Extended vs. Standard Pelvic Lymph Node Dissection in Bladder Cancer Patients Undergoing Radical Cystectomy: Systematic Review and Meta-Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors present a systematic review comparing extended with standard pelvic
lymph node dissection in bladder cancer patients undergoing radical cystectomy. The
authors conclude that extended LND does not improve oncological outcomes and is
associated with increased morbidity compared to standard LND.
The structure of the manuscript is correct. The use of English is appropriate,
although some refinements must be made.
Abstract
Line 28-30 : [RR 1.2, 95%CI 1.0-1.4] . This may puzzle the readers and lead them to
understand that there is a possibility that extended LND does not increase the risk
for Clavien-Dindo ≥3 complications , because the confidence interval includes 1.

Evidence Acquisition
Line 70-72: Often, the complications after radical cystectomy depend on the surgical
approach that was utilized , especially regarding urinary diversion
(ureterocutaneostomy vs ileal conduit vs neobladder etc.). Maybe the surgical
approaches used in the studies included in the review influenced the results
regarding complications.
Table 1
Please, explain the abbreviations in the table.
Evidence Synthesis
Line 139-140: The authors should provide some information about the most
common complications encountered in the studies, in order to give a more
comprehensive presentation of the results.
Discussion
Line 209-211 : To which systematic review does this sentence refer?
Overall, this is a well-written and interesting systematic review comparing extended
and standard pelvic lymph node dissection in patients undergoing radical cystectomy
for bladder cancer. The main concern about the results of the review is the fact that
it includes only two randomized trials. This may result in low statistical power and
inability to assess heterogeneity (I² maybe is unreliable). The results should be
interpreted cautiously, because of the overinterpretation risk.

Comments on the Quality of English Language

The use of English is appropriate, although some refinements must be made.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is well-written and easily readable. The topic addressed is highly relevant. While the role of lymphadenectomy in the management of muscle-invasive bladder cancer is well established, there is no strong consensus on the optimal lymph node dissection template to use.

This study presents a detailed, rigorous, and well-executed analysis, adhering to PRISMA guidelines and including a thorough risk-of-bias assessment. The meta-analysis is based on two high-quality randomized studies, and its findings highlight the absence of a survival benefit for extended lymphadenectomy over standard lymphadenectomy. Moreover, the study raises concerns about the potentially harmful effects of extended lymphadenectomy, particularly in contributing to major Clavien-Dindo complications.

The quality of the images and tables is excellent. The manuscript deserves to be published in its current form.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

Our urology colleagues have conducted a commendable research whose aim is to evaluate extended vs. regional cystectomy for the purposes of disease-free survival and post-operative complications. The final result is that extended lymphadenectomy has a "more stormy" post-operative period but does not change the five-year survival. In our opinion, a different reasoning must be made, equivalent to that of gastric cancer, organized and planned on the patient. In the stomach we have a D1, D2, D2+, D3 lymphadenectomy preceded by neoadjuvant therapy and followed by adjuvant therapy. Furthermore, there is a treatment in addition to the pharmacological one which is nutritional. Even for urological patients subjected to extended lymphadenectomy who lose a lot of lymph and therefore also proteins, nutritional counseling can be useful (doi.org/10.3390/nu17010188 to be read and cited in the bibliography). It is always recommended to discuss the case with the multidisciplinary committee, to make the best decisions for the patient in light of the surgical diagnosis. Furthermore, for all neoplasms, stomach, colon, pancreas, gallbladder, prostate, the therapy is based on the removal of the basic lesion together with the lymph nodes involved in the pathology. The bladder cannot obey different laws and the guidelines recommend extensive lymphadenectomies. The same authors write to us about bias, Where is the Handycup? Excellent iconography, good English, good bibliography

Comments on the Quality of English Language

good english

Author Response

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Reviewer 4 Report

Comments and Suggestions for Authors

The authors aimed to assess the impact of an extended pelvic lymphadenectomy template compared to a standard template in patients with bladder cancer undergoing radical cystectomy. They relied on meta-analysis methodology comparing eLND to sLND. The results are limited by the availability of studies. Indeed, only two RCTs were added. Specifically, eLND increased the complication rate, especially lymphocele occurrence, and did not exert a protective effect either on the OS or the DFS. Interestingly, not all the studies included neo-adjuvant chemotherapy that nowadays is highly recommended in BCA patients harboring cT > or = to 2 stages (PMID 39424431). However, subgroup analysis according to chemotherapy status, as well as sex, type of chemo/immuno, and specific stage, cannot be added and this should be mentioned in the limitation section or in the future perspective section. This point indeed may increase the clinical applicability of the current findings. 

For the figure 2, the section B is useless. Report the HR only in the main text. 

 

 

Author Response

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Reviewer 5 Report

Comments and Suggestions for Authors

The authors attempted to perform a systematic review/meta-analysis on the current evidence the oncological benefits and risks with standard vs extended lymphadenectomy in radical cystectomy for bladder cancer. They included two randomized trials in this space (LEA AB 25-02 and SWOG S1011) and reported combined analysis of primary and secondary outcomes. The biggest caveat of this approach is the two studies included patients with different baseline characteristics as authors acknowledged in the discussion - including the status of whether receiving NAC and T stages. Therefore it offers little clinical insights by combining these two studies, and this is evidenced by the significant heterogeneity measure for primary outcome. In other words, each study would be much easier to be interpreted on their own and there is no need for a systematic review based off two different studies.  

Author Response

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Reviewer 6 Report

Comments and Suggestions for Authors

This short manuscript presents a summary/analysis of 2 studies that compared standard and extended lymph node dissection in bladder cancer patients undergoing radical cystectomy. Because only 2 previous studies were included, it is difficult to call it a true meta-analysis, even though the appropriate (recommended) statistical analyses have been performed. Overall, the manuscript is concise and very clearly written, and the 2 studies, that came to similar conclusions individually, unsurprisingly produce similar conclusions when combined. This manuscript will provide a handy reference for authors to cite to support a lack of ‘oncological benefit’ of extended lymph node dissection, however the many gaps in the scope of disease interrogated in the studies curtail its importance to the field. The limitations are not related to the meta-analysis itself, but stem from the paucity of studies, the poor representation of N1 and N2 disease and exclusion of N3 disease in those studies, and other limitations that the authors have listed. I would prefer it if the authors would specifically discuss these limitations and the areas that need to be addressed, preferably through clinical trials, in order to derive more satisfactory indications for or against extended lymph node dissection at the time of radical cystectomy. However, the authors may consider that this is beyond the scope of a reviewer request!

Author Response

Comments 1: This short manuscript presents a summary/analysis of 2 studies that compared standard and extended lymph node dissection in bladder cancer patients undergoing radical cystectomy. Because only 2 previous studies were included, it is difficult to call it a true meta-analysis, even though the appropriate (recommended) statistical analyses have been performed. Overall, the manuscript is concise and very clearly written, and the 2 studies, that came to similar conclusions individually, unsurprisingly produce similar conclusions when combined. This manuscript will provide a handy reference for authors to cite to support a lack of ‘oncological benefit’ of extended lymph node dissection, however the many gaps in the scope of disease interrogated in the studies curtail its importance to the field. The limitations are not related to the meta-analysis itself, but stem from the paucity of studies, the poor representation of N1 and N2 disease and exclusion of N3 disease in those studies, and other limitations that the authors have listed. I would prefer it if the authors would specifically discuss these limitations and the areas that need to be addressed, preferably through clinical trials, in order to derive more satisfactory indications for or against extended lymph node dissection at the time of radical cystectomy. However, the authors may consider that this is beyond the scope of a reviewer request!

Response 1: We thanks the reviewer for their feedback and have made the following changes to the manuscript: "Similarly, it is important to note that the included studies excluded patients with cN3 disease and this may be a population of patients where extended node dissection provides an oncological benefit. Therefore, further trials in this space should focus on patients with higher risk/stage disease to determine if there is an improvement in survival outcomes with extended node dissection templates in those with more advanced disease."