Platinum Opinion

Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered

The role and timing of cytoreductive nephrectomy in the immunotherapy era require further investigation. Extrapolation of data from the cytokine era that demonstrated an overall survival benefit of cytoreductive nephrectomy suggest that similar results might emerge from future trials using immunotherapy agents.

Upfront cytoreductive nephrectomy (CRN) in renal cell carcinoma (RCC) has come into question in recent prospective clinical trials.

We investigated the effect of systemic therapies on primary tumor response in patients with metastatic RCC.

A pooled analysis of 12 phase II/III clinical trials of metastatic RCC patients treated with systemic therapy between 2003 and 2013 was performed. Patients with one target lesion in the kidney and no prior nephrectomy were identified as having their primary tumor in place.

The objective response rate (ORR) of the primary tumor was defined as per the Response Evaluation Criteria in Solid Tumors (RECIST). ORR was assessed in the overall population and patient subsets based on prior treatment and International Metastatic RCC Database Consortium (IMDC) risk group. Cox’s models adjusting for baseline characteristics, treatment, line of therapy, and site of metastases were used for survival analyses.

In total, 4736 patients were identified, of whom 565 had their primary tumor in place: 461 (82%) were treatment naïve, 283 (50%) received first-line vascular endothelial growth factor (VEGF)-targeted therapy, and 222 (39%) were IMDC poor risk. The ORRs of the primary tumor were 19% (95% confidence interval 16–23) in patients treated with first-line therapy (any type), 28% (22–33) in those treated with first-line VEGF-targeted therapy, and 23% (19–28) in those treated with VEGF-targeted therapy (any line). The ORRs were 9% (5–13) and 20% (15–27) in IMDC poor- and intermediate-risk patients, respectively.

Systemic therapy reduces primary tumor size in patients with metastatic RCC. Responses in primary tumors treated with VEGF-targeted therapy were observed in upward of 28% of patients. Selection of patients for immediate CRN requires careful consideration of patient and disease characteristics.

Antiangiogenic therapy meaningfully decreases the size of primary kidney tumor. Hence, for patients with metastatic disease who are not undergoing upfront cytoreductive nephrectomy, systemic therapy can palliate both primary tumor and metastases.

The current role of cytoreductive nephrectomy (CN) is controversial.

Review of the available evidence about criteria defining CN optimal candidates.

Collaborative critical narrative review of the literature focusing on CN oncological outcomes, perioperative morbidity, eligibility criteria, presurgical systemic therapy, and surgical factors.

In contrast to observational studies, the Clinical Trial to Assess the Importance of Nephrectomy (CARMENA) trial demonstrated noninferiority of targeted therapy alone relative to CN with targeted therapy. CN is associated with a significant risk of perioperative mortality (0–13%) and major complications (3–36%). Metastatic burden, haematological parameters, performance status, sarcopenia, and genetic mutations have been proposed as CN eligibility criteria. Comprehensive models including local and systemic factors are recommended. The Immediate Surgery or Surgery after sunitinib Malate In Treating Patients with Kidney Cancer (SURTIME) trial reported similar progression-free rate after immediate or deferred CN, and suggests that presurgical systemic therapy can identify candidates for CN, avoiding unnecessary surgery in nonresponders without increasing the risk of perioperative complications. Minimally invasive and nephron-sparing CNs are established surgical strategies in selected patients.

No benefit of upfront CN is observed for intermediate- and poor-risk patients who require systemic therapy in randomised controlled trials, and systemic therapy deserves priority over CN in patients with metastatic renal cell carcinoma. These findings are not applicable to all patients with metastatic kidney cancer. CN has a role in favourable cases not requiring immediate systemic therapy or in symptomatic patients. Individual patient selection to identify those patients who might profit the most from CN is critical; however, clinical decision making should be based on comprehensive models. Presurgical systemic therapy is a promising option to avoid unnecessary CN, which is associated with major morbidity.

Consideration for systemic therapy deserves priority over cytoreductive nephrectomy (CN) in patients with metastatic renal cell carcinoma. In patients eligible for systemic therapy, CN does not offer a survival benefit. The indications for CN should be evaluated on an individual basis. Risk scores and response to presurgical systemic therapy can be used for subsequent decision making.

To develop a risk-stratification model for cancer-specific survival (CSS) following cytoreductive nephrectomy (CN) in the contemporary era.

A retrospective review was performed of 313 patients who underwent CN for M1 renal cell carcinoma (RCC) from 1990 to 2010. To account for the introduction of targeted therapies, timing of surgery was classified as immunotherapy era (1990–2004) or contemporary era (2005–2010). Risk scores were developed to predict CSS using Cox proportional hazards regression models.

A total of 215 (69%) and 98 (31%) patients were treated in the immunotherapy and contemporary eras, respectively. Median follow-up among survivors was 9.6 years, during which time 291 patients died, including 279 from RCC. On multivariable analysis limited to preoperative features, age ≥ 75, (hazard ratio [HR] 1.9), female sex (HR 1.9), constitutional symptoms (HR 1.61), radiographic lymphadenopathy (HR 1.59), and IVC tumor thrombus (HR 1.65) were significantly associated with CSS. On multivariable analysis including pathologic features, the features above as well as coagulative necrosis (HR 1.51) and sarcomatoid differentiation (HR 1.44) were significantly associated with CSS (all P < 0.05). Risk scores were developed for each model and used to predict CSS according to era. Decision curve analysis revealed that the preoperative risk score conferred a net benefit over a treat-all or treat-none approach beyond a 1-year cancer-specific mortality threshold of 25%.

We developed risk scores to predict CSS for patients treated with CN in the contemporary era. Patients with poor predicted survival may consider avoiding CN as initial management.