The History of Cytoreductive NephrectomyThe notion of cytoreductive nephrectomy (CN), removal of the kidney and primary tumor in the face of metastatic disease, was based on a series of observations. First, patients treated with the primary tumor in-situ who underwent treatment with interferon fared particularly poorly.2,4 Second, case reports demonstrated that a small number of patients treated with CN experienced regression of their metastatic disease.5,6
As a result, two randomized controlled trials were undertaken to assess the value of CN in the era of cytokine-based therapy. In these two methodologically similar randomized controlled trials, Flanigan et al. and Mickish et al. randomized patients to CN plus interferon vs interferon alone.7 Reported in 2001, among 241 American patients, Flanigan et al. demonstrated a 3-month survival benefit8 whereas, among 83 European participants, Mickish et al. demonstrated a 10-month survival benefit.9 Subsequent pooled analyses showed a strongly statistically significant benefit with overall survival of 13.6 months among patients receiving CN plus interferon and 7.8 months among those receiving interferon alone (difference = 5.8 months, p=0.002).7 On the basis of these data, CN became part of the treatment paradigm for metastatic RCC.
It bears mention that despite the proven survival benefits, the mechanism of CN is unclear. Notably, the response to systemic therapy did not differ in the two pivotal RCTs.7 thus, CN does not potentiate the response to (cytokine-based) systemic therapy. Postulated mechanisms include removal of the “immunologic sink”,4,10 decreased production of cytokines and growth factors by the primary tumor,11-13 delayed metastatic progression,14 and survival benefit from nephrectomy induced azotemia.15
However, shortly after the publication of the randomized data demonstrating the survival benefit to adding cytoreductive nephrectomy to cytokine-based systemic therapy, the introduction of targeted therapies revolutionized the systemic therapy of metastatic RCC. From the aforementioned 10-month median overall survival in the cytokine-era,3 median overall survival for patients receiving a sequential regime of targeted therapies may exceed 40 months.16 Much more detail regarding systemic therapy in advanced RCC is available in the article, "Systemic Therapy for Advanced Renal Cell Carcinoma."
Cytoreductive Nephrectomy in the Targeted Therapy EraA number of retrospective studies have examined the role of cytoreductive nephrectomy in the context of targeted therapy. Summarized by Bhindi et al. in a recent systematic review,17 these 10 retrospective studies consistently demonstrated a significant survival benefit to cytoreduction. However, the potential for selection bias is significant among these studies, particularly among studies in which it was not possible to quantify the burden of metastatic disease.
The CARMENA trial (Cancer du Rein Metastatique Nephrectomie et Antiangiogéniques or, alternatively, Clinical Trial to Assess the Importance of Nephrectomy) provides the only available randomized data on the role of cytoreductive nephrectomy in the targeted therapy era.18 This study has been extensively reported on by UroToday authors including “ASCO 2018: Sunitinib Alone Shows Non-inferiority Versus Standard of Care in mRCC - The CARMENA Study," “ASCO 2018: CARMENA: Cytoreductive Nephrectomy Followed by Sunitinib vs. Sunitinib Alone in Metastatic Renal Cell Carcinoma - Results of a Phase III Noninferiority Trial," and “Nephrectomy in the Era of Targeted Therapy: Takeaways from the CARMENA Trial."
To briefly summarize, CARMENA randomized 450 patients with intermediate or poor-risk confirmed clear cell renal cell carcinoma in a 1:1 fashion to nephrectomy followed by sunitinib or sunitinib alone.18 To be eligible for enrollment in CARMENA, patients had to be naïve to systemic therapy, eligible for treatment with sunitinib and deemed amenable for cytoreductive nephrectomy by their treating surgeon. Using the Memorial Sloan Kettering Cancer Center (MSKCC) risk stratification, these patients had intermediate- or poor-risk disease. Additionally, patients had to have an ECOG performance score of 0 or 1 and no evidence of brain metastasis or have undergone prior local therapy for brain metastasis without evidence of progression for at least 6 weeks. After a median follow-up of 51 months, the median overall survival for patients receiving systemic therapy alone was 18.4 months and was 13.9 months for those patients undergoing cytoreductive nephrectomy followed by sunitinib. The resulting Cox models demonstrated non-inferiority with a hazard ratio of 0.89 (95% CH 0.71 to 1.10) based on an intention to treat analysis. In a per-protocol analysis, the resultant analysis showed comparable results (HR 0.98, 95% CI 0.77 to 1.25). However, in this case, the upper limit of the 95% confidence interval crossed the investigator's pre-specified non-inferiority threshold of 1.20.
A number of nuances regarding CARMENA bear consideration. First, the investigators required eight years at 79 sites to accrue 450 of an initially planned 576 patients. Thus, each institution enrolled fewer than a single patient each year – suggesting either that many potentially eligible patients may not have been enrolled due to either their clinician’s lack of equipoise (and thus unwillingness to leave treatment allocation to chance) or the patients’ own unwillingness to be randomized. The resulting cohort, while having a good performance status (ECOG 0 or 1) and deemed fit for cytoreductive nephrectomy, the enrolled patients had a significantly higher burden of disease that may be expected from population-based American cohorts.19 Second, there was significant cross-over within the study, with a large proportion of patients assigned to sunitinib alone eventually undergoing palliative nephrectomy for symptomatic control. Potentially more concerning, given the proven survival benefit of targeted therapy, are the patients who were not able to receive sunitinib following cytoreductive nephrectomy.
To further address the question of the timing of cytoreductive nephrectomy, the SURTIME trial (Immediate Surgery or Surgery after Sunitinib Malate In Treating Patients with Kidney Cancer (NCT01099423) randomized 99 patients to immediate CN followed by sunitinib, beginning 4 weeks after surgery and continuing for four courses, or three 6-week courses of sunitinib (in the absence of disease progression or unacceptable toxicity) followed by CN followed by 2 courses of adjuvant sunitinib. While significantly underpowered due to poor accrual, the trial reported a 28-week progression-free rate of 42% in the immediate CN arm and 43% in the deferred CN arm (p=0.6).20 Interestingly, intention-to-treat analysis of the secondary outcome of overall survival demonstrated significantly longer survival among patients in the delayed CN arm (median 32.4 months) compared to the immediate CN arm (median 15.1 months) (HR 0.57, 95% CI 0.34 to 0.95).
Since these trials were designed and accrued, a number of additional systemic therapy agents have been approved for first-line therapy in metastatic RCC. Many of these agents have demonstrated superiority to sunitinib.21 While improved overall survival increases the time for patients to develop local symptoms which may warrant surgery, improved systemic therapy is likely to reduce the value of local treatments. Notably, the efficacy of nivolumab and ipilimumab did not differ on the basis of whether the patient had previously undergoing nephrectomy.22
Taken together, CARMENA and SURTIME suggest that systemic therapy should be prioritized over cytoreductive nephrectomy for patients with metastatic RCC. However, the EAU guidelines, while emphasizing the CN is no longer the standard of care, highlight that CN may be considered for select patients including those with an intermediate-risk disease who have a long-term sustained benefit from systemic therapy and those with a good-risk disease who do not require systemic therapy.23