median radiological response.” In this context, they should specify whether tumor size decreased or describe the type of response that was observed.
2. The authors should clarify what is meant by “median absolute increase of 50 percentage.” If this refers to tumor size reduction, it should be clearly defined, as these tumors are typically stable, as the authors themselves indicate.
3. The authors do not specify which type of patients presented persistent symptoms (those treated with 3D-CRT or IMRT); this distinction is important and should be clarified.

Tables

Although the sample size (n = 15) is small, I suggest that the tables present summarized data (mean, median, percentages), grouping patients rather than presenting individual data, and that the full tables be included as supplementary material.

There are typographical errors in Tables 1, 2, and 4, which should be carefully revised.

In Table 2, under clinical outcome, the term “Stable symptoms” is used, which may be confusing for readers. I suggest using standardized terms such as Stable, Improved, Resolved, etc., and presenting clinical outcomes in a separate column or as a table footnote.

Table 2: Patients 5, 7, 14, and 15 show a response of less than 100% at 24 months; is this consistent with the designation of complete response?

Discussion

In Tables 2 and 4, the authors report an adequate response with a mean of 70%, which suggests a significant volumetric tumor reduction; however, in the Discussion they describe paragangliomas as “stable” masses associated with fibrosis. Therefore, I suggest addressing this apparent discrepancy by clarifying whether the reported 70% response corresponds to tumor size reduction or fibrotic changes, in order to avoid confusion.

Additionally, the authors state that a cohort of 15 cases is sufficient, despite the statistical limitations of such a sample size. I recommend clarifying that this is a representative but limited sample intended to demonstrate treatment success, and that further studies are required.

The authors should emphasize “tumor stability” and explicitly acknowledge the absence of auditory evaluation as an important limitation.

In the Conclusions section, the integration of genetic studies is mentioned; it should be clarified that correlating radiotherapy outcomes with genetic studies is suggested as a future approach to better evaluate tumor behavior.

Author Response

The Introduction is interesting and well written, providing a detailed description of the pathology. However, it is overly extensive and addresses topics that are not described in the methodology or results sections. As this study is primarily focused on radiotherapy and imaging-based response, I suggest that the Introduction be more clearly oriented toward these aspects.

Response Two paragraphs and three additional references have been added to the introduction section for radiological evaluation. Two paragraphs and two additional references have been added to the introduction section on radiotherapy in HNPG.

Methodology

The authors do not include hearing loss and tinnitus, which are part of the natural course of the disease, given that the cochlea is involved in the treatment of paragangliomas. Therefore, I suggest including an analysis distinguishing whether auditory damage is secondary to the treatment per se or to tumor progression; this distinction should be clearly described in the methodology.

Response Tinnitus did not improve after RT in 4 patients (26.6%). This symptom also did not improve in 1 patient (0.6%) with hearing loss. While some of these findings were present initially, and because no progression was observed in any patıent. they may also be due to RT-related toxicity. These findings clearly described in methodology and results section.

Results

The results are interesting; however, several points should be considered:

1. The authors should clearly define the term “median radiological response.” In this context, they should specify whether tumor size decreased or describe the type of response that was observed.

 

Response Radiological response was evaluated on follow-up MR imaging according to the (RECIST), version 1.1 with percentage changed volumetric evaluations

 

The authors should clarify what is meant by “median absolute increase of 50 percentage.” If this refers to tumor size reduction, it should be clearly defined, as these tumors are typically stable, as the authors themselves indicate.

Response We thank the reviewer for highlighting this ambiguity. The phrase “median absolute increase of 50 percentage” could have been misinterpreted, and has been revised. In addition to RECIST version 1.1–based unidimensional assessment, volumetric tumor analysis was performed to better characterize treatment-related changes. Tumor volumes were calculated on pre- and post-radiotherapy MRI by manual contouring of the lesion on consecutive axial slices, and total tumor volume was obtained by summation of contoured areas multiplied by slice thickness. Percentage volumetric change was calculated by comparing baseline and follow-up volumes. Volumetric analysis was used as a complementary method to RECIST, particularly given the typically stable radiological appearance and irregular morphology of head and neck paragangliomas. Based on volumetric analysis, demonstrated a median tumor reduction of 20% at 3. months and 70% after the 24 months.

This information has been added to the method and discussion section. It was supported by 1 reference in the discussion.

 

1. The authors do not specify which type of patients presented persistent symptoms (those treated with 3D-CRT or IMRT); this distinction is important and should be clarified.

Response: Among the 10 patients with persistent symptoms, 4 had been treated with 3D-CRT. Given that a total of 5 patients received 3D-CRT (80%), persistent symptoms were observed in of this group. In the IMRT cohort, 6 of 10 patients (60%) experienced persistent symptoms. This information has been added to the result section.

 

 

Tables

Although the sample size (n = 15) is small, I suggest that the tables present summarized data (mean, median, percentages), grouping patients rather than presenting individual data, and that the full tables be included as supplementary material.

Response In accordance with the recommendation, we have revised the tables in the main manuscript to present summarized data, including means, medians, and percentages, rather than individual patient-level data. The complete tables containing detailed individual patient information have been moved to the Supplementary Materials. These revisions have been implemented to improve clarity and readability while preserving data transparency (Table 1 and Supplementary Tables S1).

There are typographical errors in Tables 1, 2, and 4, which should be carefully revised.

In Table 2, under clinical outcome, the term “Stable symptoms” is used, which may be confusing for readers. I suggest using standardized terms such as Stable, Improved, Resolved, etc., and presenting clinical outcomes in a separate column or as a table footnote.

Response: In response, we have revised Table 2 by replacing the term “stable symptoms” with standardized clinical outcome terminology. Clinical outcomes are now categorized as resolved, improved, stable, or progressed. To improve clarity, clinical outcome has been presented in a separate column, and the definitions of each category have been added as a table footnote.

Table 2: Patients 5, 7, 14, and 15 show a response of less than 100% at 24 months; is this consistent with the designation of complete response?

Response There has been some confusion here as well. Although these patients did not show a complete response, complete clinical recovery was observed. A complete radiological response was seen in only one patient. This information has been corrected in the methods section and the table.

Discussion

In Tables 2 and 4, the authors report an adequate response with a mean of 70%, which suggests a significant volumetric tumor reduction; however, in the Discussion they describe paragangliomas as “stable” masses associated with fibrosis. Therefore, I suggest addressing this apparent discrepancy by clarifying whether the reported 70% response corresponds to tumor size reduction or fibrotic changes, in order to avoid confusion.

Response Percentage volumetric change was calculated by comparing baseline and follow-up volumes. Volumetric analysis was used as a complementary method to RECIST, particularly given the typically stable radiological appearance and irregular morphology of head and neck paragangliomas. Based on volumetric analysis, demonstrated a median tumor reduction after 24 months is 70%. This information has been corrected in the methods section and the table.

Additionally, the authors state that a cohort of 15 cases is sufficient, despite the statistical limitations of such a sample size. I recommend clarifying that this is a representative but limited sample intended to demonstrate treatment success, and that further studies are required.

Response: This information added to conclusion section.

The authors should emphasize “tumor stability” and explicitly acknowledge the absence of auditory evaluation as an important limitation.

Response All patients underwent auditory testing before and one year after RT. This information has been added to the methods section.

 

In the Conclusions section, the integration of genetic studies is mentioned; it should be clarified that correlating radiotherapy outcomes with genetic studies is suggested as a future approach to better evaluate tumor behavior.

Response The information you suggested has been added to the Conclusion section.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

All reviewer suggestions have been adequately addressed. The manuscript is recommended for acceptance without further revisions.