ORIGINAL ARTICLE

Predictors of Cytoreductive Nephrectomy for Metastatic Kidney Cancer in SEER and Metropolitan Detroit Databases

Ulka Vaishampayan, Julie George, Fawn Vigneau

Department of Oncology, Karmanos Cancer Center, Wayne State University, Detroit, MI, USA

Abstract

Patients without cytoreductive nephrectomy (CN) are inadequately represented in metastatic renal cell carcinoma (RCC) clinical trials. The characteristics that impact the decision of CN were explored in the SEER database. Data on primary, regional, or distant (metastatic) stage kidney cancer over the period 2000–2013 were extracted from the National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER-18) database. A sub-analysis of Metropolitan Detroit cases, to evaluate the influence of comorbidities, was conducted. Logistic regression was used to calculate the odds ratios, and Cox model was used to calculate hazard ratios; 37% of 21,052 metastatic RCC cases had CN performed. CN demonstrated significant survival advantage (HR = 0.31, 95% confidence interval [CI]: 0.30–0.33). Comorbidity data were available on 76% of distant RCC cases from the Detroit SEER database. Neither hypertension, diabetes mellitus nor the number of comorbidities (0, 1 or 2) had a statistically significant impact on the likelihood of CN. Majority of patients (63%) with distant-stage RCC do not undergo CN and have a median overall survival (OS) of 3 months as compared to a median OS of 18 months for patients who have undergone CN. Patient demographics and tumor characteristics make a significant impact on the incidence of CN. The impact of comorbidities (number and type) was modest and not statistically significant. The optimal management of patients with synchronous primary and metastatic RCC needs to be prospectively evaluated in the setting of contemporary systemic therapy.

Keywords: comorbidities; kidney cancer; nephrectomy; prognostic factors; SEER registry

Received: 02 August 2019; Accepted after revision: 02 October 2019; Published: 28 October 2019

Author for Correspondence: Ulka Vaishampayan, MD, 4100 John R, Detroit, MI 48201, USA. Email: vaishamu@karmanos.org

How to cite: Vaishampayan et al. Predictors of cytoreductive nephrectomy for metastatic kidney cancer in SEER and metropolitan Detroit databases. J Kidney Cancer VHL 2019;6(1): 13–25.

Doi: http://dx.doi.org/10.15586/jkcvhl.2019.121

Copyright: Vaishampayan et al.

License: This open access article is licensed under Creative Commons Attribution 4.0 International (CC BY 4.0). http://creativecommons.org/licenses/by/4.0

 

Introduction

Cytoreductive nephrectomy (CN) in the presence of metastatic disease is a unique feature of the therapeutics of advanced renal cancer (RCC). There are two randomized trials demonstrating the overall survival (OS) benefit favoring CN in metastatic disease compared to systemic interferon therapy alone (1, 2). The only systemic therapies available previously were cytokine-based regimens such as interleukin and interferon during the time period when these CN trials were conducted. Within the last decade, 10 additional therapies have attained Food and Drug Administration (FDA) approval in metastatic renal cancer (3). Until recently, no prospective study had been completed evaluating the role of CN in the setting of contemporary systemic therapies. The results of two randomized trials comparing CN followed by sunitinib versus systemic therapy with sunitinib followed by CN [SURTIME trial] and nephrectomy followed by sunitinib versus sunitinib alone (CARMENA) were recently reported. Both studies indicated that the clinical outcomes with sunitinib alone were at least similar and possibly slightly improved in the metastatic RCC patients randomized to deferred or no CN (4, 5). The studies showed that CN does not impart additional survival benefit in the setting of effective systemic therapy, and a proportion of patients are deprived of systemic therapy due to complications of CN. In summary, the concept of CN being an essential component of metastatic RCC therapy is being seriously questioned. These data need to be considered in future therapeutic decisions in metastatic RCC.

The National Cancer Database (NCDB), which reflects community-based data from hospitals with Commission on Cancer accreditation, continues to reveal that the incidence of CN in distant-/advanced-stage RCC is seen in about a third of the patients (6). Unlike clinical trials of systemic therapy, where 80–100% of patients are receiving nephrectomy, the majority of the patients in the real-world treatment of RCC are not receiving CN as primary management. The overall survival outcome has improved in advanced RCC; however, it also appears that the patients with CN received the maximum benefit (7). Despite randomized evidence to the contrary, the OS results in SEER show that CN patients have a large magnitude of benefit as compared to non-CN patients. This finding may be confounded by the fact that the patients undergoing CN are probably younger, healthier, and less likely to have aggressive or poor risk disease, factors that portend an improved prognosis regardless of nephrectomy status. In an attempt to overcome the confounding effect of conflicting prognostic factors, we analyzed and reported on a clinical trial population with metastatic disease and found that CN maintained a significant positive impact on clinical outcomes (8).

In the targeted therapy era, we conducted a SEER data analysis of outcomes in patients who have undergone CN versus those who have not undergone CN. The results revealed that only the post-nephrectomy population appeared to benefit from advances in systemic therapies (8). Clearly, an intervention that would increase the possibility of CN in metastatic RCC would likely improve outcomes. The controversy of whether CN should be standard in metastatic RCC continues, with the recent randomized prospective trials suggesting minimal contribution of CN in improving outcomes in metastatic RCC. In addition, there is an added nuance of analyzing the role of CN in the presence of contemporary immune checkpoint combination therapy. There is preclinical evidence that suggests that the immune checkpoint inhibitors would be primed to demonstrate improved efficacy in the presence of the primary tumor. Randomized trials of systemic therapy with immune checkpoint inhibition with or without CN are being planned in this setting.

We attempted to evaluate the magnitude of the problem by assessing the incidence of CN in metastatic RCC within the SEER data. We analyzed the factors that are likely to impact the decision of CN in the initial management of advanced RCC. We explored demographic and disease-related factors. In addition, we assessed the impact of comorbidities in receipt of initial CN using additional data from the Metropolitan Detroit Cancer Surveillance System (MDCSS). We conducted an analysis of distant/metastatic cases of RCC within the SEER-18 data between 2000 and 2013. The intention was to evaluate the incidence of CN in the contemporary systemic therapy era and to assess the factors that impacted the decision of CN. We chose to explore the impact of a few key comorbidities such as renal function, hypertension, diabetes mellitus, and lung disease.

Methods

The National Cancer Institute Surveillance, Epidemiology, and End Results Program (SEER-18) contains regional research data (1973–2011) submitted in November 2013 with the Katrina/Rita population adjustment, collected from 18 American cancer registries, chosen for their data quality and population diversity. The MDCSS is a data contributor to the SEER Program. Data for the primary analyses were extracted using SEER*Stat software (version 8.3.1), for patients diagnosed with renal cancer between the years 2000 and 2013. We restricted the analysis to the first diagnosis of regional or distant stage kidney cancer, overall referred to as “metastatic” kidney cancer. Site-specific surgery codes 30, 40, 50, 70, or 80 were defined as having received nephrectomy. The main focus was advanced or metastatic cases with RCC which are coded as “distant” in SEER. Logistic regression analysis was used to calculate odds ratios (OR) of a patient who has undergone nephrectomy, adjusted for age at diagnosis, race, gender, marital status, insurance and disease histology, and grade. Cox proportional hazards regression analysis was used to calculate adjusted hazard ratios (HR) to estimate the overall risk of death. Hazard ratios were adjusted for nephrectomy as well as for all other variables listed above. Analyses were conducted using SAS software version 9.4 (SAS Institute Inc., Cary, NC). Patients with OS < 1 month were excluded from the analysis with the assumption that any treatment would not have a chance to impact their outcomes. Figure 1 depicts the flowchart of the patient population considered and selected for analysis.



Fig 1

Figure 1: Consort diagram of patient population included in analyses.

We also performed a separate analysis using the same criteria for MDCSS data, extracted from the local SEER Database Management System (SEER*DMS) using SAS© v 9.4, to evaluate the influence of comorbidities, as these data are not collected by SEER. Logistic regression was used to calculate the odds ratios for receiving CN. Hazard ratios were calculated using Cox proportional hazards regression.

Results

Overview and predictors of nephrectomy

After exclusion of renal pelvis cases, final SEER-18 data for 2000–2013 had N = 40,524 patients. Case distribution by stage included regional stage (N = 19,472, 48%, 93% had nephrectomy) and distant stage (N = 21,052, 52%, 37% had nephrectomy). Our analyses were restricted to distant or metastatic stage patients only (Figure 1). The population characteristics of all SEER registry “regional” and “distant cases” are depicted in Table 1.

Table 1: Population Characteristics and Nephrectomy Rates of All SEER Kidney Cancer, Regional or Distant Stage: 2000–2013.
Regional 18,837 Distant 18,422
N Distribution (%) Nephr Rate (%) N Distribution (%) Nephr Rate (%)
Registry
Alaska 22 0 91 28 0 32
Atlanta 540 3 92 558 3 41
California (excl SF,SJM, & LA) 4196 22 94 4195 23 43
Connecticut 869 5 93 794 4 37
Detroit 939 5 93 947 5 39
Georgia (greater) 1381 7 92 1307 7 39
Hawaii 356 2 98 276 1 45
Iowa 896 5 96 921 5 43
Kentucky 1234 7 94 1184 6 43
Los Angeles 1845 10 95 1830 10 45
Louisiana 1370 7 91 1334 7 38
New Jersey 1985 11 94 1849 10 41
New Mexico 538 3 91 522 3 33
Rural Georgia 32 0 97 37 0 35
San Francisco 779 4 93 848 5 45
San Jose 421 2 95 448 2 43
Seattle 977 5 94 980 5 42
Utah 457 2 95 364 2 50
Age at diagnosis (year)
Under 20 626 3 98 502 3 91
20–39 577 3 96 452 2 55
40–49 1937 10 97 1855 10 56
50–59 4422 23 97 4511 24 51
60–69 5369 29 95 5184 28 42
70–79 4122 22 93 3762 20 31
80 or older 1784 9 78 2156 12 12
Sex
Female 6280 33 92 6185 34 39
Male 12,557 67 95 12,237 66 43
Race
Black 1612 9 90 1926 10 35
White 16,020 85 94 15,241 83 42
Other 1102 6 96 1208 7 44
Unknown 103 1 98 47 0 40
Marital status
Married 11,556 61 96 10,482 57 46
Divorced 1700 9 92 1994 11 39
Single 2959 16 95 3077 17 45
Widowed 1890 10 85 2230 12 22
Unknown 732 4 85 639 3 33
Insurance
Insured 8449 45 95 7573 41 43
Uninsured/medicaid 1530 8 93 1887 10 36
Unknown/missing 8858 47 93 8962 49 41
Histology
Clear cell 14,287 76 94 13,952 76 39
Renal cell carcinoma, Chromophobe 662 4 98 125 1 76
Renal cell carcinoma, Sarcomatoid 488 3 95 878 5 62
Collecting duct carcinoma 90 0 94 98 1 67
Papillary carcinoma, Oxyphilic cell 0 0 - 1 0 100
Other non-clear cell 3310 18 93 3368 18 46
Grade
Well differentiated 859 5 97 318 2 45
Moderately differentiated 5513 29 99 1750 9 71
Poorly differentiated 5902 31 98 3653 20 73
Undifferentiated 2319 12 98 2233 12 86
Unknown 4244 23 78 10,468 57 16
Surgery
Nephrectomy 17,665 94 7660 42
Other surgery 142 1 179 1
No urgery 1016 5 10,500 57
Unknown if Surgery done 14 0 83 0
Nephr Rate, nephrectomy rate.

Adjusted predictors of statistically increased likelihood of receiving nephrectomy were age (≤63 years), male sex (white race), and marital status. An interaction effect was noted between gender and marital status with married males having a significantly higher nephrectomy rate (42%) than divorced, single, and widowed men (35, 38, and 18% respectively). Single males were significantly less likely to receive nephrectomy than females (OR 0.53, 95% confidence interval [CI] 0.44–0.64). Single females had the highest (44%) likelihood of nephrectomy. Non-clear cell histology and poorly differentiated grade had a higher possibility of receiving CN as compared to clear cell histology and well-differentiated cancer, respectively (Table 2).

Table 2: All SEER Distant Stage Kidney Cancer: 2000–2013; Odd Ratios for Likelihood of Nephrectomy.
Total N 18422 Nephr. Rate 42 (%) Unadjusted OR Adjusted OR 95% CI p-value
Age at Diagnosis Diagnosis (median 63)
(ref) Under 63 8982 53 1.00 1.00
63 or Older 9440 31 0.39 0.41 (0.38–0.44) <0.001
Race (47 missing)
(ref) Black 1926 35 1.00 1.00
White 15241 42 1.34 1.51 (1.33–1.72) <0.001
Other 1208 44 1.43 1.52 (1.25–1.84) <0.001
Unknown 47 40 N/A
Insurance
(ref) Insured 7573 43 1.00 1.00
Medicaid or Uninsured 1887 36 0.75 0.65 (0.57–0.75) <0.001
Unknown or Missing 8962 41 0.93 1.17 (1.08–1.27) <0.001
Histology
(ref) Clear Cell 13952 39 1.00 1.00
Non-Clear Cell 4470 50 1.59 1.58 (1.45–1.73) <0.001
Grade
(ref) Well differentiated 318 45 1.00 1.00
Moderately differentiated 1750 71 3.06 3.35 (2.59–4.33) <0 001
Poorly differentiated 3653 73 3.32 3.24 (2.53–4.13) <0 001
Undifferentiated 2233 86 7.54 7.15 (5.49–9.31) <0 001
Unknown 10468 16 0.24 0.23 (0.18–0.29) <0 001
Sex
(ref) Female 6185 39 1.00 See interaction below
Male 12237 43 1.16
Marital Status
(ref) Married 10482 46 1.00 See interaction below
Divorced 1994 39 0.75
Single 3077 45 0.96
Widowed 2230 22 0.34
Unknown 639 33 0.58
Sex by Marital Status
Male 7767 46 1.00 1.03 (0.92–1.16) 0.567
Divorced
(ref) Female 742 40 1.00 1.00
Male 1252 38 0.93 0.79 (0.62–1.00) 0.047
Single
(ref) Female 984 49 1.00 1.00
Male 2093 43 0.76 0.53 (0.44–0.64) <0.001
Widowed
(ref) Female 1528 22 1.00 1.00
Male 702 23 1.03 1.03 (0.79–1.34) 0.963
Unknown
(ref) Female 216 28 1.00 1.00
Male 423 35 1.43 1.33 (0.84–2.09) 0.298
Married
(ref) Female 2715 46 1.00 1.00
Italic values represent missing data.

Survival status

Receipt of nephrectomy demonstrated significant survival advantage (HR = 0.31, 95% CI: 0.30–0.33) in the adjusted hazards ratio model. Median OS was 3 months in the non-CN group and 18 months in the CN group (Table 3 and Figure 2A). The demographic predictors of improved survival were age <63, white race, married status, and insured status (Table 3). Clear cell histology (HR = 1.20, 95% CI: 1.16–1.24) and well-differentiated grade are the disease-related characteristics that portend for improved OS (Figure 2B). The latter demonstrated improved OS despite a lower, 43% CN rate as compared to 84% in the undifferentiated histology group. The histology grades in SEER of well, moderate, poor, and undifferentiated RCC are likely to be concordant with the conventional Fuhrman 1–4 grading (Table 3).

Table 3: All SEER Distant Stage Kidney Cancer (2000–2013) Survival Analysis (Median Survival, Adjusted Hazard Ratio, 95% Confidence Interval, and P-value).
Total N 18422 Median Survival (months) HR 95% CI p-value
Nephr. 18 No Nephr. 5
Age at Diagnosis (median 63)
(ref) Under 63 8982 20 25 1.00
63 or Older 9440 16 4 1.16 (1.12–1.20) <0.001
Sex
(ref) Female 6185 18 4 1.00
Male 12237 19 5 0.99 (0.96–1.03) 0.702
Race (47 missing)
(ref) Black 1926 16 4 1.00
White 15241 25 5 0.98 (0.93–1.02) 0.342
Other 1208 18 5 0.88 (0.81–0.95) 0.002
Marital Status
(ref) Married 10482 17 5 1.00
Divorced 1994 16 5 1.05 (1.00–1.11) 0.051
Single 3077 29 5 0.86 (0.82–0.90) <0.001
Widowed 2230 14 4 1.09 (1.04–1.15) 0.001
Unknown 639 20 5 0.86 (0.79–0.94) 0.001
Insurance
(ref) Insured 7573 20 5 1.00
Medicaid or Uninsured 1887 21 5 1.03 (0.97–1.09) 0.427
Unknown or Missing 8962 16 4 1.16 (1.12–1.20) 0.001
Histology
(ref) Clear Cell 13952 20 5 1.00
Non-Clear Cell 4470 13 4 1.16 (1.12–1.21) <0.001
Grade
(ref) Well differentiated 318 35 9 1.00
Moderately differentiated 1750 30 6 1.30 (1.13–1.49) <0.001
Poorly differentiated 3653 18 4 1.86 (1.63–2.13) <0.001
Undifferentiated 2233 11 3 2.47 (2.16–2.83) <0.001
Unknown 10468 26 5 1.48 (1.30–1.69) <0.001
Surgery
No Nephrectomy 10762 - 5 1.00
Nephrectomy 7660 18 - 0.34 (0.32–0.35) <0.001
95% CI, 95% confidence interval; HR, hazard ratio; Nephr, nephrectomy.



Fig 2

Figure 2: (A) Overall survival data for nephrectomy or non-nephrectomy patients with advanced kidney cancer in SEER database. (B) Overall survival outcomes in metastatic RCC by clear and non-clear histology with or without nephrectomy.

Comorbidity analyses in Metro Detroit Registry

The data regarding comorbid conditions were only available for the Metro Detroit (MDCSS) Registry. While not collected as a population-based variable, comorbidity status was coded for 82% of regional and 76% of metastatic kidney cancers seen in Metropolitan Detroit. Nephrectomy was performed in 92% of regional stage and 34% of distant stage patients; our analysis pertains to only the distant-stage patients. Dichotomous comorbidities (yes or no for: hypertension, cardiac disease, diabetes mellitus, kidney disease, and lung disease) and number of comorbid conditions (none, 1, 2, 3+, and missing) are included in the patient characteristics of MDSCC (Table 4). The demographic and tumor characteristics were concordant with the all SEER data; 44.9% of the patients had none of the comorbidities. Adjusted demographic predictors of increased likelihood of receiving nephrectomy for Metropolitan Detroit patients were age < 64 years, non-black race, and married status. Non-clear cell histology (OR = 2.16, 95% CI: 1.42–3.28) and undifferentiated or high also predicted a higher likelihood of CN. Adding comorbidities and number of comorbidities to the model did not impact the likelihood of receiving nephrectomy. All comorbidity types and numbers were not statistically significant in terms of predicting the likelihood of CN and OS (Table 5). Patients with hypertension (OR = 1.75, 95% CI: 0.63–4.87) or diabetes mellitus had greater likelihood of receiving nephrectomy (OR = 1.16, 95% CI: 0.42, 3.21). The group of patients with missing comorbidity data (261/1104, 23.6%) had a significantly shorter OS in both CN and non-CN categories. The actual correlation of comorbidities with likelihood of CN remains elusive due to the group with missing data constituting 24% of the population; 26% of this group had a nephrectomy and demonstrated a median OS of 8 months as compared to the 76% with a median OS of 2 months (Tables 4 and 5; Figure 3A and 3B).

Table 4: Metropolitan Detroit Distant Stage Kidney Cancer: 2000–2013 Odd Ratios for Likelihood of Nephrectomy.
Total N 1008 Distribution Nephr. Rate 37 (%) Adjusted OR 95% CI p-value
Age at Diagnosis (median 64)
(ref) Under 64 498 49 51 1.00
64 or Older 510 51 23 0.29 (0.21–0.39) <0.001
Sex
(ref) Female 338 34 36 1.00
Male 670 66 37 0.87 (0.64–1.19) 0.389
Race
(ref) Black 206 20 34 1.00
White 788 78 38 1.48 (1.03–2.13) 0.035
Other 14 1 36 -
Marital Status
(ref) Married 507 50 40 1.00
Divorced 118 12 31 0.60 (0.38–0.95) 0.031
Single 202 20 43 0.81 (0.56–1.19) 0.285
Widowed 146 14 21 0.51 (0.31–0.83) 0.006
Unknown 35 3 37 1.13 (0.52–2.44) 0.757
Insurance
(ref) Insured 663 66 38 1.00
Medicaid or Uninsured 277 27 40 1.12 (0.79–1.59) 0.524
Unknown or Missing 67 7 18 0.41 (0.21–0.81) 0.010
Histology
(ref) Clear Cell 695 69 34 1.00
Non-Clear Cell 313 31 45 1.68 (1.25–2.27) 0.001
Grade
(ref) Well or Mod Diff 75 7 44 left out of model because of the large proportion of unknowns
Poorly Diff 168 17 70
Undifferentiated 152 15 81
Unknown 613 61 16
Number of Comorbid conditions
(ref) None of the above 465 46 36 1.00
One 165 16 41 1.25 (0.84–1.87) 0.269
Two or more 156 15 46 1.76 (1.17–2.66) 0.007
Missing data 222 22 31 0.80 (0.54–1.18) 0.249
95% CI, 95% confidence interval; Mod Diff, moderately differentiated.

 

Table 5: Metropolitan Detroit Distant Stage Kidney Cancer: 2000–2013 Survival Analysis by Nephrectomy Status for Demographic Characteristics and Comorbidities.
Total N 1008 Median Survival (months) HR 95% CI p-value
Nephr. 19 No Nephr. 5
Age at Diagnosis (median 64)
(ref) Under 64 551 22 5 1.00
64 or Older 553 15 5 1.08 (0.93–1.25) 0.335
Sex
(ref) Female 370 19 1.00
Male 734 20 1.00 (0.86–1.16) 0.990
Race (55 missing)
(ref) Black 232 30 4 1.00
White 857 18 5 1.02 (0.86–1.21) 0.824
Other 15 - - -
Marital Status
(ref) Married 552 18 5 1.00
Divorced 122 12 4 1.18 (0.95–1.46) 0.145
Single 222 43 4 0.76 (0.62–0.93) 0.007
Widowed 169 17 4 1.02 (0.82–1.25) 0.891
Unknown 39 16 8 0.71 (0.49–1.02) 0.064
Insurance
(ref) Insured 720 18 5 1.00
Medicaid or Uninsured 309 22 4 1.02 (0.86–1.22) 0.784
Unknown or Missing 75 31 4 1.35 (1.03–1.78) 0.032
Histology
(ref) Clear Cell 755 20 5 1.00
Non-Clear Cell 349 18.5 4 1.17 (1.01–1.36) 0.037
Grade
(ref) Well or Mod Diff 76 35 9 left out of model because of the large proportion of unknowns
Poorly Diff 178 19 4
Undifferentiated 158 12 3
Unknown 692 36 5
Surgery
No Nephrectomy 726 - 3 1.00
Nephrectomy 378 19 - 0.40 (0.34–0.46) <0.001
Number of Comorbid conditions
(ref) None of the above 496 24 5 1.00
One 178 24 4 1.12 (0.92–1.36) 0.275
Two or more 169 18 5 1.10 (0.90–1.35) 0.370
Missing data 261 8.5 4 1.68 (1.39–2.01) <0.001
95% CI, 95% confidence interval; Mod Diff, moderately differentiated; Nephr, nephrectomy.



Fig 3

Figure 3: (A) Overall survival noted in cases with nephrectomy correlated with missing, absence, and presence of comorbidities. (B) Overall survival seen in cases with no nephrectomy correlated with missing, absence, and presence of comorbidities.

Discussion

Our analysis reveals that CN is not being conducted in the majority of patients that present with synchronous metastatic RCC. There is a tremendous discordance between the population of advanced RCC enrolled in prospective interventional clinical trials in which 80–90% of the patients have had nephrectomy, and the application of these reported efficacy data to clinical practice in which the majority of patients do not undergo CN. There is a discrepancy between the results of retrospective population-based data such as the SEER cancer registry outcomes data and the IMDC registry data in which OS is significantly better with CN, and those seen in prospective randomized trial results such as the CARMENA and SURTIME studies that show that CN is unlikely to make an impact on improving outcomes in the setting of contemporary anti-VEGF therapy such as sunitinib (9). SEER data consistently demonstrate that lack of CN is the largest contributor of shorter OS in RCC patients with distant-stage RCC. The factors included within the IMDC are not captured within the SEER database, and hence, comparison of patients within these different registries is not possible. However, it is highly likely that the extent of the impact of each factor on OS may not be equal, and interaction between the factors is likely. In addition, it is possible that synchronous presentation of primary kidney tumor and metastases represents a distinct disease entity than the presentation with metastatic disease following a remote history of nephrectomy (>12 months) for localized renal cancer.

The advent of immune therapy with checkpoint inhibitors has introduced a new perspective to the sequencing of CN and systemic therapy in metastatic RCC. Preclinical data continue to emerge supporting the optimal use of immune checkpoint inhibition with the primary tumor in place, due to higher mutation load, increased heterogeneity of mutations and greater potential for anti-tumor CD8 T cells expansion and cytokine release (10, 11). These findings demand a deeper evaluation of the established paradigm of initial CN in metastatic RCC followed by systemic therapy. In fact, this standard is already being questioned in localized RCC by the current cooperative group trial EA8143/PROSPER, which randomizes patients to standard therapy of CN or neoadjuvant PD-1 inhibitor therapy with nivolumab followed by CN. In the metastatic disease also, deferral of nephrectomy as a potential method of enhancing the efficacy of immune checkpoint inhibition needs to be prospectively evaluated. SEER-18 limited use data do not include systemic agents, and this was a limitation of our analysis. A Southwest Oncology Group trial, S1931, is proposing to evaluate immune checkpoint inhibitor-based regimen combination with or without the addition of CN. The timing of surgery in the nephrectomy arm will be at the end of 12 weeks of immune therapy to optimize the impact of systemic therapy. The study design is that of a randomized phase III with overall survival as the primary endpoint.

Conclusions

National population registry represented by the SEER database shows that the majority of patients (63%) with metastatic RCC do not undergo CN. Nephrectomy still represents a significant factor that predicts for improved OS outcome in advanced RCC within population databases such as SEER and NCDB. Median OS of 3 months in the non-CN group and that of 18 months for cases with CN suggests the large magnitude of the disparity. Patient demographics and tumor characteristics make a significant impact on the incidence of CN. The impact of comorbidities (number and type) appeared to be modest within the population represented in the Metropolitan Detroit SEER data and was not statistically significant. The optimal management strategy of patients with advanced RCC unable to undergo nephrectomy needs to be prospectively evaluated in future clinical trials, in the setting of contemporary systemic therapy.

The subgroup of synchronous primary and metastatic kidney cancer has been underrepresented in clinical trials. Future studies geared toward addressing the issues of optimal efficacy of therapy within this patient population are being planned. Patient and disease characteristics that determine decision of CN warrant further study and may represent a key to the enhancement of outcomes in advanced renal cancer.

Conflict of Interest

The authors declare that they have no conflict of interest.

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