What is the role of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma?

1. Introduction

Substantial changes have occurred in the systemic treatment paradigm for metastatic renal cell carcinoma (mRCC) with the development of immune checkpoint inhibitors (ICIs) [1]. To date, ICI-based combination therapy is the guideline-recommended standard first-line treatment for mRCC based on results from phase III randomized controlled trials (RCTs) [1]. Although there are no head-to-head phase III randomized controlled trials (RCTs) comparing the efficacy between ICI-based combination therapies, pembrolizumab plus lenvatinib combinations seem to result in the best oncologic benefit, as suggested by several network meta-analyses [2–4]. Within these ever-evolving treatment sequences of the last decades, the role of cytoreductive nephrectomy (CN) has changed substantially. Indeed, several questions remain unknown, in which patients and when a CN could be beneficial. The heterogeneous populations enrolled in the RCTs of ICI-based combinations did not report survival data stratified by CN or even nephrectomy consistently. Therefore, to date, the potential impact and the optimal timing of CN on oncologic outcomes remain unclear. Our editorial review aims to summarize recent evidence and discuss the knowledge gap regarding CN for mRCC.

2. Evidence acquisition

A literature search on PubMed/Medline databases was performed in February 2023 to identify studies investigating the outcomes of CN for mRCC. The detailed search strategy is as follows: (renal cell carcinoma) AND (metastatic) AND (cytoreductive nephrectomy). In addition, we reviewed abstracts presented at recent major conferences, such as the American Society of Clinical Oncology and the European Society for Medical Oncology, to include unpublished RCTs and trial updates.

3. Evidence synthesis

3.1. CN in the targeted therapy era

CN had been considered a standard treatment for over 20 years until the CARMENA trial put its role into question for intermediate- and poor-risk mRCC treated by tyrosine kinase inhibitors (TKIs) in 2018 [5]. The updated results from the CARMENA trial highlighted a noninferiority of sunitinib alone in terms of overall survival (OS) over immediate CN followed by sunitinib in synchronous mRCC patients (hazard ratio [HR] for OS: 0.97, 95% confidence interval [CI]: 0.79–1.19) [6]. In addition, in the subgroup analysis of patients with two or more IMDC risk factors, OS was significantly longer in patients treated with sunitinib alone compared to those treated with immediate CN followed by sunitinib (HR for OS: 0.65, 95% CI: 0.44–0.97) [6]. A recently published study using 12,766 mRCC patients treated with systemic targeted therapy from National Cancer Database confirmed potential no superiority of CN, demonstrating that CN was not associated with improved OS in metastatic clear cell RCC patients after adjusting for the effect of unmeasured confounders (HR: 0.92, 95% CI: 0.78–1.09) [7].

In the argument of immediate versus deferred CN, the SURTIME trial investigated the differential oncologic outcomes between immediate CN followed by sunitinib versus 3-month sunitinib followed by deferred CN [8]. This study failed to show the benefit of deferred CN in terms of 28-week progression-free rates as a surrogate primary endpoint (42% in the immediate CN arm vs. 43% in the deferred CN arm, p = 0.6) [8]. However, despite critical limitations in study design, this study showed that intention-to-treat OS was significantly better in the deferred CN arm than in the immediate CN arm (HR: 0.57, 95% CI: 0.34–0.95) [8]. In addition, systemic progression before planned deferred CN was noted in 14 of 48 patients (29%); these patients avoided an unnecessary CN [8]. An international multicenter retrospective study comprising 1542 patients confirmed these findings [9]. The authors demonstrated that sunitinib followed by deferred CN was associated with significantly improved OS (HR: 0.45, 95% CI: 0.33–0.60) in multivariable Cox regression analysis [9]. Taken together, despite the potential selection bias, deferred CN provides promising oncologic outcomes as initial systemic treatment can identify patients who are most likely to respond to CN based on non-regional metastatic site response to systemic therapy. In other words, response to upfront systemic therapy has been proposed as a ‘litmus test’ to identify the ideal candidates most likely to benefit from CN. While there is no high-level evidence that this holds true in the age of ICI-based combinations, the oncologic concept and lower quality data point in this direction.

3.2. Prognostic factors in patients who underwent CN

Identification of the optimal patient who is likely to benefit from CN presents a challenge in the daily clinical decision-making process. To avoid unnecessary CN and identify reliably patients with poor prognosis irrespective of systemic and surgical interventions, several studies with a large cohort have assessed the prognostic factors for survival in patients who underwent CN in the contemporary era [10,11]. In a retrospective study of 608 mRCC patients who underwent CN from 2005 to 2017 at the MD Anderson Cancer Center, McIntosh et al. identified nine prognosticators for OS; systemic symptoms at diagnosis, retroperitoneal and supradiaphragmatic lymphadenopathy, bone metastasis, clinical T4 disease, a hemoglobin level < lower limit of normal (LLN), a serum albumin level <LLN, a serum lactate dehydrogenase level > upper limit of normal, and a neutrophil/lymphocyte ratio ≥4 [11]. The authors developed a novel classification/risk stratification tool based on these factors successfully stratifying OS; of note, patients with three or more risk factors had significantly poor OS and an increase in the rate of perioperative adverse events [11]. Similarly, Marchioni et al. developed a novel prognostic model using an international multicenter database of mRCC patients who underwent CN from 2005 to 2019 [10]. These authors identified, in contrast, six prognosticators: obesity, bone metastasis, liver metastasis, lung metastasis, number of metastases, and performance status <80%. Notably, the novel risk classification based on these variates outperformed the IMDC classification regarding prognostication of OS [10]. Besides the IMDC classification, novel risk classification including novel tumor and patient-related characteristics as well as novel hematologic markers will certainly lead to more accurate and reproducible clinical decision-making process. Further investigations with external validations using different datasets of patients treated with first-line ICI-based systemic therapy is needed to ensure reliable and generalizable.

3.3. CN in the ICI era

As ICI-based combination therapy achieved favorable objective response rates (ORRs), including a primary lesion, the treatment strategy of de novo mRCC has shifted to upfront ICI-based systemic therapy followed by deferred CN rather than immediate CN. The proportion of patients who underwent antecedent nephrectomy has been decreasing in recent trials, presumably due to the impact of the CARMENA trial [5,12]. For example, the recently reported COSMIC-313 trial, which assessed the efficacy of nivolumab + ipilimumab + cabozantinib, comprised the lowest proportion of patients who underwent previous nephrectomy (64%), possibly affecting the ORRs and outcomes by a statistically significant margin [13]. Therefore, RCTs should at least report in subgroup analysis on the efficacy of the investigated therapy stratified by nephrectomy and CN separately to shed some light on the impact of CN and the true efficacy of ICI-based combination therapy. Detailed individual patient data and longer follow-up may help in the assessment of the impact of CN in the ICI era; indeed, most investigations have suffered from low number of patients and short follow-up duration as well as lack of essential confounders.

3.3.1. Oncologic impact of CN in retrospective cohort studies

In the era of ICI-based combination therapy, the potential impact of CN has been debated until ongoing RCTs clarify the optimal candidate and timing of CN. Several population-based cohort studies using the National Cancer Database have assessed the oncologic impact of CN in the ICI era (Table 1) [7,14]. In 2020, Singla et al. compared metastatic clear cell RCC patients treated with CN + ICI (n = 221) and those treated with ICI only (n = 171) [14]. The authors showed the superiority of CN + ICI treatment strategy over ICI only in terms of OS after adjusting possible confounders (i.e. age, clinical T/N stage, metastatic sites) in multivariable analysis; there was, however, no differences in OS between immediate and deferred CN [14]. Recently, Bakouny et al. reported the results of a retrospective study comprising 4639 patients (4202 patients treated with TKI and 437 patients treated with ICI) using the International Metastatic RCC Database Consortium [15]. This study revealed that immediate CN was associated with improved OS in both patients treated with ICI (HR: 0.61, 95% CI: 0.41–0.90) and those treated with TKI (HR: 0.72, 95% CI: 0.67–0.78) in multivariable analyses. However, indelible selection bias due to the retrospective nature and possible unmeasured confounders are likely to affect the results; these results need to be interpreted with caution.

Table 1. Summary of recent findings regarding outcomes of CN in mRCC patients treated with ICI.

Authors	Year	Design	Inclusion	Number of patients	Major findings
Oncologic impact of CN
Singla et al. [14]	2020	NCDB	mccRCC	391 (CN+ICI: n = 221, ICI only: n = 171)	Patients who underwent CN + ICI had superior OS (median NR vs. 11.6 months; HR 0.23, P < 0.001), which was upheld after adjusting possible confounders (ie, age, clinical T/N stage, metastatic sites) on multivariable analysis
Bakouny et al. [15]	2023	Retrospective multicenter (International Metastatic RCC Database Consortium)	De novo mRCC (clear cell: 85%)	4639 (TKI: n = 4202, ICI: n = 437)	Immediate CN was associated with improved OS in both patients treated with ICI (HR: 0.61, 95% CI: 0.41–0.90) and those treated with TKI (HR: 0.72, 95% CI: 0.67–0.78) in multivariable analyses
Safety and oncologic outcomes of deferred CN
Shirotake et al. [18]	2022	Retrospective single center	mRCC pts. treated with Nivo + Ipi	61 (Deferred CN: n = 10)	7 patients safely underwent laparoscopic CN. Surgery was difficult in many cases because of severe adhesion in the renal hilum or with surrounding organs.
Graafland et al. [19]	2022	Retrospective multicenter	mRCC pts. treated with ICI-based combinations	21 (Nivo + Ipi: n = 19, Nivo + Cabo: n = 2)	In 15 patients (71%), fibrosis/adhesions was encountered during surgery, which was graded as minor (not negatively influencing surgery) in 7 (33%) and severe (negatively influencing surgical planes) in 8 patients (38%). There were 3 (14%) postoperative Clavien–Dindo grade 1 complications.
Pignot et al. [20]	2022	Retrospective multicenter	mRCC pts. treated with ICI and CR or major PR to ICI at metastatic sites	30 (Nivo + Ipi: n = 12, ICI + TKI: n = 3, Nivo alone: n = 15)	In 19 cases (63%), surgeons faced difficulties due to adhesions or inflammatory changes. Patients with CR of the metastases had better progression-free survival than those with PR.
Meerveld-Eggink et al. [21]	2022	Retrospective multicenter	De novo mRCC pts. treated with Nivo + Ipi	71 (Deferred CN: n = 13)	4 patients who underwent CN achieved disease free. 3 of 13 patients with CR or PR at the metastatic sites underwent deferred CN in order to control the growing primary tumor after initial downsizing

CN: cytoreductive nephrectomy, ICI: immune checkpoint inhibitor, TKI: tyrosine kinase inhibitor, NCT: National Clinical Trial, NCDB: National Cancer Database, RCC: renal cell carcinoma, mRCC: metastatic RCC, mccRCC: metastatic clear cell RCC, pts.: patients, Nivo: nivolumab, Ipi: ipilimumab, Cabo: cabozantinib, NR: not reached, HR: hazard ratio, PR: partial response, CR: complete response, IMDC: International Metastatic RCC Database Consortium, OS: overall survival.

Although some retrospective cohort studies have shown the survival benefit of CN in patients with de novo mRCC patients in the era of ICI, several controversies need to be discussed. For example, the impact of CN in patients who harbor an adverse pathologic feature (i.e. sarcomatoid, non-clear RCC) or the optimal timing of CN, such as immediate or deferred CN, has not been well investigated [16].

3.3.2. Deferred CN after ICI treatment

Table 1 summarizes the studies reporting outcomes of deferred CN after ICI treatment. Regarding the technical feasibility of deferred CN after ICI treatment, from a surgical perspective, ICI-based combination therapy results in a severe desmoplastic reaction, increasing perinephric adhesions and inflammation, thereby increasing the surgical complexity and potential complication rates [17]. Shirotake et al. reported on the efficacy and safety of 10 patients who underwent deferred CN following nivolumab + ipilimumab [18]. Although all patients safely underwent laparoscopic nephrectomy without any perioperative complications, severe adhesion at the renal hilum or at the borders to the surrounding organs has been noticed [18]. Similarly, Graafland et al. confirmed the challenges but eventual technical feasibility and safety of deferred CN in 21 patients after ICI-based combination therapy [19]. Despite sometimes challenging surgery, Pignot et al. reported favorable short-term oncologic outcomes of deferred CN in 30 patients who had achieved CR or PR at the metastatic sites following ICI-based combination therapy [20]. The authors highlighted that patients with CR of the metastases had better progression-free survival than those with PR, resulting in the omission of further systemic treatment [20]. A retrospective study of 71 de novo mRCC patients who did not undergo immediate CN treated with nivolumab + ipilimumab showed differential ORRs between the primary (33%) and the metastatic sites (54%) [21]. Notably, three of 13 patients who underwent deferred CN with CR or PR at the metastatic sites was performed in order to control the growing primary tumor after initial downsizing [21]. The different biology between the primary and metastatic sites as well as temporal and spatial heterogeneities in tumor behavior need to be understood and considered to ensure optimal management of mRCC, specifically when it comes to integrating CN.

4. Recommendation and future perspective

Despite the lack of solid data regarding the oncologic benefit of CN in the ICI era, current publications suggest that CN continues to play an important role in select patients. Removing the primary tumor is necessary to achieve no evidence of disease (i.e. CR of all lesions) which is the ultimate goal of our therapeutic strategy. Moreover, it would help discontinue therapy temporarily (i.e. intermittent therapy) or perpetually. Discontinuation of systemic treatment can not only spare costs but also toxicities, improving the patient’s quality of life by a tangible margin. According to current publications and clinical guidelines, our recommendation of indications for CN in the ICI era includes

1. For palliation in patients with significant local symptoms related to tumors.

2. Either immediate or deferred CN may be offered to selected de novo mRCC patients, preferentially for patients with IMDC intermediate-risk disease [22]

3. Deferred CN seems a reasonable treatment strategy in the ICI era, preferentially for patients with continuous PR or CR at the metastatic site after systemic therapy. However, some issues, such as the optimal duration of presurgical systemic therapy, the need for perioperative management of immune-related adverse events (irAEs), and possible surgical challenges, remain to be considered in clinical practice.

A well-designed, controlled head-to-head comparison between never (i.e. systemic therapy only) vs. immediate vs. deferred CN for patients with PR or CR after ICI-based combinations would be a study that would advance the field significantly. Ongoing trials, such as the Cyto-KIK (NCT04322955), PROBE (NCT04510597), and NORDIC-SUN (NCT03977571) trials, will provide further insights into the potential role of deferred CN in the ICI era (Table 2).

Table 2. Ongoing trials assessing oncologic outcomes of CN in the ICI era.

Study name	NCT number	Phase/ design	No. of estimated pts.	Indication	Intervention arm	Control arm	Primary outcomes	Estimated completion date
Cyto-KIK	NCT04322955	2	48	De novo mRCC	Nivo + Cabo (12 weeks) followed by deferred CN	NA	CR rate	May. 2026
PROBE	NCT04510597	Phase 3 RCT	364	De novo mRCC pts. treated with induction ICI-based combinations and who achieved PR or CR	ICI-based combination followed by deferred CN	ICI-based combination only	OS	Jul. 2033
NORDIC-SUN	NCT03977571	RCT	400	De novo mRCC pts. treated with induction ICI-based combinations (3 months) and suitable patients based on IMDC score	ICI-based combination followed by deferred CN	ICI-based combination only	OS	Sep. 2026

RCT, randomized controlled trial; CN, cytoreductive nephrectomy,; ICI, immune checkpoint inhibitor; NCT, National Clinical Trial; mRCC, metastatic renal cell carcinoma; pts., patients; Nivo, nivolumab; Cabo, cabozantinib; PR, partial response; CR, complete response; IMDC: International Metastatic RCC Database Consortium; OS, overall survival.

Declaration of interest

M Schmidinger has received Honoraria for lectures of advisory boards from Ipsen, Exelixis, Bristol Myers Squibb, Merck Sharp & Dohme, Merck, Eusa, Eisai, Astellas, Janssen. T Kimura is a paid consultant/advisor of Astellas, Bayer, Janssen and Sanofi.

SF Shariat has received honoraria from Astellas, AstraZeneca, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck Sharp & Dohme, Olympus, Pfizer, Roche, Takeda, has served in a consulting or advisory role for Astellas, AstraZeneca, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck Sharp & Dohme, Olympus, Pfizer, Pierre Fabre, Roche, Takeda, and has served on the speakers bureau for Astellas, Astra Zeneca, Bayer, Bristol Myers Squibb, Ferring, Ipsen, Janssen, Merck Sharp & Dohme, Olympus, Pfizer, Richard Wolf, Roche and Takeda.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this paper is the PI of the PROBE trial which is being conducted to randomize met RCC patients to nephrectomy or not.

Additional information

Funding

This paper was not funded.