The effect of cytoreductive nephrectomy on survival in patients with metastatic renal cell carcinoma receiving tyrosine kinase inhibitors

Abstract

OBJECTIVE

The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) is controversial. The aim of this study was to compare survival outcomes between nephrectomy and non-nephrectomy groups in patients with de novo metastatic renal cell carcinoma receiving tyrosine kinase inhibitors (TKI).

METHODS

This retrospective study included 99 patients with de novo metastatic renal cell carcinoma, stratified according to receipt of cytoreductive nephrectomy. Baseline clinicopathological variables, including International Metastatic RCC Database Consortium (IMDC) risk category, Eastern Cooperative Oncology Group (ECOG) performance status, sarcomatoid features, Fuhrman grade, and TKI regimen, were collected. Overall survival was evaluated using Kaplan–Meier analysis.

RESULTS

Among 99 patients, IMDC risk categories were favorable in 21 (21.2%), intermediate in 52 (52.5%), and poor in 26 (26.3%). CN was performed in 67 patients (67.7%). Pazopanib and sunitinib were used in 50 (50.5%) and 49 (49.5%) patients, respectively. In comparison with the nephrectomy cohort, a greater percentage of patients in the non-nephrectomy cohort were classified as poor risk (37.5% vs. 20.8%, p=0.010). Overall survival differed significantly across IMDC risk groups (p=0.001). In the favorable-risk subgroup, median overall survival was longer with nephrectomy than without surgery (42 vs. 12 months, p=0.042). There was no significant difference in survival between pazopanib and sunitinib treatment (14 vs. 16 months, p=0.251).

CONCLUSION

CN was associated with improved overall survival in the favorable-risk subgroup, whereas no significant survival difference was observed in intermediate- or poor-risk groups.

Highlight key points

• In de novo metastatic renal cell carcinoma treated with TKIs, cytoreductive nephrectomy was associated with longer overall survival in the favorable IMDC risk group (median 42 vs 12 months; p=0.042).

• No statistically significant overall survival difference with cytoreductive nephrectomy was observed in the intermediate or poor IMDC risk groups.

• These findings support IMDC-based risk stratification to guide patient selection for cytoreductive nephrectomy in the TKI era.

• Overall survival did not differ significantly between pazopanib and sunitinib (median 14 vs 16 months; p=0.251).

Over time, therapeutic approaches for metastatic renal cell carcinoma (mRCC) have evolved substantially [1]. Evidence from early randomized controlled trials suggested improved survival among patients receiving nephrectomy before immunotherapy, relative to immunotherapy alone, in metastatic RCC [2, 3]. During the cytokine therapy era, cytoreductive nephrectomy became widely adopted after randomized phase III evidence from the SWOG 8949 and EORTC 30947 trials demonstrated its benefit [2, 3]. These investigations examined survival outcomes associated with resection of the primary renal tumor in patients with metastatic disease and subsequently assessed the effects of combining surgery with cytokine-based therapy [2]. Both studies concluded that CN followed by interferon-alpha 2b provided a superior overall survival compared to interferon monotherapy [2–4].

With the proven efficacy of targeted therapies, a new era in the management of RCC has begun. Advances in therapies directed against VEGF receptors, mTOR, c-Met, and immune checkpoint pathways have substantially reshaped therapeutic strategies for metastatic renal cell carcinoma [5]. Retrospective data have indicated favorable outcomes with cytoreductive nephrectomy combined with targeted treatments; however, results from the CARMENA trial demonstrated that targeted therapy alone was not inferior to cytoreductive nephrectomy followed by sunitinib in metastatic renal cell carcinoma [6]. Observational evidence supports improved survival with a surgical-first approach before systemic targeted treatment, while U.S. registry-based data similarly favor nephrectomy over primary systemic therapy alone [7, 8]. Consequently, the role of CN in combination with targeted therapy remains controversial. In this study, we aimed to contribute to the current literature by identifying the subgroup of patients who benefit most from CN when combined with tyrosine kinase inhibitor (TKI) therapy.

MATERIALS AND METHODS

A total of 99 patients were included in this retrospective study. Patients with de novo metastatic renal cell carcinoma who either underwent or did not undergo nephrectomy were enrolled. Recorded variables included age, sex, prognostic risk classification according to the International Metastatic RCC Database Consortium (IMDC) as favorable, intermediate, or poor risk; presence of sarcomatoid differentiation; Fuhrman grade; and history of nephrectomy. Cytoreductive nephrectomy, when performed, was carried out as an upfront surgical procedure prior to the initiation of tyrosine kinase inhibitor therapy.

Additional clinical data such as Eastern Cooperative Oncology Group Performance Status (ECOG PS) and the type of tyrosine kinase inhibitor (TKI) used were also collected. The demographic and clinicopathological characteristics of the patients are presented in the tables. Ethical approval was obtained from the institutional ethics committee.

Statistical Analysis

Distribution-dependent summary statistics were used, with continuous data described by mean±standard deviation or median with interquartile range, and categorical data expressed as counts and percentages. Appropriate parametric or nonparametric methods were applied for group comparisons, while survival was evaluated using Kaplan-Meier estimation and compared with the log-rank test. Factors associated with overall survival were examined with univariate Cox regression, with hazard ratios and 95% confidence intervals reported. A two-sided p value <0.05 indicated statistical significance. Analyses were performed using IBM SPSS Statistics (IBM Corp., Armonk, NY, USA).

RESULTS

The study cohort comprised 99 patients. Of these, 73.3% were male and 26.7% were female. Sixty-nine patients (69.7%) had a Karnofsky Performance Score of ≥80%. Histopathologically, sarcomatoid differentiation was present in 28.3% of cases. Based on Fuhrman grading, 34 patients (34.3%) had grade ≤2, 40 patients (40.4%) had grade 3, and 25 patients (25.3%) had grade 4 disease.

Cytoreductive nephrectomy had been performed in 67 patients (67.7%). According to IMDC prognostic classification, 21 patients (21.2%) were in the favorable risk group, 52 (52.5%) in the intermediate group, and 26 (26.3%) in the poor risk group. All patients received tyrosine kinase inhibitor therapy, 50 patients (50.5%) received pazopanib and 49 patients (49.5%) received sunitinib (Table 1).

Table 1.

Demographic and clinicopathological characteristics of the patients (n=99)

	%
Gender
Male	73.3
Female	26.7
Karnofsky performance score
≥80%	69.7
<80%	30.3
Sarcomatoid differentiation
Yes	28.3
No	71.7
Fuhrman grade
≤2	34.3
3	40.4
4	25.3
Prior nephrectomy
Yes	67.7
No	32.3
IMDC
Favorable	21.2
Intermediate	52.5
Poor	26.3
TKI
Pazopanib	50.5
Sunitinib	49.5

IMDC: International Metastatic RCC Database Consortium; TKI: Tyrosine kinase inhibitor.

Patients were analyzed in two groups: those who underwent nephrectomy and those who did not. Baseline characteristics were generally similar between the two groups (Table 2). The non-nephrectomy cohort exhibited a significantly greater proportion of patients with poor IMDC risk compared with the nephrectomy cohort (37.5% vs. 20.8%; p=0.010).

Table 2.

Comparison of baseline characteristics between the cytoreductive nephrectomy and non-nephrectomy groups

	Nephrectomy		p
	No (n=32)%	Yes (n=67)%
Gender			0.493
Male	78.1	71.6
Female	21.9	28.4
Karnofsky performance score			0.282
≥80%	62.5	73.1
<80%	37.5	26.9
Sarcomatoid differentiation			0.616
Yes	25.0	29.9
No	75.0	70.1
Fuhrman grade			0.876
≤2	31.2	35.8
3	43.8	38.8
4	25.0	25.4
IMDC			0.010
Favorable	28.1	17.9
Intermediate	34.4	61.1
Poor	37.5	20.8
TKI			0.352
Pazopanib	43.8	53.7
Sunitinib	56.2	46.3

IMDC: International Metastatic RCC Database Consortium; TKI: Tyrosine kinase inhibitor.

Factors affecting overall survival were assessed using univariate analysis (Table 3). Patients in the favorable IMDC risk group had significantly better overall survival compared to those in the intermediate or poor risk groups (p=0.001). In the favorable-risk group, overall survival was significantly longer in the nephrectomy group compared to the non-nephrectomy group (Fig. 1). Conversely, no significant difference in survival was observed between the treatment groups in the intermediate (Fig. 2) or poor IMDC risk categories (Fig. 3).

Table 3.

Univariate analysis of factors affecting overall survival

	Median OS, months (95% CI)	p
Karnofsky performance score		0.486
≥80%	15 (13.6–16.4)
<80%	12 (9.3–14.6)
Sarcomatoid differentiation		0.061
Yes	11 (8.5–13.4)
No	18 (14.5–21.5)
Fuhrman grade		0.125
≤2	21 (13.1–28.9)
3	16 (11.7–20.3)
4	12 (5.6–18.4)
Prior nephrectomy		0.326
Yes	16 (12.9–19.0)
No	14 (10.5–17.5)
IMDC		0.001
Favorable	42 (18.0–65.0)
Intermediate	15 (13.4–16.6)
Poor	6 (1.4–10.6)
TKI		0.251
Pazopanib	14 (11.5–18.5)
Sunitinib	16 (11.9–19.4)

IMDC: International Metastatic RCC Database Consortium; TKI: Tyrosine kinase inhibitor; OS: Overall survival; CI: Confidence interval.

Figure 1.

Overall survival according to treatment strategy in patients with favorable IMDC risk, depicted using Kaplan–Meier estimates (CN vs. no CN).

In the favorable risk group, overall survival was significantly longer in the nephrectomy group compared to the non-nephrectomy group (42 vs. 12 months, p=0.042).

Figure 2.

Kaplan–Meier estimates illustrating overall survival by treatment approach among patients classified as intermediate IMDC risk.

In the intermediate group, survival was 17 vs. 15 months in the nephrectomy and non-nephrectomy groups, respectively (p=0.362).

Figure 3.

Comparison of overall survival between CN and non-surgical management in the poor IMDC risk subgroup, based on Kaplan–Meier analysis.

In the poor risk group, survival was 7 vs. 4 months, respectively (p=0.468).

DISCUSSION

In our study, all patients received tyrosine kinase inhibitor (TKI) therapy as targeted treatment. In favorable-risk patients, cytoreductive nephrectomy correlated with markedly prolonged overall survival, whereas among those with intermediate or unfavorable prognostic profiles, survival outcomes did not differ significantly. Many previous studies have demonstrated that CN contributes positively to overall survival [9–21]. Although most of these studies are retrospective and observational in nature, their findings remain relevant and cannot be overlooked. CN is commonly performed in patients with limited metastatic disease and good performance status. Despite advances in systemic therapy, high-quality evidence endorsing the routine application of cytoreductive nephrectomy remains insufficient [22]. Findings from the CARMENA trial indicated that, among patients with metastatic renal cell carcinoma classified as intermediate or poor risk based on MSKCC criteria, sunitinib monotherapy was non-inferior to cytoreductive nephrectomy followed by sunitinib. Careful selection of candidates is essential in the context of cytoreductive nephrectomy. The surgical procedure carries risks of morbidity and mortality, and complications following surgery may delay the initiation of systemic therapy [23]. It is well recognized that patients with multiple risk factors do not benefit from CN [7]. The timing of nephrectomy is also an important consideration. In the SURTIME trial, a delay in cytoreductive nephrectomy was not associated with improvements in progression-free rate (PFR) or progression-free survival (PFS) measured at 28 weeks. However, even though it was not statistically significant, delayed surgery was associated with better overall survival in that study [24]. An analysis of 4,223 cases from the National Cancer Database demonstrated inferior survival outcomes when nephrectomy was performed following targeted therapy, relative to surgery undertaken before the initiation of systemic treatment [18]. Cytoreductive nephrectomy was carried out as an initial intervention, and systemic therapy was subsequently initiated after adequate postoperative recovery.

The SURTIME trial suggested that initiating treatment with sunitinib, a TKI, and performing CN only in patients who did not progress may be superior to upfront surgery followed by systemic therapy [24]. In our study, all patients received upfront surgery; there were no cases of deferred nephrectomy. Among these patients, a survival benefit was observed in the favorable risk group. Consistent with these findings, the CARMENA trial compared cytoreductive nephrectomy plus sunitinib with sunitinib alone and demonstrated that sunitinib monotherapy was non-inferior among patients classified as having intermediate or unfavorable prognostic risk [6]. Similarly, in our study, only patients in the favorable IMDC risk group showed a statistically significant survival benefit with CN. No survival benefit was seen in intermediate or poor risk groups. The SURTIME results support the conclusions of the CARMENA trial, suggesting that upfront CN may not provide additional benefit. Rather, nephrectomy might be more advantageous when performed after observing treatment response in patients who do not progress under systemic targeted therapy [24]. In SURTIME, most patients were categorized as intermediate risk according to MSKCC [24], whereas in CARMENA, 47% of patients were in the poor risk group. In that analysis, cytoreductive nephrectomy was not linked to favorable clinical outcomes among patients with unfavorable prognostic profiles but showed potential survival advantages for intermediate-risk patients who achieved a response to systemic therapy. In our study, the proportion of poor-risk patients who underwent CN was lower than in CARMENA (20.8%).

Our study has limitations inherent to retrospective designs, including potential selection bias and unmeasured confounders. In addition, patients selected for cytoreductive nephrectomy may have had more favorable baseline performance status, which could have contributed to improved survival outcomes independent of the surgical intervention. The number of patients could also be increased in future studies. Additionally, the potential impact of immunotherapy and combination regimens of immunotherapy with TKIs, which are now part of current treatment protocols, on survival outcomes in conjunction with CN remains to be clarified. In our study, patients received either sunitinib or pazopanib following surgery. According to modern treatment algorithms, first-line combination therapies may offer improved survival outcomes. In a recent retrospective analysis by Singla et al. [19], combined treatment with immunotherapy and cytoreductive nephrectomy was associated with improved overall survival compared with immunotherapy monotherapy (hazard ratio, 0.23; 95% confidence interval, 0.15–0.37). Similarly, Bakouny et al. [21] showed in a retrospective analysis that upfront CN provided a survival benefit, regardless of whether patients subsequently received targeted therapy or immunotherapy. In our study, all patients underwent upfront surgery. Whether CN provides a survival benefit in patients who respond to systemic therapy remains to be determined in prospective studies with larger patient cohorts.

Conclusion

In summary, our results align with existing evidence, indicating that upfront cytoreductive nephrectomy is associated with improved survival outcomes among patients classified as having favorable prognostic risk at diagnosis. All patients received systemic therapy following surgery, and a survival benefit was only observed in the favorable-risk group. Prospective randomized trials evaluating CN in the context of modern immunotherapy-TKI combinations are urgently needed. Further prognostic models and biomarker-based studies may help to better identify patient subgroups who will benefit most from surgery.

Ethics Committee Approval

The University of Health Sciences Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital Clinical Research Ethics Committee (date: 26.05.2021, number: 2021-05/1183).

Informed Consent

Written informed consents were obtained from patients who participated in this study.

Conflict of Interest

The authors declare that there is no conflict of interest.

Financial Disclosure

The authors declared that this study has received no financial support.

Use of AI for Writing Assistance

The authors declare that no artificial intelligence (AI)-assisted technologies (such as Large Language Models [LLMs], chatbots, or image creators) were used in the production of the submitted work.

Authorship Contributions

Concept – IB; Design – IB, EO; Supervision – IB, ZA, BO, EO, CK, FBB; Materials – IB, ZA; Data collection and/or processing – IB, FBB, ZA; Analysis and/or interpretation – IB, CK, BO, ZA; Literature search – IB; Writing – IB; Critical review – IB, ZA, EO.

Peer-review

Externally peer-reviewed.