Cytoreductive Nephrectomy in the Era of Tyrosine Kinase and Immuno-Oncology Checkpoint Inhibitors

The role for cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma (mRCC) has evolved with advancements in systemic therapy. During the cytokine-based immunotherapy era, CN provided a clear survival benefit and was considered standard of care in management of mRCC. The development of targeted systemic therapy directed at the vascular endothelial growth factor pathway altered the treatment paradigm and accentuated the importance of risk stratification in treatment selection. This article reviews the literature evaluating the benefit of CN during the evolution of systemic therapy and provides clinical recommendations for current utilization of CN in patients with mRCC.

Key points

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The role of cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) continues to evolve with advancements in systemic therapy.
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Although CN previously was standard of care for all patients with mRCC, the vascular endothelial growth factor (VEGF)-targeted therapy era highlighted the importance of systemic therapy in improving oncologic outcomes and the importance of risk stratification to identify patients more likely to benefit from CN.
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Immuno-oncology (IO) checkpoint inhibitors and combination IO and VEGF-targeted therapy agents (IOVE) currently are transforming the management of mRCC.
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CN continues to play an important role in specific patient populations, including those with low-volume, favorable-risk mRCC and those with stable or regressive disease on systemic therapy, and in delaying initiation of toxic systemic therapy in patients who can be observed.
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The role of CN needs to be re-examined in the new IO/IOVE era.

Introduction

Renal cell carcinoma (RCC) is the twelfth most common cancer. In the United States, in 2019, there were approximately 74,000 new cases diagnosed and 15,000 deaths. The incidence has increased with routine use of imaging modalities, increasing the number of incidentally diagnosed renal malignancies, which has resulted in stage migration, leading to approximately 70% of newly detected kidney tumors being low stage, clinically localized (cT1) renal masses. Historically, 25% to 30% of patients presented with distant metastases, but with earlier detection the current metastatic rate at presentation is closer to 10% to 15% in the United States and Europe. Disseminated disease still carries a dismal prognosis, with 5-year survival rates at approximately 10%, although survival rates over the past 30 years have improved with the advent of novel targeted therapies. ^,

Extirpative surgery has been a primary treatment option for patients with locally advanced, lymph node–positive, and distant metastatic RCC (mRCC), although its role in metastatic disease continues to evolve with advancements in systemic therapy. ^, Cytoreductive nephrectomy (CN) refers to the removal of the kidney with the primary tumor in patients with synchronous mRCC. During the cytokine therapy era, CN provided a clear survival benefit in patients with metastatic disease. The development of targeted therapies, such as tyrosine kinase inhibitors (TKIs), vascular endothelial growth factor (VEGF) monoclonal antibodies, and mammalian target of rapamycin (mTOR) inhibitors, have made the indications for CN less clear, and the recent advent of novel immune-oncologic (IO) agents have blurred its value further.

New efforts have been made to define the indications for CN, considering patient characteristics and disease pathology, the oncologic benefits of surgical management compared with modern systemic therapy, and the morbidity of surgery. Exploration into the timing of CN in relation to systemic therapy also is needed. This article aims to critically review the current literature to provide guidance on the therapeutic role of CN, including patient selection and surgical timing, in treating patients with mRCC in the modern systemic therapy era.

Benefit of cytoreductive therapy alone in metastatic renal cell carcinoma

CN until recently has been considered standard of care for all patients with mRCC. Its mechanism in altering the course of disease is unclear, but the pathophysiologic benefit likely is multifactorial. The elimination of the primary tumor reduces disease burden and the potential for development of aggressive biological clones capable of metastases. RCC is known to be highly immunogenic, and CN has been proposed to alter the immune systems response to metastases. In the early 1990s, prior to Food and Drug Administration approval of interleukin (IL)-2, CN alone was observed to result in spontaneous regression of distant metastatic lesions in a minority of patients. Although cure in these cases is rare and unpredictable even with risk stratification, the witnessed abscopal effect led to the realization of RCC immunogenicity. In theory, the immune system may be primed to target renal cancer cells, but the response is consumed by the primary tumor until it is removed, possibly due to the volume of disease or the immunosuppressive nature of the tumor microenvironment, inhibiting T-cell function. ^, Recent clinical studies have demonstrated correlation of RCC metastatic immunogenicity, in particular pulmonary and skeletal metastases, with clinical outcome. ^, CN had a theoretic basis to improve survival in patients with mRCC, by removing a potential source for new metastases and freeing the immune system to combat existing metastatic disease.

Cytokine-based immunotherapy era

The recognition of RCC’s immunogenicity led to the evaluation of immunotherapy, including IL-2 and interferon (IFN)-α, in treating metastatic disease. In 2001, the Southwest Oncology Group (SWOG) and European Organisation for Research and Treatment of Cancer (EORTC) published 2 randomized controlled trials (RCTs) with nearly identical protocols, randomizing patients with mRCC to CN followed by IFN-α or to IFN-α alone ( Table 1 ). ^, Both studies demonstrated improved overall survival in patients receiving surgery plus immunotherapy. SWOG 8949 included 241 total patients and showed an improved median overall survival of 3 months (11.1 mo vs 8.1 mo respectively; P = .05). EORTC 30947 included 85 total patients and had a difference in median overall survival of 10 months (17 mo vs 7 mo respectively; P = .03). A combined analyses of these 2 trials with 331 patients showed an improved median survival of 13.6 months in the CN plus IFN-α group in comparison to 7.8 months for IFN-α alone (31% decrease in the risk of death), independent of performance status and metastatic site. When evaluating CN in mRCC, it is important to note the percentage of patients who actually receive systemic therapy, because surgery can consequently delay initiation of or eliminate the possibility of systemic treatment. In these trials, only 1.8% of patients in the IFN-α–only arm did not receive IFN-α, whereas 5.6% of patients in the combined treatment arm did not receive IFN-α after nephrectomy. Therefore, CN improved overall survival despite fewer patients receiving systemic treatment. This combined analysis led to the conclusion that CN significantly improves overall survival in patients receiving IFN-α.

Table 1

Summary of randomized control studies in metastatic renal cell carcinoma

Data from Refs. ^,^,^,^,^,

Trial Name	Authors	N	Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium Risk Category				Arms		Outcomes		Notes
Trial Name	Authors	N	Favorable	Intermediate	Poor	Unknown	Arm	Arm Description	Complete Response, Partial Response, or Objective Response Rate	Survival (Median Survival, Overall Survival, Progression-Free Survival)	Notes
SWOG 8949	Flanigan et al, 2001	241	—	—	—	241	Arm 1	CN followed by IFN-α	—	MS 11.1 mo
SWOG 8949	Flanigan et al, 2001						Arm 2	IFN-α	—	MS 8.1 mo
EORTC 30947	Mickisch et al, 2001	85	—	—	—	85	Arm 1	CN followed by IFN-α	CR 11.9%	MS 17 mo
EORTC 30947	Mickisch et al, 2001						Arm 2	IFN-α	CR 2.3%	MS 7 mo
N/A	Motzer et al	750	264	421	48	0	Arm 1	Sunitinib	OR 31%	Median PFS 11 mo	MSKCC
N/A	Motzer et al						Arm 2	IFN-α	OR 6%	Median PFS 5 mo
Global ARCC Trial	Hudes et al, 2007	626	0	164	462	0	Arm 1	Temsirolimus	OR 8.6%	MS 10.9 mo
Global ARCC Trial	Hudes et al, 2007						Arm 2	IFN-α	OR 4.8%	MS 7.3 mo
TARGET Study	Escudier et al, 2016	903	461	441	0	1	Arm 1	Sorafenib	PR 10%	MS 17.8 mo, PFS 5.5 mo	MSKCC; 48% of patients in placebo group crossed over to receive sorafenib
TARGET Study	Escudier et al, 2016						Arm 2	Placebo	PR 2%	MS 14.3 mo, PFS 2.8 mo
CARMENA	Mejean et al, 2018	450	0	256	193	0	Arm 1	CN + sunitinib	OR 27.4%; CR 0.6%	MS 13.9 mo	MSKCC
CARMENA	Mejean et al, 2018						Arm 2	Sunitinib	OR 29.1%; CR 0%	MS 18.4 mo
SURTIME	De Bruijn et al, 2019	99	0	87	12	0	Arm 1	Sunitinib + deferred CN	—	MS 32.4 mo	MSKCC
SURTIME	De Bruijn et al, 2019						Arm 2	Immediate CN + Sunitinib	—	MS 15.1 mo
CheckMate 214	Motzer et al	1096	249	847 (intermediate risk or poor risk)	0	Arm 1	Ipi-nivo	OR 42%; CR 11%	MS not reached	IMDC	CheckMate 214
CheckMate 214	Motzer et al					Arm 2	Sunitinib	OR 29%; CR 2%	MS 26.6 mo
KEYNOTE-426	Rini et al	861	269	484	108	0	Arm 1	Pembrolizumab + axitinib	OR 59.3%; CR 5.8%	-y OS 89.9%; PFS 15.1 mo	IMDC
KEYNOTE-426	Rini et al						Arm 2	Sunitinib	OR 35.7%; CR 1.9%	1-y OS 78.3%; PFS 11.1 mo	IMDC

Abbreviations: CR, complete response; MS, median survival; OR, objective response; OS, overall survival; PFS, progression-free survival; PR, partial response.

After these trials, CN with cytokine therapy became standard of care in surgical candidates with synchronous mRCC. Despite the limited survival advantage, however, overall outcomes remained poor, emphasizing the need for more effective systemic treatments.

Risk stratification and patient selection

Metastatic RCC is a disease spectrum encompassing varied pathology at presentation and diverse natural history. As SWOG 8949 and EORTC 30947 demonstrate, trials with similar entry criteria may result in disparate outcomes, possibly attributable to dissimilar sample sizes or significant differences in baseline disease severity despite randomization. Risk stratification is vital to counsel patients and choose treatments that align with patient goals. Several models have been developed based on functional status and serum factors to prognosticate outcomes, guide treatment strategies, and evaluate therapeutic plans.

The Memorial Sloan Kettering Cancer Center (MSKCC) model, also known as the Motzer criteria, was published in 1999 during the immunotherapy era ( Table 2 ). It stratifies patients into 3 risk classifications, including favorable risk, intermediate risk, and poor risk, based on time to initiation of systemic therapy, Karnofsky performance scale status, and serum hemoglobin, calcium, and lactate dehydrogenase levels. During the targeted therapy era, the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), or Heng criteria, was created, separating patients into the same 3 categories based on prognostic factors for overall survival in patients with mRCC treated with VEGF-TKI. IMDC is similar to MSKCC criteria except for the elimination of serum lactic acid dehydrogenase and the inclusion of neutrophil and platelet counts. The performance of the IMDC model was found similar to that of the MSKCC criteria (see Table 2 ).

Table 2

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