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. 2024 Mar 28;19(3):e0299102. doi: 10.1371/journal.pone.0299102

Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: An analysis of the TriNetX database

Gu-Shun Lai 1,2, Jian-Ri Li 1,2,3, Shian-Shiang Wang 1,2,4, Chuan-Shu Chen 1,2, Chun-Kuang Yang 1,2, Chia-Yen Lin 1,2, Sheng-Chun Hung 1,2, Kun-Yuan Chiu 1,2,4, Shun-Fa Yang 1,5,*
Editor: Mirosława Püsküllüoğlu6
PMCID: PMC10977795  PMID: 38547226

Abstract

Background

The role of upfront cytoreductive nephrectomy remains debatable in the present era of tyrosine kinase inhibitors and immune checkpoint inhibitors. Here, we aimed to evaluate the outcomes of metastatic renal cell carcinoma patients treated with upfront CN and modern systemic therapies.

Methods

Using the TriNetX network database, we identified patients, in the period from 2008 to 2022, who were diagnosed with metastatic renal cell carcinoma, receiving first-line systemic therapies with tyrosine kinase inhibitors or immune checkpoint inhibitors. Their overall survivals were evaluated using the Kaplan-Meier method as well as multivariable regressions.

Results

We identified 11,094 patients with metastatic renal cell carcinoma. Of them, 2,914 (43%) patients in the tyrosine kinase inhibitor cohort (n = 6,779), and 1,884 (43.7%) in the immune checkpoint inhibitors cohort (n = 4315) underwent upfront cytoreductive nephrectomy. Those receiving upfront cytoreductive nephrectomy showed survival advantages with either tyrosine kinase inhibitor (Hazard ratio 0.722, 95% Confidence interval 0.67–0.73, p<0.001) or immune checkpoint inhibitors (Hazard ratio 65.1, 95% Confidence interval 0.59–0.71, p<0.001). In multivariable analysis, upfront cytoreductive nephrectomy was a factor for improved OS in both cohorts: tyrosine kinase inhibitors (Hazard ratio 0.623, 95% Confidence interval 0.56–0.694, p<0.001) and immune checkpoint inhibitors cohort (Hazard ratio 0.688, 95% Confidence interval 0.607–0.779, p<0.001).

Conclusions

Upfront cytoreductive nephrectomy was associated with an improved overall survival for patients with metastatic renal cell carcinoma receiving either first-line tyrosine kinase inhibitors or immune checkpoint inhibitors. Our results support a clinical role of upfront cytoreductive nephrectomy in the modern era.

Introduction

Over the past two decades, cytoreductive nephrectomy (CN) has been a standard treatment for patients with metastatic renal cell carcinoma (mRCC). The supporting evidence includes results from several randomized trials showing survival benefits from CN plus interferon treatment compared with interferon therapy alone [1–4]. With the introduction of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (IO), the treatments for mRCC evolved a lot in the past decade [5–8]. Since the role of CN was established before the era of TKI and IO, it is necessary to reassess its influence on oncological outcomes.

In 2018, the randomized phase III trial CARMENA (Cancer du Rein MétastatiqueNéphrectomie et Antiangiogéniques) showed that treatment outcomes in overall survival (OS) with sunitinib alone is not inferior to CN followed by sunitinib for patients with intermediate- or high-risk mRCC [9]. However, subgroup analyses revealed that patients with one risk factor from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) have survival benefits with CN. Several studies showed CN plus TKI is associated with improved OS compared with TKI alone for patients with mRCC [10–13]. Recent ASCO guidelines on mRCC also recommended CN as a treatment option for selected patients [14].

Despite the results of the CARMENA trial, CN remains debated in the era of TKI and IO, while it has been used in clinical practice for mRCC patients. Herein, we conducted a retrospective cohort study to assess the role of upfront CN on survival for patients with mRCC receiving either TKI or IO.

Materials and methods

Study design, population and outcomes

A retrospective study was performed using TriNetX network, a global database that provides real-world data of ≥250 million people. In this study, we used the US Collaborative Network including 57 healthcare organizations across the US.

We enrolled patients with mRCC and aged ≥18 years old. They received first-line systemic treatment between January 1, 2008 and December 30, 2022. Patients were identified using the International Classification of Diseases, 10th edition, Clinical Modification (ICD-10-CM) codes: ICD-10-CM C64 for malignant neoplasm of kidney, and ICD-10-CM: C78 (lung metastases), C78.7 (liver metastases), C79.3 (brain metastases), or C79.5 (bone metastases) to confirm the diagnosis of distant metastases. The starting date of first-line therapy was set as the index date. Upfront cytoreductive nephrectomy needed to be performed within 3 months before the index date (initiation of first-line therapy). We recognized patients receiving nephrectomy using ICD-10-CM: Z90.5. Comorbidities were identified using ICD-10-CM: I10-I16 for hypertension, ICD-10-CM: I20-I25 for ischemic heart diseases, ICD-10-CM: E08-E13 for diabetes mellitus, and ICD-10-CM: I60-I69 for cerebrovascular disease. The first-line systemic therapies were either TKI (sunitinib, pazopanib, axinitib, or cabozatinib) or IO (nivolumab, ipilumab, atezolizumab, or pembrolizumab). Patients receiving IO-base combination therapy (IO+TKI) were included into the IO cohort.

The primary outcome was OS. OS was defined as the duration from the index date to the date of death from any cause, or censored at the end of study, whichever happened first.

Statistical analyses

Patient baseline characteristics, in case of continuous variables, were expressed as mean and standard deviation (SD), and categorical variables, as number and percentage. For evaluating inter-group differences, Student’s t test was used for continuous variables, and chi-square test for categorical variables. Survival was evaluated using Kaplan-Meier methodology with a median OS and 95% confidence interval (95% CI), as well as a log-rank test to evaluate inter-group differences in OS. Logistic regression was used to assess various risk factors for death. All analyses were performed on the TriNetX platform. Statistical significance was set at p <0.05.

Ethics in research

Our study was approved by the institutional review board (IRB) of Taichung Veterans General Hospital (number: SE:22220A). Given information for patient identification was not provided on the TriNetX platform, the IRB waived the requirement for informed consent.

Results

Baseline characteristics

Patient characteristics are shown in Table 1. In total, we identified 11,094 patients with mRCC with most of the patients being white. Of them, 6,779 received TKI therapy (the TKI cohort), and 2,914(43%) of them had CN. Also, 4,315 of these patients received IO therapy (the IO cohort), and 1,884 (43.7%) had CN. In the TKI cohort, the majority of patients receive sunitinib (n = 1,984, 29.2%) and pazopanib (n = 1,947, 28.7%). In the IO cohort, the most frequently used treatments were pembrolizumab (n = 1,558, 36.1%) and nivolizumab (n = 1140, 26.4%). Pei chart of races and first-line systemic therapies in the TKI and IO cohorts was illustrated in Fig 1.

Table 1. Baseline characteristics for patients with metastatic renal cell carcinoma receiving first-line tyrosine kinase inhibitors or immune checkpoint inhibitors.

TKI with CN
n = 2914		 TKI without CN
n = 3865		 P IO with CN
n = 1884		 IO without CN
n = 2431		 P
Age, years, mean (SD) 63.3 (11.2) 62.9 (12) 0.0607 66.2 (11.7) 65.9 (12.7) 0.534
Sex, male (%) 2063 (71) 2666 (69) 0.106 1322 (70) 1641 (68) 0.061
Race, n (%)
White 2363(81) 2781 (72) <0.001 1478 (79) 1880 (77) 0.359
Black 202 (7) 274 (10) <0.001 102 (5) 204 (8) 0.0002
Asian 58 (2) 86 (2) 0.507 66(4) 78 (3) 0.0593
Others/unknown 291(9) 724 (19) <0.001 93 (16) 269 (11) 0.2163
BMI, mean (SD) 29.2 (6.48) 28.6 (6.37) 0.009 28.6 (6.25) 28 (6.24) 0.0152
ECOG, mean (SD) 0.562 (0.666) 0.943 (0.802) 0.0106 0.596(0.64) 0.781(0.72) 0.044
Metastatic site, n (%)
Lung 1370 (47) 859 (22) <0.001 801 (43) 774 (32) <0.001
Liver 457 (16) 391 (10) <0.001 267 (14) 361 (15) 0.531
Bone 932 (32) 883 (23) <0.001 496 (26) 764 (31) 0.0003
Brain 368 (13) 291 (8) <0.001 191 (10) 272 (11) 0.2687
Comorbidity, n (%)
Diabetes Mellitus 919 (32) 766 (20) <0.001 629 (33) 700 (29) 0.0012
Hypertension 2053 (70) 1707(44) <0.001 1389 (74) 1492 (61) <0.001
Cerebrovascular disease 416 (14) 317 (8) <0.001 333 (18) 391 (16) 0.1653
Ischemic heart disease 760(26) 529 (14) <0.001 727 (39) 630 (26) <0.001
Types of TKI, n (%)
Sunitinib 866 (30) 1118 (29)
Pazopanib 867 (30) 1080 (28)
Cabozatinib 558 (19) 728 (19)
Axitinib 372 (13) 584 (15)
Unknowns 251 (9) 355 (9)
Types of IO, n (%)
Pembrolizumab 636 (34) 922 (38)
Ipilimumab + Nivolumab 550 (29) 536 (22)
Nivolumab 521 (28) 619 (25)
Atezolizumab 119 (6) 172 (7)
Unknowns 58 (3) 182 (7)
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BMI: Body mass index; CN: Cytoreductive nephrectomy; ECOG, eastern cooperative oncology Group; IO: Immune checkpoint inhibitor; SD, standard deviation; TKI: Tyrosine kinase inhibitor.

Fig 1.

Fig 1

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Pie charts of (A) races and (B) first-line systemic therapies for patient with metastatic renal cell carcinoma in the TKI and IO cohorts. IO: Immuno-oncology; TKI: Tyrosin kinase inhibitor.

In the TKI cohort, patients receiving CN had significantly more distant metastases and comorbidities when compared with those without CN (all with p<0.001). Similarly, in the IO cohort, patients receiving CN had more instances of hypertension (p<0.001), diabetes mellitus (p = 0.0012), ischemic heart disease (p<0.001), and lung metastasis (p<0.001), while bone metastasis occurred more frequently for patients not receiving CN (p<0.001) (Fig 2). The Eastern cooperative oncology group (ECOG) performance status was better for patients receiving CN in both TKI and IO cohorts (TKI cohort: p = 0.016, IO cohort: p = 0.044).

Fig 2.

Fig 2

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Bar graph of (A) sites of distant metastases and (B) comorbidities for patients with metastatic renal cell carcinoma in the TKI with/without CN and IO with/without CN cohorts. CN: Cytoreductive nephrectomy; IO: Immune checkpoint inhibitors; TKI: Tyrosin kinase inhibitor.

Outcomes

In the TKI cohort, the median follow-up time was 30.1 months, and in the IO cohort, this was 28.8 months. By the end of this study (December, 2022), 3,540 (52.2%) patients in the TKI cohort reached primary end point (deaths), and 2,086 (48.3%) in the IO cohort.

In the TKI cohort, for patients with CN, their survival probability at the 12th month was 73.9% [95% confidence interval (CI) 72.1–75.5] compared with 64.9% (95% CI 63.2–66.5) for those without CN. In the IO cohort, for patients with CN, their survival probability at the 12th month was 71.4% (95% CI 69.1–73.5), compared with 60.3% (95% CI 57.8–62.1) for those without CN. In the TKI cohort, their median OS was 38.3 months for patients with CN, and 23.3 months for those without CN. In the IO cohort, their median OS was 40.5 months for patients with CN, and 19.1 months for those without CN. Patients undergoing CN had survival benefits in OS for both TKI [Hazard ratio (HR) 0.722, 95% CI 0.67–0.73, p<0.001] and IO (HR 65.1, 95% CI 0.59–0.71, p<0.001) cohorts (Fig 3). For patients receiving CN, there was no significant difference in OS between TKI and IO cohorts.

Fig 3.

Fig 3

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Kaplan-Meier survival curves of overall survival for patients with metastatic renal cell carcinoma treated with (A) TKI with/without CN and (B) IO with/without CN. CI: Confidence Interval; CN: Cytoreductive nephrectomy; HR: Hazard ration; IO: Immune checkpoint inhibitor; TKI: Tyrosin kinase inhibitor.

Based on multivariable logistic regression analyses, CN was associated with a reduced risk of death in both TKI (HR 0.623, 95% CI 0.56–0.694, p<0.001) and IO (HR 0.688, 95% CI 0.607–0.779, p<0.001) cohorts (Table 2 and Fig 4).

Table 2. Multivariable analysis for overall survival in patients with metastatic renal cell carcinoma receiving first-line tyrosine kinase inhibitors or immune checkpoint inhibitors.

TKI IO
HR 95% CI P HR 95% CI P
Age at index date 1.007 1.003 1.012 0.001 1.018 1.013 1.023 <0.001
Male Gender (Male/Female) 1.125 1.015 1.247 0.024 1.089 0.962 1.232 0.177
Upfront cytoreductive nephrectomy 0.623 0.56 0.694 <0.001 0.688 0.607 0.779 <0.001
Bone metastases 1.351 1.215 1.503 <0.001 1.396 1.227 1.587 <0.001
Brain metastases 1.373 1.165 1.617 <0.001 1.221 1.006 1.481 0.043
Liver metastases 1.596 1.38 1.847 <0.001 1.857 1.57 2.196 <0.001
Lung metastases 1.228 1.108 1.361 <0.001 1.223 1.082 1.382 0.001
ECOG performance status (≥2/0-1) 1.171 0.56 3.625 0.785 1.021 0.52 2.005 0.951
Clear cell/non-clear cell histology 1.132 0.972 1.317 0.111 0.788 0.627 0.988 0.039
Hypertension 1.074 0.963 1.197 0.202 1.006 0.877 1.155 0.932
Diabetes mellitus 1.048 0.931 1.179 0.436 1.02 0.893 1.165 0.772
Cerebrovascular disease 1.365 1.161 1.605 <0.001 1.381 1.173 1.632 <0.001
Ischemic heart disease 1.128 0.99 1.285 0.071 1.202 1.046 1.379 0.009
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ECOG: Eastern cooperative oncology group; HR: Hazard ratio; IO: Immune checkpoint inhibitor; TKI: Tyrosin kinase inhibitor; CI: Confidence interval.

Fig 4. Forest plot of multivariable analysis for overall survival in patients with metastatic renal cell carcinoma treated with TKI and IO.

Fig 4

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CI: Confidence interval; HR: Hazard ration; IO: Immune checkpoint inhibitors; OS: Overall survival; TKI: Tyrosin kinase inhibitor.

We performed subgroup analyses and found similar results. Patients with mRCC experienced survival benefits from CN treated with either TKI monotherapy (HR 0.643, 95% CI 0.598–0.692, p<0.001), IO monotherapy (HR 0.675, 95% CI 0.607–0.75, p<0.001), Ipilimumab + Nivolumab (HR 0.491, 95% CI 0.422–0.571, p<0.001), or Axitinib + Pembrolizumab (HR 0.461, 95% CI 0.369–0.575, p<0.001) (Fig 5).

Fig 5. Subgroup analysis of overall survival for patients with metastatic renal cell carcinoma treated with TKI momotherapy, IO monotherapy, Ipilimumab+Nivolumab, and Axitinib + Pembrolizumab.

Fig 5

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CI: Confidence interval; CN: Cytoreductive nephrectomy; HR: Hazard ratio; IO: Immune checkpoint inhibitors; OS: Overall survival; TKI: Tyrosin kinase inhibitor.

Discussion

In the present study, we conducted a retrospective cohort study on the TriNetX platform to evaluate the benefits of upfront CN for patients with mRCC receiving first-line systemic therapy with either TKI or IO. We found that patients receiving upfront CN, compared with those without CN, were associated with improved OS.

CN was historically the standard care option for patients with mRCC. Its evidence is based on several trials reporting survival benefits of surgical intervention in the era of cytokines [1–4]. With the advent of targeted therapies and immune checkpoint inhibitors, several studies reported survival advantages of these new systemic treatments over traditional cytokines [5–8]. Given the rapid evolution of these novel and more efficient agents, the role of CN has become controversial. CARMENA, a phase 3, randomized trial on patients with mRCC, reported that sunitinib alone is not inferior in OS when compared with CN followed by sunitinib [9]. SURTIME is a randomized trial, which demonstrated a survival advantage of deferred CN compared with immediate CN, indicating that surgical intervention could be an option for patients with objective response to sunitinib [10]. Nevertheless, a subgroup analysis in the CARMENA trial reported that patients with one IMDC risk factor have survival benefit from CN, and multiple studies also supported the role of CN in the modern era [11–17]. In this study, we found that patients undergoing upfront CN were associated with better OS in both TKI and IO cohorts [18,19]. One hypothesis of the underlying mechanisms is that primary RCC releases cytokines to stimulate inflammation, and they also reducing immune responses against the tumor [20,21]. CN reduces cytokines and prevents metastatic tumors from progression. The potential immune modulation effects of surgery may be further aggravated in patients treated with IO therapies.

According to previous studies, patients with fewer sites of metastases and better performance status have survival benefit from surgical intervention [9,13,22,23]. In this study, we found that patients receiving CN have better ECOG performance. Interestingly, they had more incidences of distant metastases and co-morbidities. Multiple variables analyses confirmed that fewer metastases and CN were associated with better OS. Results indicated that patients with more distant metastases and co-morbidities may still get survival benefit from surgery. The discrepancy of these findings highlighted the survival advantages of CN in mRCC, suggesting that multiple factors should be considered for clinicians in evaluating these patients.

There are some limitations of our study. First, its retrospective design and non-randomization are subject to selection bias. Second, some patient information and statistics analyses were not available on the platform, such as IMDC risk stratification and Cox regression analysis. Despite these limitations, our study involved a large population in a real-world setting. Our findings provide clinicians some useful information in the management of these patients while awaiting the results from the ongoing trials that assess the role of CN in the era of TKI and IO.

Conclusion

Results of our study supported the OS benefits of upfront CN for mRCC patients in the modern TKI and IO era. Before reports emerge from prospective and randomized trials, our findings are helpful for clinicians in treating these patients.

Supporting information

S1 File. Values for Kaplan-Meier survival analysis in patients with TKI treatment.

(XLSX)

pone.0299102.s001.xlsx (121.3KB, xlsx)
S2 File. Values for Kaplan-Meier survival analysis in patients with IO treatment.

(XLSX)

pone.0299102.s002.xlsx (84.2KB, xlsx)

Acknowledgments

This study was based on the data from the TriNetX network.

Data Availability

All relevant data are within the paper and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Mirosława Püsküllüoğlu

11 Jan 2024

PONE-D-23-31046Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: an analysis of the TriNetX databasePLOS ONE

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Academic Editor

PLOS ONE

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[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: No

Reviewer #3: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: A major shortcoming of the manuscript is graphical representation of the scientific data. I strongly suggest inclusion of graphs to match both the standard of the journal and also global reporting criteria.

Reviewer #2: I read the manuscript with interest and it addresses an important issue about the role of CN in modern era. There are however serious issues with technical aspects, especially the analysis.

the authors need to clearly mention in the methods section which all variables were used for multivariable analysis. Also, IMDC or other composite measures of disease burden (if present) are welcome in the analysis. There is mention of logistic regression used for analysis of death. Death is a time to event data and cox proportional hazard regression is more appropriate design. if time to event data is available to draw OS curves, then cox PH analysis should be feasible. please also give data on number at risk below the OS curves. Try to see if Charlson comorbidity index score can be assigned to make a composite score for comorbidities.

Reviewer #3: Well written study examining CN for RCC using the TriNetX database.

Major Points:

- Consider citing the recent ASCO guideline on metastatic RCC as it specifically addresses upfront CN.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

Rathmell WK, Rumble RB, Van Veldhuizen PJ, Al-Ahmadie H, Emamekhoo H, Hauke RJ, Louie AV, Milowsky MI, Molina AM, Rose TL, Siva S, Zaorsky NG, Zhang T, Qamar R, Kungel TM, Lewis B, Singer EA.

J Clin Oncol. 2022 Sep 1;40(25):2957-2995. doi: 10.1200/JCO.22.00868. Epub 2022 Jun 21.

PMID: 35728020

- Consider performing separate analyses for TKI monotherapy, IO monotherapy, and doublet therapy (IO/IO and IO/TKI) instead of combining IO and doublets.

Minor Points:

- None

**********

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Reviewer #1: No

Reviewer #2: Yes: Jiten Jaipuria

Reviewer #3: No

**********

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Attachment

Submitted filename: Review Comments_4.pdf

pone.0299102.s003.pdf (23.9KB, pdf)
PLoS One. 2024 Mar 28;19(3):e0299102. doi: 10.1371/journal.pone.0299102.r002

Author response to Decision Letter 0

20 Jan 2024

Reviewer #1: A major shortcoming of the manuscript is graphical representation of the scientific data. I strongly suggest inclusion of graphs to match both the standard of the journal and also global reporting criteria.

We included number of patients and related data to present the outcomes in the survival curves (Fig 3). Please check it in the revised manuscript.

Reviewer #2: I read the manuscript with interest and it addresses an important issue about the role of CN in modern era. There are however serious issues with technical aspects, especially the analysis.

the authors need to clearly mention in the methods section which all variables were used for multivariable analysis. Also, IMDC or other composite measures of disease burden (if present) are welcome in the analysis. There is mention of logistic regression used for analysis of death. Death is a time to event data and cox proportional hazard regression is more appropriate design. if time to event data is available to draw OS curves, then cox PH analysis should be feasible. please also give data on number at risk below the OS curves. Try to see if Charlson comorbidity index score can be assigned to make a composite score for comorbidities.

All variables and related ICD codes used in the multivariable analysis were added in the method section. Number at risk were added below the survival curves (Fig 3). Please check it in the revised manuscript. We regretted that time to event, Charlson comorbidity index and IMDC data are currently not available on the TriNetX database.

Reviewer #3: Well written study examining CN for RCC using the TriNetX database.

Thanks for the comments.

Major Points:

- Consider citing the recent ASCO guideline on metastatic RCC as it specifically addresses upfront CN.

Management of Metastatic Clear Cell Renal Cell Carcinoma: ASCO Guideline.

Rathmell WK, Rumble RB, Van Veldhuizen PJ, Al-Ahmadie H, Emamekhoo H, Hauke RJ, Louie AV, Milowsky MI, Molina AM, Rose TL, Siva S, Zaorsky NG, Zhang T, Qamar R, Kungel TM, Lewis B, Singer EA.

J Clin Oncol. 2022 Sep 1;40(25):2957-2995. doi: 10.1200/JCO.22.00868. Epub 2022 Jun 21.

PMID: 35728020

The journal regarding recent ASCO guideline on metastatic RCC was cited in the revised manuscript (reference No. 14). Please check it.

- Consider performing separate analyses for TKI monotherapy, IO monotherapy, and doublet therapy (IO/IO and IO/TKI) instead of combining IO and doublets.

Subgroup analyses for TKI monotherapy, IO monotherapy, and doublet therapy (IO/IO with Ipilimumab + Nivolumab and IO/TKI with Axitinib + Pembrolizumab) were performed and added in the revised manuscript (Fig 5). Please check it.

Review Comments on “Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: an analysis of the TrinetX database”

Overall comments:

The authors report potential clinical implications and survival of cytoreductive nephrotomy in patients. The manuscript is a well-written one and describes the limitations of the study too. However, I do have the following suggestions as it would help the reader to understand the fi ndings more conveniently, specifi cally tables 1 and 2, than how it is now. Because it is difficult now to go through the data and the graphs are crucial to be a part of the scientific data presentation in the manuscript, also required to match the standards of the journal.

1. From Table 1, it is suggested that addition of pie-charts to show the points mentioned in the chart like age, sex, ethnicity, organs, etc. in both TKI and IO, is done. This way it will depict the data in a better presentable manner.

2. From Table 1, similarly a bar graph representation with the statistics included for the BMI and co-morbidities is what is needed.

3. A volcano plot is also preferred to be added to show the distribution of the experimental groups amongst the individuals studied, with and without the treatments.

4. The above-mentioned points need to be addressed for table 2 too.

Pei-charts and bar graphs to report the scientific data in the Table 1 were included in the revised manuscript (Fig 1 and 2). We used a Forest plot to present the data in Table 2 (Fig 4). Please check it.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0299102.s004.docx (17.6KB, docx)

Decision Letter 1

Mirosława Püsküllüoğlu

6 Feb 2024

Outcome benefits of upfront cytoreductive nephrectomy for patients with metastatic renal cell carcinoma: an analysis of the TriNetX database

PONE-D-23-31046R1

Dear Dr. Lai,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Mirosława Püsküllüoğlu, MD, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: According to me, most of the concerns that were raised by the reviewers, has been addressed. The data, with the addition of graphs, has a better representation in a scientific way. Although I have mentioned about some minor changes regarding the formatting issues.

Reviewer #3: All queries have been addressed. No additional queries. I recommend publication.

Thank yo for the opportunity to review.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #3: No

**********

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 File. Values for Kaplan-Meier survival analysis in patients with TKI treatment.

    (XLSX)

    pone.0299102.s001.xlsx (121.3KB, xlsx)
    S2 File. Values for Kaplan-Meier survival analysis in patients with IO treatment.

    (XLSX)

    pone.0299102.s002.xlsx (84.2KB, xlsx)
    Attachment

    Submitted filename: Review Comments_4.pdf

    pone.0299102.s003.pdf (23.9KB, pdf)
    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0299102.s004.docx (17.6KB, docx)

    Data Availability Statement

    All relevant data are within the paper and its Supporting Information files.

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