The Paradigm Shift in Clinical Stage II Non-Small-Cell Lung Cancer Management: A Comprehensive Review of Optimal Surgical and Systemic Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Wilson and Donington have presented a review manuscript titled, “The Paradigm Shift in Clinical Stage II Non-Small Cell Lung  Cancer Management: A Comprehensive Review of Optimal  Surgical and Systemic Approaches”. The authors aimed to investigate the significant role of optimal treatments and emerging therapies in NSCLC (Stage II), including immunotherapy and targeted therapy, and their implications for surgery. The authors addressed Immune Checkpoint Inhibitors, adjuvant, neoadjuvant, perioperative immunotherapy, and sequencing therapies. Further, an account of targeted therapies targeting molecular targets such as EGFR and ALK, in addition to surgical procedures. All the sections are provided with recent literature reports on the studied topic. All tables are presented clearly and appropriately supported by literature reports. However, revision is required to be suitable for publication.

1. Wherever applicable, authors should provide recent citations to the literature.
2. Future perspectives to be included after the conclusion.
3. Since it is a non-systematic review, the PRISMA chart may not be applicable; however, it was suggested to include the PRISMA chart as a figure.

Author Response

Reviewer 1: Wilson and Donington have presented a review manuscript titled, “The Paradigm Shift in Clinical Stage II Non-Small Cell Lung  Cancer Management: A Comprehensive Review of Optimal  Surgical and Systemic Approaches”. The authors aimed to investigate the significant role of optimal treatments and emerging therapies in NSCLC (Stage II), including immunotherapy and targeted therapy, and their implications for surgery. The authors addressed Immune Checkpoint Inhibitors, adjuvant, neoadjuvant, perioperative immunotherapy, and sequencing therapies. Further, an account of targeted therapies targeting molecular targets such as EGFR and ALK, in addition to surgical procedures. All the sections are provided with recent literature reports on the studied topic. All tables are presented clearly and appropriately supported by literature reports. However, revision is required to be suitable for publication.

1. Wherever applicable, authors should provide recent citations to the literature.
2. Future perspectives to be included after the conclusion.
3. Since it is a non-systematic review, the PRISMA chart may not be applicable; however, it was suggested to include the PRISMA chart as a figure.

Response: Thank you for the kind words regarding our manuscript. We have reviewed the manuscript and included citations at all locations where we felt the information should be cited directly. Future Perspectives were included in each section, and a brief section was added at the end. PRISMA not included.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript provides an excellent, comprehensive, and timely review of the evolving treatment landscape in clinical Stage II non-small cell lung cancer. The authors successfully synthesize a rapidly expanding body of high-impact clinical trial data into a clear and clinically meaningful narrative.

The review is particularly strong in outlining the paradigm shift from a surgery-first approach toward a biomarker-driven, multimodal strategy integrating immunotherapy and targeted therapies. The discussion of perioperative treatment concepts, including neoadjuvant and “sandwich” approaches, is well-structured and reflects current clinical practice and future directions. Furthermore, the inclusion of both immunotherapy and molecularly targeted strategies adds significant depth and relevance.

The manuscript is well organized, scientifically rigorous, and balanced. The tables summarizing landmark trials (e.g., immunotherapy and targeted therapy studies) are highly informative and enhance readability and clinical applicability (see detailed trial overview, pp. 3–5 ).

Importantly, the authors also address surgical implications in a nuanced and realistic manner, acknowledging both technical challenges and the central role of surgery within modern multimodality care.

Overall, this is a high-quality, authoritative review that will be of significant value to thoracic surgeons, oncologists, and multidisciplinary teams involved in lung cancer care.

Author Response

Reviewer 2: This manuscript provides an excellent, comprehensive, and timely review of the evolving treatment landscape in clinical Stage II non-small cell lung cancer. The authors successfully synthesize a rapidly expanding body of high-impact clinical trial data into a clear and clinically meaningful narrative. The review is particularly strong in outlining the paradigm shift from a surgery-first approach toward a biomarker-driven, multimodal strategy integrating immunotherapy and targeted therapies. The discussion of perioperative treatment concepts, including neoadjuvant and “sandwich” approaches, is well-structured and reflects current clinical practice and future directions. Furthermore, the inclusion of both immunotherapy and molecularly targeted strategies adds significant depth and relevance. The manuscript is well organized, scientifically rigorous, and balanced. The tables summarizing landmark trials (e.g., immunotherapy and targeted therapy studies) are highly informative and enhance readability and clinical applicability (see detailed trial overview, pp. 3–5 ). Importantly, the authors also address surgical implications in a nuanced and realistic manner, acknowledging both technical challenges and the central role of surgery within modern multimodality care. Overall, this is a high-quality, authoritative review that will be of significant value to thoracic surgeons, oncologists, and multidisciplinary teams involved in lung cancer care.

Response: Thank you for your review and kind words regarding our manuscript. It was our aim to provide a comprehensive review of this topic for all involved in lung cancer care, and we are pleased to hear that in your review, we accomplished that aim.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript provides a timely and comprehensive review of evolving treatment strategies for Stage II NSCLC. The topic is clinically relevant; however, several issues should be addressed to improve rigor and clarity.

1. Limited methodological transparency

The review is described as non-systematic, but the literature selection process is not sufficiently detailed. Please clarify the search strategy and inclusion/exclusion criteria to reduce potential selection bias.

2. Weak Stage II-specific focus

Most evidence is derived from trials including Stage II–III populations, with Stage II often analyzed as a subgroup. The limitations of extrapolating these results to Stage II disease should be more clearly discussed.

3. Insufficient discussion of immunotherapy limitations

The manuscript emphasizes efficacy but provides limited discussion of risks such as immune-related adverse events, perioperative complications, and patient selection. A more balanced benefit–risk discussion is needed.

4. Unclear biomarker-driven treatment strategy

Although PD-L1 and driver mutations are discussed, their integration into clinical decision-making is not clearly presented. Consider adding a treatment algorithm based on biomarker status. Also expand on ctDNA/MRD, which are only briefly mentioned.

5. Tables lack synthesis

Tables are comprehensive but difficult to interpret, particularly for Stage II. Consider simplifying or adding a Stage II-focused summary and/or a schematic of treatment sequencing.

Author Response

Reviewer 3: This manuscript provides a timely and comprehensive review of evolving treatment strategies for Stage II NSCLC. The topic is clinically relevant; however, several issues should be addressed to improve rigor and clarity.

1. Limited methodological transparency. The review is described as non-systematic, but the literature selection process is not sufficiently detailed. Please clarify the search strategy and inclusion/exclusion criteria to reduce potential selection bias.

Response: Our search strategy focused heavily on prospective trials and supporting preclinical work. We revised the wording of the methods section to clarify this point.

1. Weak Stage II-specific focus. Most evidence is derived from trials including Stage II–III populations, with Stage II often analyzed as a subgroup. The limitations of extrapolating these results to Stage II disease should be discussed more clearly.

Response: Thank you for raising this important point. We agree that the literature on Stage II NSCLC treatment is most often presented as subgroup analyses of larger trials that encompass a broader range of patients (Stage I-III) and, as such, does pose limitations. To address this, we have added a sentence to the paper's introduction (lines 62-64) highlighting this fact and expanded on the limitations of extrapolating data in section 3.4 (Evidence in Stage II-Specific Subgroups) of the manuscript. Additionally, we did readdress these limitations in section 5, surgical considerations.

 

1. Insufficient discussion of immunotherapy limitations. The manuscript emphasizes efficacy but provides limited discussion of risks such as immune-related adverse events, perioperative complications, and patient selection. A more balanced benefit–risk discussion is needed.

Response: Thank you for pointing out the skew toward the benefits of immunotherapy in our manuscript. To create a more balanced benefit-risk discussion, as recommended, we added a paragraph addressing immunotherapy safety, toxicity, and perioperative considerations to Section 5 – Surgical Considerations, where we had already outlined some of the surgical implications of chemoimmunotherapy.

1. Unclear biomarker-driven treatment strategy. Although PD-L1 and driver mutations are discussed, their integration into clinical decision-making is not clearly presented. Consider adding a treatment algorithm based on biomarker status. Also, expand on ctDNA/MRD, which are only briefly mentioned.

Response: Thank you for bringing this to our attention. We attempted to integrate biomarker-driven treatment strategies into clinical decision-making throughout the manuscript, but we understand that we may not have presented this clearly to readers. To improve the readability and clarity of the clinically pertinent information, we have created Figure 1 that outlines the condensed treatment recommendations based on the literature discussed throughout the manuscript. Additionally, we incorporated a section on the incredible potential of ctDNA and MRD in the management of NSCLC (lines 387-404), as suggested, even though it is not currently recommended for clinical decision making in resectable stage II NSCLC.

1. Tables lack synthesis. Tables are comprehensive but difficult to interpret, particularly for Stage II. Consider simplifying or adding a Stage II-focused summary and/or a schematic of treatment sequencing.

Response: Thank you for raising this concern. To make the tables and information easier to digest, we have revised them to present the information more organically. This included creating a Stage II-focused table, as recommended. We have also included a schematic of treatment sequencing based on the literature discussed throughout the manuscript (Figure 1), as outlined in our response to comment 4. (3) for this information.

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript entitled The Paradigm Shift in Clinical Stage II Non-Small Cell Lung Cancer Management: A Comprehensive Review of Optimal Surgical and Systemic Approaches is a timely and well-organized review on recent development of immunotherapies on NSCLC. The manuscript did a great job summarizing the recent clinical trials on immunotherapies, probe guided targeted therapies and combinatorial therapies. The manuscript not only simply lists the trials but also discusses them with depth and bring important points on treatment time and surgical intervention. However, there are a few factual errors could be corrected before publication. I suggest a minor revision. 

1. Line 269. EGFP is not Endothelial. It is Epidermal.
2. Line 83. Checkpoint inhibitors do not simply disrupt PD-L1. E.g. nivolumab targets PD-1.
3. The manuscript directly uses TxNxMx abbreviation to describe the NSCLC stages. The authors could briefly introduce this system.
4. Table 2 row ALINA/ column Included stages is incorrect. 

Author Response

Reviewer 4: The manuscript entitled The Paradigm Shift in Clinical Stage II Non-Small Cell Lung Cancer Management: A Comprehensive Review of Optimal Surgical and Systemic Approaches is a timely and well-organized review on recent development of immunotherapies on NSCLC. The manuscript did a great job summarizing the recent clinical trials on immunotherapies, probe guided targeted therapies and combinatorial therapies. The manuscript not only simply lists the trials but also discusses them with depth and bring important points on treatment time and surgical intervention. However, there are a few factual errors could be corrected before publication. I suggest a minor revision. 

1. Line 269. EGFP is not Endothelial. It is Epidermal.
2. Line 83. Checkpoint inhibitors do not simply disrupt PD-L1. E.g. nivolumab targets PD-1. 
3. The manuscript directly uses TxNxMx abbreviation to describe the NSCLC stages. The authors could briefly introduce this system. 
4. Table 2 row ALINA/ column Included stages is incorrect.

Response: We appreciate your review of our manuscript and thank you for your comments. We have made appropriate changes to the incorrect information as you outlined in comments 1 and 3 of your review. Similarly, the wording of our introduction to checkpoint inhibitors was revised to be more inclusive of other regulatory proteins they target. A description of the principles of TNM staging system for lung cancer is beyond the scope of this review and we would assume that anyone reading this work would be familiar with it. The full reference to the staging project is included.