Surgical Approach to Liver Metastasis from Gastroenteropancreatic Neuroendocrine Tumors in the Era of Precision Oncology^†

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

• The manuscript does not provide sufficient novelty for publication as it largely summarizes already well-established concepts regarding surgical management of neuroendocrine liver metastases (NELMs), without presenting a substantially new perspective, updated framework, or critical reinterpretation of existing evidence. Much of the discussion reiterates current guideline recommendations from ENETS, NANETS, and ESMO without significant conceptual advancement.
• The review lacks a clearly defined methodology for literature selection. There is no description of search strategy, database sources, inclusion/exclusion criteria, time frame, or quality assessment of included studies. This significantly weakens the scientific rigor and reproducibility expected from a high-quality review article.
• The manuscript is heavily dependent on retrospective studies and single-center experiences, while critical appraisal of evidence quality is insufficient. The authors frequently present survival outcomes without adequately discussing selection bias, heterogeneity, and limitations of retrospective comparisons, particularly in sections on liver resection and transplantation.
• The discussion on liver transplantation is disproportionately extensive compared with other treatment modalities and tends to overemphasize transplantation benefits despite its applicability to only a very small subset of patients (<1%). A more balanced discussion of practical clinical relevance is needed.
• Important contemporary developments such as molecular biomarkers, radiomics, circulating tumor DNA, and AI-assisted patient selection for surgical decision-making are not adequately discussed, limiting the manuscript’s relevance for modern precision oncology and translational clinical practice.
• Figures 1 and 2 are overly simplified and largely schematic without sufficient explanatory depth. Figure 1 (classification system) and Figure 2 (therapeutic algorithm) appear descriptive rather than evidence-driven and do not significantly enhance the scientific value of the manuscript. Their originality and citation sources should also be clarified.
• Table 1 and Table 2 summarize guideline recommendations and transplant criteria, but they largely duplicate already published consensus statements without providing comparative interpretation, controversy analysis, or practical decision-making guidance for clinicians.
• Several sections contain grammatical errors, awkward sentence construction, and syntax problems that reduce readability and professionalism. For example, phrases such as “when curative resection it is not feasible” and “derived from retrospective registries” require substantial language revision throughout the manuscript.
• The manuscript lacks sufficient discussion of negative outcomes and postoperative morbidity, including complications after aggressive cytoreduction, ALPPS, and liver transplantation. Surgical risk, perioperative mortality, and quality-of-life tradeoffs are underrepresented compared with survival-focused reporting.
• The section “Practical limitations and unmet needs” is too brief and generic for a review article intended for a high-impact oncology journal. It does not provide a robust future research roadmap, prospective trial design suggestions, or institutional strategies to address the identified gaps.
• Several references are outdated relative to the rapidly evolving field, especially in sections addressing systemic therapy integration and PRRT. More recent prospective studies and 2024–2025 consensus updates should be critically incorporated rather than relying predominantly on older retrospective surgical literature.

Author Response

We thank the Reviewer for the constructive comments. We have revised the manuscript accordingly and summarize the main changes below.

 

• The manuscript does not provide sufficient novelty for publication as it largely summarizes already well-established concepts regarding surgical management of neuroendocrine liver metastases (NELMs), without presenting a substantially new perspective, updated framework, or critical reinterpretation of existing evidence. Much of the discussion reiterates current guideline recommendations from ENETS, NANETS, and ESMO without significant conceptual advancement.

The manuscript has been reframed to better emphasize its original contribution as a critical, biology-driven synthesis of surgical decision-making, with strengthened sections on treatment sequencing, multidisciplinary integration, and areas of controversy. The manuscript has been reframed to better emphasize its original contribution as a critical, biology-driven synthesis of surgical decision-making, with strengthened sections on treatment sequencing, multidisciplinary integration, and areas of controversy.

 

 

• The review lacks a clearly defined methodology for literature selection. There is no description of search strategy, database sources, inclusion/exclusion criteria, time frame, or quality assessment of included studies. This significantly weakens the scientific rigor and reproducibility expected from a high-quality review article.

We clarified that this is a narrative review and added a description of literature sources, timeframe (updated to 2024–2025), and selection approach to improve transparency.

 

• The manuscript is heavily dependent on retrospective studies and single-center experiences, while critical appraisal of evidence quality is insufficient. The authors frequently present survival outcomes without adequately discussing selection bias, heterogeneity, and limitations of retrospective comparisons, particularly in sections on liver resection and transplantation.

The critical appraisal of the evidence has been reinforced, with explicit discussion of selection bias, study heterogeneity, and the limitations of retrospective data throughout the manuscript.

 

• The discussion on liver transplantation is disproportionately extensive compared with other treatment modalities and tends to overemphasize transplantation benefits despite its applicability to only a very small subset of patients (<1%). A more balanced discussion of practical clinical relevance is needed. The section on liver transplantation has been streamlined and balanced, clearly emphasizing its applicability to a highly selected minority of patients (<1%) and its limited generalizability.

 

 

• Important contemporary developments such as molecular biomarkers, radiomics, circulating tumor DNA, and AI-assisted patient selection for surgical decision-making are not adequately discussed, limiting the manuscript’s relevance for modern precision oncology and translational clinical practice

We expanded the discussion of molecular biomarkers and liquid biopsy (NETest), while acknowledging their current investigational role.

 

 

• Figures 1 and 2 are overly simplified and largely schematic without sufficient explanatory depth. Figure 1 (classification system) and Figure 2 (therapeutic algorithm) appear descriptive rather than evidence-driven and do not significantly enhance the scientific value of the manuscript. Their originality and citation sources should also be clarified.

Figures 1 and 2 have been revised with expanded legends and clearer rationale, highlighting their function as conceptual, clinically oriented frameworks. Tables have been refined to provide a comparative interpretation of guidelines, emphasizing differences and practical implications rather than duplication.

 

• Table 1 and Table 2 summarize guideline recommendations and transplant criteria, but they largely duplicate already published consensus statements without providing comparative interpretation, controversy analysis, or practical decision-making guidance for clinicians

We have revised the tables and accompanying text to enhance their analytical value. This includes a clearer identification of shared recommendations (e.g., indications for cytoreductive surgery and the ≥70% debulking threshold) as well as key discrepancies and ongoing controversies, particularly regarding liver transplantation criteria, timing of surgery, and management of borderline resectable disease. Furthermore, we have explicitly emphasized that current guideline recommendations are largely based on low- to moderate-level evidence, primarily derived from retrospective and heterogeneous studies. This clarification underscores the need for cautious interpretation and supports our broader argument regarding the necessity for prospective, high-quality data to guide surgical decision-making in patients with neuroendocrine liver metastases.

 

 

• Several sections contain grammatical errors, awkward sentence construction, and syntax problems that reduce readability and professionalism. For example, phrases such as “when curative resection it is not feasible” and “derived from retrospective registries” require substantial language revision throughout the manuscript. The manuscript has undergone a comprehensive language revision.

All grammatical and syntactical errors have been corrected, and the overall sentence structure has been carefully revised to improve clarity, coherence, and readability throughout the text.

 

• The manuscript lacks sufficient discussion of negative outcomes and postoperative morbidity, including complications after aggressive cytoreduction, ALPPS, and liver transplantation. Surgical risk, perioperative mortality, and quality-of-life tradeoffs are underrepresented compared with survival-focused reporting.

We acknowledge the importance of surgical morbidity and mortality in the evaluation of treatment strategies. However, a detailed analysis of procedure-related complications was not considered a primary focus of the present review, which is centered on the evolving role of surgical approaches within a broader, multidisciplinary and biology-driven treatment framework. A comprehensive assessment of perioperative outcomes and complication profiles would extend beyond the intended scope of this work.

 

• The section “Practical limitations and unmet needs” is too brief and generic for a review article intended for a high-impact oncology journal. It does not provide a robust future research roadmap, prospective trial design suggestions, or institutional strategies to address the identified gaps.

The section on unmet needs has been expanded, outlining future research priorities, the need for prospective trials, and the development of standardized decision-making frameworks.

 

• Several references are outdated relative to the rapidly evolving field, especially in sections addressing systemic therapy integration and PRRT. More recent prospective studies and 2024–2025 consensus updates should be critically incorporated rather than relying predominantly on older retrospective surgical literature.

The reference list has been updated to include recent studies (2023–2025), particularly in the areas of systemic therapy and PRRT.

 

We believe these revisions have improved the rigor, balance, and clinical relevance of the manuscript and we thank the Reviewer for helping strengthen our work.

 

 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides a comprehensive review of currently used surgical strategies for the management of neuroendocrine liver metastases (NELMs), including liver resection, cytoreductive surgery, and liver transplantation. The topic is clinically relevant and timely, particularly in the context of evolving systemic therapies and multidisciplinary treatment approaches. The manuscript is generally well-structured and clearly written, and the inclusion of practical limitations and unmet clinical needs is commendable. However, the section on future perspectives remains relatively limited. In particular, the manuscript would benefit from a more in-depth discussion on emerging research directions, especially from the perspective of therapeutic development. Given the increasing interest in novel treatment modalities (e.g., targeted therapies, nanomedicine-based approaches, tumor microenvironment modulation, and combination strategies), the authors are encouraged to expand this section to better guide researchers working in cancer therapeutics.

Author Response

the manuscript provides a comprehensive review of currently used surgical strategies for the management of neuroendocrine liver metastases (NELMs), including liver resection, cytoreductive surgery, and liver transplantation. The topic is clinically relevant and timely, particularly in the context of evolving systemic therapies and multidisciplinary treatment approaches. The manuscript is generally well-structured and clearly written, and the inclusion of practical limitations and unmet clinical needs is commendable.

However, the section on future perspectives remains relatively limited. In particular, the manuscript would benefit from a more in-depth discussion on emerging research directions, especially from the perspective of therapeutic development. Given the increasing interest in novel treatment modalities (e.g., targeted therapies, nanomedicine-based approaches, tumor microenvironment modulation, and combination strategies), the authors are encouraged to expand this section to better guide researchers working in cancer therapeutics.

We thank the Reviewer for the positive evaluation of our manuscript and for highlighting its clinical relevance, structure, and clarity. We particularly appreciate the suggestion to strengthen the section on future perspectives. In response, we have expanded this section to provide a more in-depth and forward-looking discussion of emerging research directions, with particular emphasis on therapeutic development. Specifically, we have broadened the discussion on novel systemic strategies, including next-generation targeted therapies and their potential integration with surgical approaches, emphasizing its role in disease progression and as a potential therapeutic target, expanded the overview of combination strategies, highlighting the evolving interplay between surgery, PRRT, and systemic treatments.

 

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive overview of surgical strategies for the management of neuroendocrine liver metastases (NELMs), including liver resection, cytoreductive surgery, and liver transplantation. The topic is clinically relevant, and the manuscript successfully summarizes a large body of literature, incorporating guideline-based recommendations and contemporary studies. The inclusion of figures and comparative tables is helpful in structuring the content and improving readability.
However, the manuscript remains largely descriptive and does not provide sufficient critical synthesis or novel perspective to distinguish it from existing review articles in this field. The discussion of surgical approaches—particularly liver resection and cytoreduction—reiterates well-established concepts without offering a clear framework for clinical decision-making. For example, although survival outcomes and recurrence rates are extensively reported, there is limited analysis of how these data should influence patient selection or treatment sequencing in practice. Similarly, the proposed ≥70% debulking threshold is presented without adequately addressing variability across studies or the underlying biological rationale.
Another important limitation is the insufficient integration of modern systemic therapies into the surgical paradigm. While peptide receptor radionuclide therapy (PRRT), targeted therapies, and somatostatin analogues are mentioned, their role in neoadjuvant, adjuvant, or conversion settings is not meaningfully discussed. Given the evolving treatment landscape, a more balanced and integrated discussion of multimodal strategies would significantly strengthen the manuscript.
The section on liver transplantation is detailed but somewhat unbalanced, with strong emphasis on outcomes in highly selected populations without sufficiently addressing real-world applicability, ethical considerations related to organ allocation, and the limited proportion of eligible patients. A more critical appraisal of these aspects would improve the credibility of the review.
Finally, the manuscript would benefit from improved focus and conciseness. Several sections are repetitive, particularly in the reporting of survival data and recurrence patterns, which reduces clarity and impact. A more structured synthesis highlighting key clinical take-home messages would enhance the usefulness of the review for readers.

Comments on the Quality of English Language

The manuscript is generally understandable; however, the English language requires improvement for clarity and precision. There are minor grammatical errors, occasional awkward phrasing, and inconsistencies in terminology (e.g., interchangeable use of NETs and NENs). In addition, some sentences are overly long and could be simplified to improve readability. Careful language editing is recommended.

Author Response

This manuscript provides a comprehensive overview of surgical strategies for the management of neuroendocrine liver metastases (NELMs), including liver resection, cytoreductive surgery, and liver transplantation. The topic is clinically relevant, and the manuscript successfully summarizes a large body of literature, incorporating guideline-based recommendations and contemporary studies. The inclusion of figures and comparative tables is helpful in structuring the content and improving readability.
We thank the Reviewer for the thoughtful and balanced assessment, and for recognizing the clinical relevance, structure, and clarity of the manuscript. We have carefully revised the manuscript to address the important points raised, as detailed below.

1- However, the manuscript remains largely descriptive and does not provide sufficient critical synthesis or novel perspective to distinguish it from existing review articles in this field. The discussion of surgical approaches—particularly liver resection and cytoreduction—reiterates well-established concepts without offering a clear framework for clinical decision-making. For example, although survival outcomes and recurrence rates are extensively reported, there is limited analysis of how these data should influence patient selection or treatment sequencing in practice. Similarly, the proposed ≥70% debulking threshold is presented without adequately addressing variability across studies or the underlying biological rationale.

We acknowledge the concern regarding the predominantly descriptive nature of the review. In response, we have substantially strengthened the manuscript to provide a more critical and interpretative synthesis. We have reframed the discussion of surgical strategies to emphasize how available evidence should inform clinical decision-making, rather than simply reporting outcomes. We now explicitly address the limitations of survival data and recurrence rates, and their implications for patient selection and treatment sequencing in real-world practice. Regarding cytoreductive surgery, we have completed the discussion of the ≥70% debulking threshold, highlighting the variability across studies, the lack of standardized definitions, and the absence of robust biological justification.

2- Another important limitation is the insufficient integration of modern systemic therapies into the surgical paradigm. While peptide receptor radionuclide therapy (PRRT), targeted therapies, and somatostatin analogues are mentioned, their role in neoadjuvant, adjuvant, or conversion settings is not meaningfully discussed. Given the evolving treatment landscape, a more balanced and integrated discussion of multimodal strategies would significantly strengthen the manuscript.

We also agree that integration of systemic therapies is a key aspect of modern management. Accordingly, we have significantly expanded the sections on PRRT, targeted therapies, and somatostatin analogues, with particular emphasis on their role in neoadjuvant, conversion, and multimodal strategies. The revised manuscript now better reflects the evolving paradigm in which surgery is positioned within a dynamic, multidisciplinary treatment sequence, rather than as a standalone modality.

3- The section on liver transplantation is detailed but somewhat unbalanced, with strong emphasis on outcomes in highly selected populations without sufficiently addressing real-world applicability, ethical considerations related to organ allocation, and the limited proportion of eligible patients. A more critical appraisal of these aspects would improve the credibility of the review.

With respect to liver transplantation, we have revised this section to provide a more balanced and critical perspective. While maintaining the discussion of outcomes, we now more clearly emphasize itslimited applicability in real-world practice, the small proportion of eligible patients, and the constraints related to organ allocation and ethical considerations
4- Finally, the manuscript would benefit from improved focus and conciseness. Several sections are repetitive, particularly in the reporting of survival data and recurrence patterns, which reduces clarity and impact. A more structured synthesis highlighting key clinical take-home messages would enhance the usefulness of the review for readers.

To address the issue of repetition and clarity, the manuscript has undergone substantial editing to improve conciseness and focus. Redundant reporting of survival outcomes has been reduced, and sections have been reorganized to enhance readability. We have also strengthened the manuscript by incorporating clearer clinical take-home messages, particularly within the discussion and concluding sections.

We thank the Reviewer again for the valuable comments, which have significantly contributed to improving the quality of our work.

 

 

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “Surgical Approach to Liver Metastasis from Gastroenteropancreatic Neuroendocrine Tumors in the Era of Precision Oncology: A Narrative Review with Focus on the Controversial and Evolving Role of Liver Transplantation” presents a comprehensive and clinically relevant review of the current surgical management strategies for neuroendocrine liver metastases (NELMs).

The authors provide a well-structured and balanced discussion covering hepatic resection, cytoreductive surgery, liver transplantation, neoadjuvant systemic therapies, and the emerging role of molecular profiling in surgical decision-making. The manuscript successfully integrates current evidence, guideline recommendations, and evolving concepts in precision oncology into a coherent narrative.

The manuscript is well referenced, scientifically sound, and clinically informative. The figures and tables effectively summarize complex management strategies and improve readability.

Author Response

We truly appreciate the reviewer's thoughtful assessment of our work as well as their supportive and complimentary remarks. We are happy that the reviewer found the review to be thorough, well-organized, and clinically relevant, and that the integration of the most recent research and precision oncology concepts was deemed balanced and clear.

We also value the acknowledgement of the manuscript's general scientific soundness and clinical significance, as well as the clarity of the figures and tables. These remarks are much valued and support the applicability of our work.

Although no particular modifications were asked for, we have thoroughly reviewed the material to make sure it is accurate, consistent, and clear throughout.

Thank you again for your constructive feedback.

Reviewer 3 Report

Comments and Suggestions for Authors

The revision substantially improves the manuscript and addresses several of the previous concerns. In particular, the authors now provide a more balanced and critical discussion of the limitations of the available surgical literature, repeatedly acknowledging the retrospective nature of the evidence, selection bias, lack of randomized trials, and uncertainty regarding optimal treatment sequencing. The discussion surrounding the ≥70% cytoreduction threshold is also more nuanced and appropriately cautious.
Importantly, the integration of systemic therapies into the surgical framework has improved considerably. The newly added sections on neoadjuvant systemic therapy, PRRT, CAPTEM, and targeted agents provide a much more contemporary discussion of multimodal management and better reflect current clinical practice. The manuscript also expands the discussion of biological selection, genomic profiling, and dynamic biomarkers, which strengthens the overall conceptual framework.
The liver transplantation section is now more balanced as well. The authors more explicitly discuss organ scarcity, strict selection criteria, recurrence risk, and real-world applicability, which improves the credibility of the review.
The manuscript also benefits from the addition of more structured figures and comparative tables summarizing resectability patterns, treatment algorithms, and guideline recommendations. These additions improve readability and practical utility for clinicians.
That said, some limitations remain. Despite the expanded discussion, the manuscript still occasionally reads as a broad synthesis of the literature rather than a strongly opinionated or practice-changing review. Several sections remain lengthy and somewhat repetitive, particularly regarding recurrence rates and retrospective survival comparisons. In addition, while the review now discusses multimodal treatment sequencing more explicitly, a clearer proposed framework for integrating surgery with PRRT, CAPTEM, and transplantation in different clinical scenarios would further strengthen the article.
Overall, however, the revision addresses the major prior concerns in a meaningful way. The manuscript is now considerably more balanced, clinically relevant, and reflective of the complexity of modern NELM management.

Comments on the Quality of English Language

The English language has improved substantially in the revised manuscript and is generally understandable. However, several sections would still benefit from additional editing for clarity, sentence structure, and precision of wording. In particular, some mechanistic descriptions remain repetitive or overly complex, and occasional phrasing still overstates associative findings. Further refinement of grammar and scientific wording would improve readability and overall presentation.

Author Response

We sincerely thank the Reviewer for the careful and thoughtful reassessment of our manuscript and for the comprehensive and constructive feedback provided.

We are grateful for the positive evaluation of the revisions, particularly the recognition that the manuscript now presents a more balanced and critical appraisal of the available literature. We appreciate the acknowledgment of our efforts to more clearly address key limitations, including the retrospective nature of most studies, the impact of selection bias, the absence of randomized evidence, and the ongoing uncertainty surrounding optimal treatment sequencing.

We are also pleased that the Reviewer found the discussion on cytoreductive surgery, especially regarding the ≥70% threshold, to be more nuanced and appropriately cautious. Similarly, we appreciate the favorable comments on the expanded sections addressing multimodal management, including the integration of systemic therapies such as PRRT, CAPTEM, and targeted agents, as well as the strengthened discussion on biological selection, genomic profiling, and dynamic biomarkers.

The remaining recommendations were carefully reexamined, and as a result, the manuscript has been revised to eliminate redundancies across sections, especially with regard to survival outcomes and recurrence rates from retrospective data; improve conciseness and streamline longer paragraphs; enhance the clarity, readability, and precision of the language while avoiding over interpretation of associative findings; and further strengthen a more structured conceptual framework for therapeutic integration by clarifying, whenever possible, the potential roles of liver transplantation, PRRT, CAPTEM, and surgery in various clinical scenarios.

We have also performed an additional comprehensive English language revision to improve sentence structure, grammar, and scientific clarity throughout the manuscript.

We are grateful to the Reviewer for the insightful comments, which have significantly contributed to improving the quality, clarity, and clinical relevance of our work.