Radioligand Therapy in Meningiomas: Today’s Evidence, Tomorrow’s Possibilities

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Gabor Sipka et al. focus on the evolving role of PRRT in meningioma treatment, providing a comprehensive overview of preclinical research findings (including radiosensitization mechanisms) and summarizing relevant clinical literature, with a particular emphasis on advancements in dosimetry, quantitative imaging, and radiomics.

However, I would like to recommend that the authors solve the following issues before considering accepting the manuscript:

Major comments:

1. Figure 1 contains several errors. Firstly, the paper should specify which software was used to create the image. Secondly, typos such as “Modells” need to be corrected and verified, and the quotation mark formatting needs to be checked.
2. Meningioma tumor cells exhibit significant intra-tumoral and inter-patient heterogeneity. A human longitudinal meningioma single-cell atlas has already been published. I suggest the authors could supplement this section with information on the sources of heterogeneity and the tumor microenvironment.
3. For the content in the later sections, such as “future directions”, it is suggested that the authors include a scientific table to list current and ongoing clinical trials. For instance, a table of ongoing and upcoming clinical trials.
4. The author should base their work on the latest epidemiological, pathological, and guideline data, avoiding generalizations. The introductory section is too brief, and the introduction of the molecular basis and radioligand therapy is insufficient. It is suggested that a simple and clear table summarizing the WHO classification, recurrence rates, and SSTR expression be added after the first part of the introduction. This type of summary would be more intuitive and logical.
5. A very important flaw is that the author did not properly cite relevant articles. As for the treatment of meningioma, including images from clinical papers, patient data, and pathological analysis diagrams, would provide a more intuitive understanding of the disease.

Minor comments:

1. Some terms, such as “in vitro” and “in vivo”, should be changed to italics.
2. A schematic diagram could be considered for the “Combination Therapies with PRRT” section.

Author Response

We sincerely thank the reviewer for the thorough and constructive evaluation of our manuscript and for the insightful suggestions that helped us improve its clarity, scientific rigor, and structure. We have carefully revised the manuscript to address all comments as detailed below.

Major comments

Figure 1 (now Figure 2) formatting and errors
We corrected all typographical errors in Figure 2, standardized quotation mark formatting, and clarified the figure legend. The software used for image preparation is now explicitly stated in the caption, in accordance with the reviewer’s recommendation.

Tumor heterogeneity and tumor microenvironment
To address this important point, we added a contextual paragraph at the beginning of the Meningioma models subsection that summarizes key insights from recent human longitudinal single-cell and spatial transcriptomic studies. This new paragraph highlights intra-tumoral and inter-patient heterogeneity, temporal evolution from primary to recurrent disease, and the role of the tumor microenvironment, and explicitly links these features to the limitations of current preclinical meningioma models. This addition provides biological context without expanding the section beyond its preclinical focus.

Scientific table for ongoing clinical trials
In response to this suggestion, we added a concise scientific table (Table 4) in the Future Directions section summarizing key ongoing and clinically investigated PRRT-based strategies in meningioma, including randomized trials, combination approaches, delivery optimization strategies, and dosimetry-guided treatment concepts.

Expansion of the Introduction and inclusion of a summary table
The Introduction was substantially revised and expanded to incorporate up-to-date epidemiological, pathological, and guideline-based information, with reduced generalization. In addition, a clear summary table (Table 1) outlining WHO classification, recurrence risk, and somatostatin receptor expression was added to improve conceptual clarity and logical flow.

Citation of relevant literature and use of illustrative material
We carefully reviewed and expanded the reference list to ensure appropriate citation of relevant and up-to-date literature throughout the manuscript. We have strengthened the Diagnostics section by clarifying the complementary roles of conventional MRI and SSTR-targeted molecular imaging in meningioma evaluation. In addition, we have included a representative institutional imaging example comparing contrast-enhanced MRI with SSTR-targeted SPECT (Figure 1). This figure visually illustrates the superior lesion-to-background contrast of SSTR imaging and supports its diagnostic and theranostic relevance. All images were obtained during routine clinical care and anonymized in accordance with institutional guidelines.

Minor comments

Formatting of “in vitro” and “in vivo”
All instances of in vitro and in vivo have been corrected and consistently formatted in italics throughout the manuscript.

Schematic diagram for combination therapies
A schematic diagram could be considered for the “Combination Therapies with PRRT” section.
We carefully considered this suggestion. Instead of introducing an additional figure, we revised and refined the existing illustration to improve clarity and schematic representation of combination strategies involving PRRT.

Reviewer 2 Report

Comments and Suggestions for Authors

This is a comprehensive, well-structured narrative review that synthesises current evidence on PRRT in meningioma across diagnostics, preclinical biology, and clinical outcomes. The manuscript is timely and clearly written, with strong integration of imaging, dosimetry, and theranostic concepts. With targeted clarifications and tighter critical framing in selected sections, it would be suitable for publication.

Introduction: clarify more explicitly the unmet clinical need and where PRRT fits relative to surgery and radiotherapy across WHO grades, rather than introducing PRRT primarily as an emerging option.

Diagnostics: strengthen discussion on limitations and variability of SSTR imaging (e.g. heterogeneity, false positives, temporal changes in expression) and how this affects PRRT eligibility and response prediction.

Standard of Care: Add a clearer distinction between evidence-based standard treatments and investigational systemic options, explicitly positioning PRRT as non-standard and typically later-line.

PRRT: The section would benefit from a concise critical appraisal of applying NET-derived protocols to meningioma, including uncertainties around dose, cycles, and patient selection.

Preclinical studies: Highlight more explicitly the translational gap between preclinical models and clinical meningioma biology, especially given limited meningioma-specific PRRT models. Also, consider streamlining the extensive mechanistic detail and adding a short synthesis paragraph that prioritises which preclinical strategies are most likely to reach clinical testing.

Clinical Studies: Emphasise the heterogeneity and bias across clinical cohorts (grade mix, prior therapies, endpoints), and caution against over-interpretation of disease stabilisation rates. Also, expand the discussion on what remains unknown (optimal sequencing, comparative efficacy, biomarkers) and clearly frame LUMEN-1 as hypothesis-defining rather than practice-changing at this stage.

Author Response

We thank the reviewer for the positive overall assessment of our manuscript and for the insightful comments that helped strengthen its clinical framing, critical balance, and translational relevance. We have revised the manuscript accordingly, as detailed below.

Introduction and clinical positioning

The Introduction was revised to more explicitly emphasize the unmet clinical need in meningioma management, particularly in patients with recurrent, inoperable, or radiation-refractory disease. PRRT is now clearly positioned in relation to established treatment modalities—surgery and radiotherapy—across WHO grades, and framed as an investigational, later-line option rather than a general emerging therapy.

Diagnostics

We expanded the Diagnostics section to address important limitations of SSTR-targeted imaging, including intra-tumoral and inter-lesional heterogeneity, false-positive uptake, and temporal changes in receptor expression. The implications of these factors for PRRT eligibility, patient selection, and response prediction are now discussed in greater detail.

Standard of care

The Standard of Care section was revised to more clearly distinguish evidence-based treatments from investigational systemic options. PRRT is explicitly described as non-standard and typically considered in later-line settings, following exhaustion of surgery and radiotherapy where feasible.

PRRT section

We added a concise critical appraisal of applying neuroendocrine tumor–derived PRRT protocols to meningioma, highlighting existing uncertainties related to administered activity, number of cycles, treatment intervals, and patient selection. The extrapolative nature of current practice is now explicitly acknowledged.

Preclinical studies

The preclinical section was revised to more clearly highlight the translational gap between available experimental models and clinical meningioma biology, particularly given the limited number of meningioma-specific PRRT models. Extensive mechanistic detail was streamlined, and a synthesis paragraph was added to prioritize preclinical strategies with the highest likelihood of clinical translation.

Clinical studies

The clinical section was updated to emphasize heterogeneity and potential sources of bias across published cohorts, including differences in WHO grade distribution, prior treatments, and clinical endpoints. We added explicit caution against over-interpretation of disease stabilization rates and expanded the discussion of remaining uncertainties, such as optimal treatment sequencing, comparative efficacy, and biomarker development. In addition, the ongoing LUMEN-1 trial is now clearly framed as hypothesis-defining rather than practice-changing at the current stage.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is strong and publishable, but its impact would be further improved following the suggestions below:

INTRODUCTION

The Introduction would benefit from a clearer articulation of the clinical problem that PRRT is intended to address.

• While the epidemiology, grading, and molecular heterogeneity of meningiomas are well described, the unmet clinical need—particularly for patients with multiply recurrent, inoperable, or radiation-refractory disease—could be emphasized more explicitly.

• The rationale for focusing on PRRT should be sharpened earlier, clearly positioning it as a response to the failure of existing systemic therapies rather than as a general emerging technology.

• A brief paragraph outlining the specific aims and scope of this review (e.g., preclinical mechanisms, clinical efficacy benchmarks, and future integration strategies) would help guide readers and frame the subsequent sections.

METHODOLOGY

The manuscript lacks a description of the literature search and selection methodology, which limits transparency and reproducibility.

• Although this is a narrative review, readers would benefit from a short subsection describing:

  • Databases searched (e.g., PubMed, Scopus, Embase),

  • Time frame covered,

  • Types of studies included (preclinical, retrospective clinical studies, prospective trials),

  • Any exclusion criteria (e.g., case reports, abstracts only).

• Given the extensive and detailed clinical summary (especially Table 2), it is unclear how studies were selected and whether the review aimed to be exhaustive or selective.

• Including a brief methodological statement would strengthen the academic rigor of the manuscript and align it with current expectations for high-quality narrative reviews.

RESULTS

The evidence synthesis is thorough but highly heterogeneous, and clearer differentiation between levels of evidence is needed.

• The manuscript integrates preclinical findings, early-phase clinical studies, retrospective cohorts, and meta-analyses in a continuous narrative. While informative, this occasionally blurs the distinction between:

  • Hypothesis-generating preclinical data,

  • Exploratory clinical observations,

  • Evidence that may reasonably inform current clinical practice.

• In the clinical sections, disease stabilization and PFS-6 are appropriately emphasized; however, the limitations of these endpoints—particularly in non-randomized studies—should be more explicitly acknowledged.

• Table 2 (page 11) is comprehensive but would benefit from a short interpretive synthesis highlighting:

  • Typical ranges of PFS-6 across grades,

  • The rarity of objective radiological responses,

  • The consistency (or inconsistency) of benefit across different radionuclides and study designs.

DISCUSSION

The Discussion is forward-looking and scientifically compelling, but at times overextends beyond the current strength of clinical evidence.

• Combination strategies (e.g., PRRT with EBRT, DNA-repair inhibitors, mTOR inhibition) are discussed in depth and with strong biological rationale; however, the manuscript should more clearly distinguish theoretical or preclinical promise from clinically validated approaches.

• Potential risks and challenges—such as cumulative toxicity, patient selection, and feasibility in heavily pretreated populations—are underrepresented relative to the enthusiasm for combination therapies.

• The positioning of PRRT within the current treatment algorithm remains somewhat implicit. A more explicit statement on:

  • When should PRRT be considered today?

  • In which patient subgroups is it most defensible?

  • How it compares pragmatically to re-irradiation or best supportive care,
    Could substantially enhance the clinical relevance of the Discussion?

• The section would also benefit from a clearer acknowledgment that many conclusions remain contingent on the results of possible ongoing randomized trials (e.g., LUMEN-1).

Author Response

We appreciate the reviewer’s thoughtful and detailed critique and their constructive suggestions aimed at further enhancing the clarity, evidentiary balance, and clinical relevance of the manuscript.

 

Introduction

The Introduction was revised to more clearly articulate the specific clinical problem that PRRT is intended to address, with explicit emphasis on patients with multiply recurrent, inoperable, or radiation-refractory meningioma. The rationale for focusing on PRRT is now sharpened and positioned as a response to the limited efficacy of currently available systemic therapies rather than as a broadly emerging technology. In addition, a brief paragraph outlining the aims and scope of the review was added to guide readers through the preclinical, clinical, and future-oriented sections.

Methodology

To improve transparency and academic rigor, we added a concise methodological statement describing the literature search and selection process. This includes the databases searched, the time frame covered, the types of studies included, and general exclusion criteria. While maintaining the narrative review format, this addition clarifies whether the review was intended to be selective rather than exhaustive, particularly with respect to the clinical studies summarized in Table 2.

Results and evidence hierarchy

The Results sections were revised to more clearly differentiate between levels of evidence, explicitly distinguishing hypothesis-generating preclinical data, exploratory clinical observations, and evidence that may inform current clinical practice. In the clinical sections, we expanded the discussion of the limitations of commonly used endpoints, including disease stabilization and PFS-6, particularly in non-randomized and heterogeneous cohorts. In addition, a short interpretive synthesis was added following Table 2, summarizing typical PFS-6 ranges across WHO grades, the rarity of objective radiological responses, and the consistency of observed benefit across different radionuclides and study designs.

Discussion

The Discussion was refined to more clearly distinguish biologically plausible or preclinical combination strategies from approaches that have been clinically investigated. Potential risks and challenges—such as cumulative toxicity, patient selection, and feasibility in heavily pretreated populations—are now more explicitly acknowledged. Furthermore, the positioning of PRRT within the current treatment algorithm is clarified, including when PRRT may be considered in contemporary practice, which patient subgroups are most defensible candidates, and how PRRT compares pragmatically with alternative options such as re-irradiation or best supportive care. Finally, we explicitly acknowledge that many forward-looking conclusions remain contingent on the results of ongoing randomized trials, including LUMEN-1, which is now clearly framed as hypothesis-defining rather than practice-changing at this stage.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed most of my previous concerns. I don't have any further questions.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for your revision