The Current Status of Cytoreductive Nephrectomy

Kidney cancer is the 6th most common malignancy among men and 10th most among women.1 Renal cell carcinoma (RCC) accounts for the vast majority of these tumors. Further details regarding the epidemiology of kidney cancer have been discussed in, "Epidemiology and Etiology of Kidney Cancer." While 20-30% of patients undergoing nephrectomy will develop metastases during follow-up,2 a significant proportion (historically up to 25-30%) of patients with renal cell carcinoma present with metastases at the time of diagnosis.3 More recent estimates suggest that, with stage migration due to an increasing incidental diagnosis of kidney cancer, approximately 15% of patients newly diagnosed with kidney cancer have metastases at the time of diagnosis.1 Historically, patients treated with cytokine-based systemic therapy had a median overall survival of 10 months.3 Therefore, options to improve outcomes for these patients were sought.

The History of Cytoreductive Nephrectomy

The 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 Era

A 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
Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:
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  10. Spencer WF, Linehan WM, Walther MM, et al. Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. The Journal of urology. 1992;147(1):24-30.
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  15. Gatenby RA, Gawlinski ET, Tangen CM, Flanigan RC, Crawford ED. The possible role of postoperative azotemia in enhanced survival of patients with metastatic renal cancer after cytoreductive nephrectomy. Cancer research. 2002;62(18):5218-5222.
  16. Escudier B, Goupil MG, Massard C, Fizazi K. Sequential therapy in renal cell carcinoma. Cancer. 2009;115(10 Suppl):2321-2326.
  17. Bhindi B, Abel EJ, Albiges L, et al. Systematic Review of the Role of Cytoreductive Nephrectomy in the Targeted Therapy Era and Beyond: An Individualized Approach to Metastatic Renal Cell Carcinoma. European Urology. 2019;75(1):111-128.
  18. Mejean A, Ravaud A, Thezenas S, et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. The New England journal of medicine. 2018.
  19. Arora S, Sood A, Dalela D, et al. Cytoreductive Nephrectomy: Assessing the Generalizability of the CARMENA Trial to Real-world National Cancer Data Base Cases. European urology. 2019;75(2):352-353.
  20. Bex A, Mulders P, Jewett M, et al. Comparison of Immediate vs Deferred Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Renal Cell Carcinoma Receiving Sunitinib: The SURTIME Randomized Clinical Trial. JAMA Oncol. 2018.
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  22. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. The New England journal of medicine. 2018;378(14):1277-1290.
  23. Bex A, Albiges L, Ljungberg B, et al. Updated European Association of Urology Guidelines for Cytoreductive Nephrectomy in Patients with Synchronous Metastatic Clear-cell Renal Cell Carcinoma. European Urology. 2018;74(6):805-809.
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