The Role of Cytoreductive Nephrectomy in Renal Cell Carcinoma with Sarcomatoid Histology: A Case Series and Review of the Literature

Round 1

Reviewer 1 Report

The authors present a case report of patients diagnosed RCC with sarcomatoid histology putting focus on cytoreductive nephrectomy

From my point of view the paper deserves publication after all changes added

The paper needs slight English review

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

The authors reported a series of patients who have undergone CN in combination with ICI. They have included many cases of upfront CN, and this report is interesting since the multiple guidelines suggest the use of CN after the systemic therapy. Furthermore, they presented the rare cases of RCC, sRCC, which are found to be aggressive and potential surrogate for ICI response. Since the role of CN in the immunotherapy era is undetermined, suggesting the upfront CN in combination with ICI in sRCC is promising therapeutic strategies.  

1.     The authors should discuss more about upfront and delayed CN since this concept is important when considering the role of CN in combination with systemic therapy. SURTIME trials have not recommended upfront CN and most studies have suggested to perform CN after monitoring the response by systemic therapy. However, since sRCC is aggressive, it will be more risky to wait for the response by systemic therapy. Future prospective studies are needed to compare the risk and benefit of waiting for the response of systemic therapy in sRCC.

2.     Please make the sentences from 62-93 more concise. The introduction section is too long.

3.     Please include recent articles as references such as,

Yoshida, Takashi, et al. "Eosinophilic features in clear cell renal cell carcinoma correlate with outcomes of immune checkpoint and angiogenesis blockade." Journal for immunotherapy of cancer 9.9 (2021).

Chakiryan, Nicholas H., et al. "Survival Outcomes Associated With Cytoreductive Nephrectomy in Patients With Metastatic Clear Cell Renal Cell Carcinoma." JAMA Network Open 5.5 (2022): e2212347-e2212347.

Minor comments are below:

1.     Please include all figures and table in the manuscript, not as supplementary files.

2.     Denote “patient 2” in figure 2 legend.

3.     Please explain why the surgery was incomplete in patient 2. Furthermore, please include initial CT images and compare with the images right after the surgery. The authors only presented CT images after CN.

4.     Pleas denote in table legend why sarcomatoid component of patient 4 has not been unavailable in table 1.

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

The authors present a case report of patients diagnosed RCC with sarcomatoid histology putting focus on cytoreductive nephrectomy

Paper and discussion are well written supporting prospective data in this setting of patients about immunotherapy efficacy and adding real world evidence about nephrectomy in this setting

The only minor comment is that the paper needs English review. The authors should adapt references to journal style.

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

The authors present a case series of 6 patients with M1 sarcomatoid RCC (sRCC) diagnosed in the immunotherapy era (post 2015), most of them being treated with upfront cytoreductive nephrectomy (CN) and ipilimumab-nivolumab afterwards. Furthermore, they discuss the current scarce literature on sRCC.

The paper is well written. This is a small case series, so no firm conclusions can be drawn from this, but nonetheless, this paper can be informative for clinicians when dealing with M1 sRCC. While the management of patients was standard of care at the time being, following results of the CARMENA trial, upfront CN is no longer standard of care in most patients, especially in patients with poor prognosis. There are some further issues that need to be handled, listed below.

INTRODUCTION

- “Herein we report six cases identified in our database in whom CN was considered upfront or delayed depending on the response to immunotherapy.”

Where these 6 patients all patients that were diagnosed with M1 sRCC in this time period ? Or only the patients that were considered for CN ? Please state this more clearly. If these were not all M1 sRCC patients, please state how many M1 sRCC patients were encountered during this time period as only reporting outcome of 6 patients will otherwise be associated with significant selection bias.

CASE PRESENTATION

- Table 1: please add patients’ gender

- Did all patients undergo tumor biopsy  prior to treatment ? Since the CARMENA trial, upfront CN is no longer standard of care in most patients with M1 RCC and upfront systemic therapy is started in case of ccRCC. Therefore, most patients undergo biopsy nowadays.

- The details on ICI treatment and toxicity in most patients are too extensive and are not very relevant. The parapgraphs should be shortened.

- Please indicate the date (or month) of last follow-up and disease status for all patients.

- case 5: the patient had disease progression on sunitinib, but receivd no further therapy and is alive 18 months later. Why did she not have subsequent therapy (e.g. cabozantinib) ? Did she receive any further CT scans ?

DISCUSSION

- “Based on the experience in the present cohort, we speculate that removing the large primary tumor could have had an impact on response to subsequent immunotherapy. “

This is in contrast to date from CARMENA trial, where patients with M1 ccRCC with >2 IMDC factors did not benefit from CN and had improved outcome with immediate TKI. Of course, we do not know whether this is the same in sRCC. I, however, do not fully agree with the rationale presented in the paper that patients might have benefitted from upfront local treatment. M1 sRCC is a rapidly progressive disease with a median estimated survival <1 year in the absence of treatment. Therefore, postponing systemic therapy with several weeks/months following CN might compromise patient survival. Furthermore, extensive surgery might cause a drop in immunosurveillance and rapid disease progression. Lastly, as patients’ demise is usually due to the metastatic disease burden, it seems more plausible to start systemic therapy first and perform deferred CN in case of response. 

While in your paper the arguments pro upfront CN are stated, these counter arguments should also be discussed. 

Author Response

Please see attachment.

Author Response File: Author Response.pdf