Current Treatment Standards for Metastatic Uveal Melanoma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review article presents a comprehensive summary of current treatment standards for metastatic uveal melanoma (mUM). It highlights significant advances in the management of uveal melanoma, an aggressive and rare malignancy characterized by a high risk of metastasis and limited systemic treatment options.

The manuscript is particularly strong in synthesizing existing knowledge on the epidemiology, genetic background, clinical features, and therapeutic approaches for mUM. The focused discussion on liver metastases accurately reflects the natural history of the disease, as the liver is the most common site of distant spread.

Nevertheless, the manuscript would benefit from several revisions, which are outlined below under two main categories:

1) Abbreviation consistency: All abbreviations (e.g., OS, HLA-A*02:01) should be defined at their first occurrence in the main text (for example, in Section 1, Introduction, or Section 3, Treatment), even if they are already defined in the Abstract or in a list of abbreviations.

2) Strengthening the discussion on combination therapies: In the Discussion section (Section 7), the increasing integration of systemic and liver-directed therapies is acknowledged. Given the robust retrospective data cited (median overall survival of 22.5 months versus 11.4 months for systemic therapy alone when combined with immune checkpoint inhibitors and liver-directed treatments), the importance of this multidisciplinary approach should be more strongly emphasized in both the Discussion and Conclusion sections as a key factor in improving clinical outcomes.

Author Response

Comment 1: Abbreviation consistency: All abbreviations (e.g., OS, HLA-A*02:01) should be defined at their first occurrence in the main text (for example, in Section 1, Introduction, or Section 3, Treatment), even if they are already defined in the Abstract or in a list of abbreviations

Response to Comment 1: Thank you for your comment. The abbreviations have been corrected as suggested.

Comment 2: Strengthening the discussion on combination therapies: In the Discussion section (Section 7), the increasing integration of systemic and liver-directed therapies is acknowledged. Given the robust retrospective data cited (median overall survival of 22.5 months versus 11.4 months for systemic therapy alone when combined with immune checkpoint inhibitors and liver-directed treatments), the importance of this multidisciplinary approach should be more strongly emphasized in both the Discussion and Conclusion sections as a key factor in improving clinical outcomes.

Response to Comment 2: Thank you for your suggestions. The Discussion and Conclusion sections have been revised and updated as suggested. 

Reviewer 2 Report

Comments and Suggestions for Authors

Rogala et al. provided an up-to-date overview of metastatic uveal melanoma assessment and management. Would recommend re-organization and major editing to improve clarity and consistency. Illustration of metastatic sites and treatment modalities can also be appealing to readers who are visual learners and increase accessibility of review articles which are often heavy in content. The authors may wish to consider the following for revision: 

1. The 2^nd section could benefit from a more specific title than just “Metastatic Uveal Melanoma”. It discussed work up for risk stratification and surveillance of extraocular disease in UM. In line 105-106 as well as Table 1, please clarify the context for staging system and follow-up guidelines as these often vary by country and region. Citation #20-23 indicated mixed settings (Europe and North America), but this was not clear in the text.        
2. Again, the title for the 3^rd section can be more specific to improve scannability and overall clarity of the review. This section focused primarily on localized options directed against hepatic metastasis as opposed to systemic approaches discussed later.
   1. The first paragraph before subsections could be shortened and/or combined with the introduction for better flow
   2. Organization can be improved with further division of 3.2, which included ablative techniques and vascular approaches (embolic vs nonembolic). Also, the last paragraph of this subsection would better fit in section 5 where combination of locoregional and systemic therapy were discussed.  
   3. Since over 90% of metastatic UM is to the liver, it is reasonable to focus on liver-directed therapies. Is there any literature that can be cited for management of extrahepatic mUM? For the sake of comprehensiveness, a short discussion of locoregional approaches to extrahepatic disease would add depth to the article. This was briefly mentioned in 3.3.
3. Section 6 provided minor additional value to the article as it was too generic and repeated information discussed earlier, e.g. regarding tebentafusp. It would be valuable to hear the authors' perspectives on drugs in the horizon and/or drug repurposing informed by genetic insights from recent multi-omic profiling studies.  
4. Table 3 would benefit from re-structuring for directed purposes
5. Comments on editing (likely due to different writing styles of co-authors)
   1. Redundancy in spelling out full term and justifying its abbreviation, e.g. “metastatic uveal melanoma” as mUM, isolated hepatic perfusion as IPH .
   2. Inconsistent use of abbreviation, such as median overall survival (median OS vs mOS), adverse events vs AE
   3. Please make sure all abbreviations are justified, e.g. EBRT (line 215), MWA, MDT (table 2)
   4. Please add appropriate citation in line 410

Author Response

General comment: Would recommend re-organization and major editing to improve clarity and consistency. Illustration of metastatic sites and treatment modalities can also be appealing to readers who are visual learners and increase accessibility of review articles which are often heavy in content. 

Response to general comment: Thank you for your suggestions. The manuscript has been reviewed and re-organized. The illustration of metastatic sites and the algorithm representing general treatment rules in patients with mUM have been added.

Comment 1: The 2^nd section could benefit from a more specific title than just “Metastatic Uveal Melanoma”. It discussed work up for risk stratification and surveillance of extraocular disease in UM. In line 105-106 as well as Table 1, please clarify the context for staging system and follow-up guidelines as these often vary by country and region. Citation #20-23 indicated mixed settings (Europe and North America), but this was not clear in the text.   

Response to Comment 1: Thank you for pointing this out. The title of section 2 has been updated as suggested. The context of staging system and FU guidelines has been reviewed and updated accordingly.

Comment 2.1: Again, the title for the 3^rd section can be more specific to improve scannability and overall clarity of the review. This section focused primarily on localized options directed against hepatic metastasis as opposed to systemic approaches discussed later.

1. The first paragraph before subsections could be shortened and/or combined with the introduction for better flow
2. Organization can be improved with further division of 3.2, which included ablative techniques and vascular approaches (embolic vs nonembolic). Also, the last paragraph of this subsection would better fit in section 5 where combination of locoregional and systemic therapy were discussed.  
3. Since over 90% of metastatic UM is to the liver, it is reasonable to focus on liver-directed therapies. Is there any literature that can be cited for management of extrahepatic mUM? For the sake of comprehensiveness, a short discussion of locoregional approaches to extrahepatic disease would add depth to the article. This was briefly mentioned in 3.3.

Response to Comment 2: Thank you for your suggestions. The Chapters have been reviewed and reorganized for better clarity of the review. The introduction of metastatic disease treatment has been updated with a general algorithm. The chapters dedicated to local and systemic therapies are also updated accordingly. The embolic and non-embolic treatments are currently described separately. Extrahepatic disease has been described more extensively.

Comment 3: Section 6 provided minor additional value to the article as it was too generic and repeated information discussed earlier, e.g., regarding tebentafusp. It would be valuable to hear the authors' perspectives on drugs on the horizon and/or drug repurposing informed by genetic insights from recent multi-omic profiling studies. 

Comment 4: Table 3 would benefit from re-structuring for directed purposes

Response to Comments 3 and 4: Thank you for your suggestions. The section dedicated to drugs in development has been reorganized, and the Table has been updated to include trials based on the treatment type and disease stage.

Comment 5:

Comments on editing (likely due to different writing styles of co-authors)

1. Redundancy in spelling out full term and justifying its abbreviation, e.g. “metastatic uveal melanoma” as mUM, isolated hepatic perfusion as IPH .
2. Inconsistent use of abbreviation, such as median overall survival (median OS vs mOS), adverse events vs AE
3. Please make sure all abbreviations are justified, e.g. EBRT (line 215), MWA, MDT (table 2)
4. Please add appropriate citation in line 410

Response to Comment 5: Thank you for your comments. 1-3. the abbreviations have been revised in the whole manuscript and updated. 4. Citation in line 410 has been added.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Appreciate the efforts to address comments from prior submission. Sufficient for publication