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

Figures & data

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.

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.

Singla N, Hutchinson RC, Ghandour RA, et al. Improved survival after cytoreductive nephrectomy for metastatic renal cell carcinoma in the contemporary immunotherapy era: an analysis of the National Cancer Database. Urol Oncol. 2020;38:e604.9–e604.17.

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Shirotake S, Miyama YU, Baba Y, et al. Impact of cytoreductive nephrectomy following nivolumab plus ipilimumab therapy for patients with advanced renal cell carcinoma. Anticancer Res. 2022;42:2727–2735.

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Graafland NM, Szabados B, Tanabalan C, et al. Surgical safety of deferred cytoreductive nephrectomy following pretreatment with immune checkpoint inhibitor-based dual combination therapy. Eur Urol Oncol. 2022;5:373–374.

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Pignot G, Thiery-Vuillemin A, Albigès L, et al. Oncological outcomes of delayed nephrectomy after optimal response to immune checkpoint inhibitors for metastatic renal cell carcinoma. Eur Urol Oncol. 2022;5:577–584.

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Meerveld-Eggink A, Graafland N, Wilgenhof S, et al. Primary renal tumour response in patients treated with nivolumab and ipilimumab for metastatic renal cell carcinoma: real-world data assessment. Eur Urol Open Sci. 2022;35:54–58.

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