Interventional Clinical Trials in Metastatic Pulmonary Large-Cell Neuroendocrine Carcinoma: A Systematic Review of Prospective, Interventional Trials
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe paper of Dr Merola et al. focused on a systematic review addressing a gap in advanced and metastatic pulmonary LCNEC by restricting inclusion to prospective interventional studies. The manuscript is generally well-written and clinically relevant.
Please authors should standardize terminology (LCNEC) and explicitly define the diagnostic criteria accepted (WHO 2021 definition?)
Authors state filters for “randomized controlled trials and clinical trials” were applied (page 3), yet all included studies are non-randomized, and the immunotherapy study is described as “real-world pilot” (pages 6–7). Please could you refine this paragraph
Table 1 mixes “n (%)” in a confusing way: for Le Treut and Niho, n is shown as 29 and 30 with percentages (69.0 and 68.2) that seem to represent central review-confirmed LCNEC proportions from larger enrolled cohorts, whereas other rows use 100%. This is important and should be made explicit in the column header and footnote
Toxicity reporting is missing (“-”) for Le Treut and Niho in Table 1 despite toxicity being a secondary endpoint
The LANCE pilot study (17 patients, non-randomized, “real-world,” single-center) is described as showing a “significant survival advantage” (page 7). Given the design, very small n, and likely imbalances, please soften language
In the discussion section I suggest a brief clinical implications paragraph: what regimens have the best prospective signal today ? what should clinicians do when choosing SCLC-like vs NSCLC-like regimens in the absence of prospective stratification?
Furthermore authors could add some minimal requirements for future LCNEC trials: i.e. mandatory central pathology, molecular subgrouping, endpoints beyond ORR such as DOR, QoL, translational studies
Author Response
Reply to reviewer 1
We sincerely thank you for your careful and constructive evaluation of our manuscript. We found all comments appropriate, insightful, and highly valuable, and we believe that they have substantially improved the clarity, methodological transparency, biological framing, and clinical relevance of our work.
We have revised the manuscript accordingly and provide below a point-by-point response to each comment.
Comment 1
Please standardize terminology (LCNEC) and explicitly define the diagnostic criteria accepted (WHO 2021 definition?).
Response
We fully agree. Given the diagnostic complexity of pulmonary neuroendocrine neoplasms, explicit reference to the accepted classification framework is essential. These changes are now reported in yellow (lines 66-70) and also supported by the modified Supplementary Table 1.
Comment 2
Authors state filters for “randomized controlled trials and clinical trials” were applied, yet all included studies are non-randomized... and the immunotherapy study is described as “real-world pilot” (pages 6–7). Please could you refine this paragraph.
Response
We thank the Reviewer for the comment. Our search strategy was designed broadly, to capture prospective interventional studies, including both randomized and non-randomized clinical trials. However, after screening and full-text review, no randomized trial fulfilled the eligibility criteria. We have revised the Methods section to make this distinction explicit and to avoid any misunderstanding regarding the study design of the included evidence base (lines 129-131). We have also modified the Results section reinforcing this observation (lines 239-240; 266).
Comment 3
Table 1 mixes “n (%)” in a confusing way: for Le Treut and Niho, n is shown as 29 and 30 with percentages (69.0 and 68.2) that seem to represent central review-confirmed LCNEC proportions from larger enrolled cohorts, whereas other rows use 100%. This is important and should be made explicit in the column header and footnote
Response
We agree and thank the Reviewer for this important observation. In the studies by Le Treut et al. and Niho et al., the percentages represent the proportion of patients with centrally confirmed LCNEC after pathological review among the originally enrolled populations. We have therefore revised the column heading and added a clarifying footnote to improve transparency and interpretability.
Comment 4
Toxicity reporting is missing for Le Treut and Niho in Table 1 despite toxicity being a secondary endpoint.
Response
We agree. After re-checking the original reports, we confirmed that toxicity data were reported for the overall study populations, but not separately for the centrally confirmed LCNEC subgroup. We have now clarified this explicitly in Table 1 to avoid overinterpretation and to preserve methodological accuracy.
Comment 5
The LANCE pilot study (17 patients, non-randomized, “real-world,” single-center) is described as showing a “significant survival advantage” (page 7). Given the design, very small n, and likely imbalances, please soften language
Response
We fully agree. Given the very small sample size, non-randomized design, and single-centre setting, the original wording was too definitive. We have revised the Results section to emphasize the exploratory and hypothesis-generating nature of the LANCE findings while still acknowledging the signal of potential interest reported by the authors (lines 273-274).
Comment 6
In the discussion section I suggest a brief clinical implications paragraph: what regimens have the best prospective signal today ? what should clinicians do when choosing SCLC-like vs NSCLC-like regimens in the absence of prospective stratification?
Response
We thank the Reviewer for this excellent suggestion. We have added a dedicated paragraph in the Discussion to summarize the current practical implications of the available prospective evidence. Specifically, we now clarify that platinum-based regimens still represent the most consistent prospective therapeutic signal, while also acknowledging that LCNEC molecular heterogeneity may partly explain why a uniform SCLC-derived strategy is unlikely to be optimal for all patients (lines 308-335).
Comment 7
Furthermore authors could add some minimal requirements for future LCNEC trials: i.e. mandatory central pathology, molecular subgrouping, endpoints beyond ORR such as DOR, QoL, translational studies
Response
We fully agree. We have expanded the Discussion to define the methodological priorities that future LCNEC trials should, in our view, incorporate (lines 395-416).
Reviewer 2 Report
Comments and Suggestions for AuthorsThis systematic review is particularly relevant given the existing lack of prospective therapeutic data for metastatic pulmonary large cell neuroendocrine carcinoma (LCNEC) that has been reported as both rare and clinically aggressive, and thus can be used to identify areas of priority in future research on managing LCNEC.
- The title is appropriate to reflect the content of this review. However, the title may benefit from including the fact that it is a systematic review of prospective therapeutic data to better define its purpose.
- Overall, the abstract effectively describes the findings of the study, although it would be improved if the number of trials included in the study and/or the total number of participants were provided to increase the transparency of the methodology of the study.
- The introduction establishes context for LCNEC in terms of pulmonary neuroendocrine tumors; however, the justification for limiting focus to prospective, interventional trials should be more clearly articulated.
- The description of current treatment approaches for LCNEC relies extensively on extrapolation from small cell lung cancer (SCLC); therefore, the authors' discussion of the biologic differences between LCNEC and SCLC would enhance the conceptual background.
- Although the authors indicate they followed the PRISMA guidelines for their review, the authors should include either the full search strategy and/or the keywords used in the search in the body of the paper and/or supplemental materials to improve reproducibility.
- The eligibility criteria were clearly established; however, the authors should justify the decision to exclude studies with less than 10 LCNEC patients to clarify the methods of the study.
- The authors clearly illustrated study selection using the PRISMA flow diagram (Fig. 1), and while reporting the total number of LCNEC patients included in each trial would add clarity to the evidence base, it would also assist in understanding how to apply the results.
- Further comparative analysis of the treatment outcome data across trials would also strengthen the Results Section.
- Table 1 was effective in summarizing the treatments administered and the resultant outcomes. Confidence intervals around the response rates and/or survival outcomes wherever possible would add to the interpretability of Table 1.
- The authors could strengthen their Conclusion by proposing specific research directions that could help guide the development of research in the field such as biomarker-driven trials and/or international multicenter collaborations.
In summary, while the authors have identified a critical clinical need and have conducted a useful synthesis of prospective therapeutic evidence for metastatic LCNEC, there are several methodological clarifications and enhancements needed in the analytical interpretation to ensure publication. Specifically, the authors should include a clear description of the search strategies used, a more detailed comparison of the outcomes of the individual trials, and a greater discussion of the biological heterogeneity of the disease to significantly enhance the quality of the manuscript.
Author Response
Reply to reviewer 2
We sincerely thank you for your careful and constructive evaluation of our manuscript. We found all comments appropriate, insightful, and highly valuable, and we believe that they have substantially improved the clarity, methodological transparency, biological framing, and clinical relevance of our work.
We have revised the manuscript accordingly and provide below a point-by-point response to each comment.
Comment 1
The title is appropriate to reflect the content of this review. However, the title may benefit from including the fact that it is a systematic review of prospective therapeutic data to better define its purpose.
Response
Thank you. We agree and have revised the title accordingly.
Comment 2
The abstract would be improved if the number of trials included and/or the total number of participants were provided. Overall, the abstract effectively describes the findings of the study, although it would be improved if the number of trials included in the study and/or the total number of participants were provided to increase the transparency of the methodology of the study.
Response
We agree and have revised the Abstract to better clarify the number of included studies with confirmed LCNEC, thereby improving methodological transparency.
Comment 3
….The justification for limiting focus to prospective interventional trials should be more clearly articulated.
Response
We thank the Reviewer for this important methodological point. We have clarified in the Introduction that prospective interventional studies represent the highest level of therapeutic evidence currently available specifically for advanced pulmonary LCNEC, given the absence of randomized disease-specific trials (lines 113-119)
Comment 4
The authors’ discussion of the biologic differences between LCNEC and SCLC would enhance the conceptual background.
Response
We fully agree. This was a central limitation of the original version, and we have now substantially expanded this aspect in both the Introduction and the Discussion (lines 89-101; 358-363).
Comment 5
Please include the full search strategy and/or the keywords used.
Response
Dear reviewer, the complete search strategies is explicitly indicated as available in Supplementary Material 1.
Comment 6
Please justify the exclusion of studies with fewer than 10 LCNEC patients.
Response
We thank the Reviewer for this methodological observation. We have now clarified that this criterion was introduced to limit the disproportionate influence of very small uncontrolled datasets and case-series-type evidence on the overall synthesis (lines 138-140).
Comment 7
The authors clearly illustrated study selection using the PRISMA flow diagram (Fig. 1), and while reporting the total number of LCNEC patients included in each trial would add clarity to the evidence base, it would also assist in understanding how to apply the results.
Response
Thanks for the suggestion. We have reported the number of patients in Table 1 and not in the PRISMA flow-chart for graphical reasons. We hope that data reported in table 1 enriched with footnotes are clearer in this last version of the manuscript.
Comment 8
Further comparative analysis of the treatment outcome data across trials would strengthen the Results section.
Response
We fully agree and have expanded the Results section accordingly by adding a comparative narrative paragraph summarizing the cross-trial patterns in objective response rate, progression-free survival, and overall survival (lines 229-237).
Comment 9
Table 1 was effective in summarizing the treatments administered and the resultant outcomes. Confidence intervals around the response rates and/or survival outcomes wherever possible would add to the interpretability of Table 1.
Response
We agree. Confidence intervals reported in the original publications are reported in Table 1 wherever available, particularly for progression-free survival and overall survival. For the Le Treut study, we preserved the value as reported in the original publication, while explicitly flagging the numerical inconsistency of the reported 95% confidence interval for median overall survival.
Comment 10
Please strengthen the Conclusion by proposing specific research directions.
Response
We thank the Reviewer for this suggestion and have substantially strengthened the Conclusion to include explicit research priorities, including biomarker-driven trial design, international collaboration, central pathology review, and translational integration (lines 309-336; 396-417).
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThe revised version of the manuscript has substantially improved following the authors’ careful responses to the reviewer comments. The authors have adequately addressed the major concerns raised during the previous round of review, and the revisions have significantly strengthened the clarity, organization, and overall scientific presentation of the manuscript. The figures, tables, and supporting explanations have also been improved to better reflect the conceptual framework discussed in the text.
