Radical nephrectomy before or after systemic therapy for mRCC

Cytoreductive nephrectomy (CN) is a debulking procedure intended to reduce the overall cancer burden in the setting of metastatic disease by extirpating the renal unit containing the primary tumor. This is done without intending to eradicate the disease and is performed with the goal of improving survival outcomes. CN prior to or following upfront systemic therapy has long been considered an important treatment paradigm for metastatic renal cell carcinoma (mRCC). The recent publication of 2 highly anticipated randomized controlled trials, however, has renewed controversy regarding the role of CN for mRCC.

The scientific rationale for performing CN has long been on the basis of level 1 evidence from 2 trials published in 2001. These demonstrated superior overall survival (OS) for mRCC patients undergoing CN plus interferon alfa compared with interferon alfa alone.^1,2 However, since the introduction of targeted agents in 2005, the assumption that CN portends a survival benefit has always been extrapolated from this data, which was formed on that basis of inferior and now obsolete systemic therapy. Prior to 2018, multiple retrospective series demonstrated an OS benefit to CN, but no level 1 data existed to support it.^3-5 All of this ignores the fact that we have again ushered in a revolution in systemic therapeutics for mRCC with immuno-oncology therapy, further clouding the picture of who should or should not receive CN.

Interpreting the CARMENA and SURTIME trials

The CARMENA randomized trial (NCT00930033), published by Méjean et al in 2018, compared OS in mRCC patients receiving the tyrosine kinase inhibitor sunitinib (Sutent) alone versus those receiving sunitinib and CN.⁶ They were able to demonstrate that OS for the sunitinib-alone arm was non-inferior to sunitinib plus CN (18.4 vs 13.9 months) in the intention-to-treat (ITT) analysis. Naturally, the publication of this trial raises important questions about the validity of CN as a therapeutic endeavor in the targeted therapy era.

However, this trial has significant limitations, and its findings must be interpreted with caution. Patient accrual was slow and the accrual goal was not reached. More significantly, only 0.7 procedures per center were performed. The trial cohort also contained a high proportion of high-risk patients (43%) by Memorial Sloan Kettering Cancer Center (MSKCC) criteria,⁷ and the remainder (57%) were intermediate risk. Taken together, this suggests that some exclusion bias likely exists, because more favorable patients were presumably being offered CN outside of the trial.

It is also probable that the inclusion of such a high proportion of MSKCC high-risk patients limited the overall survival (OS) of the study cohort. This is reflected by the truncated median OS experienced by the CN arm. Median OS of 13.9 months is very short and does not reflect most contemporary CN cohorts. Additionally, significant contamination of the study arms occurred, with 7% of the CN arm not undergoing surgery and 17% of the sunitinib-only arm receiving CN.

The SURTIME trial (NCT01099423) was intended to evaluate survival outcomes for patients receiving upfront CN followed by sunitinib versus those receiving sunitinib followed by deferred CN.⁸ Due to poor recruitment (n = 99), the authors were forced to revise the primary end point from OS to a 28-week progression-free survival (PFS) rate, which limits the generalizability of the results. No difference in PFS rates was found between cohorts. Only in an exploratory OS analysis could an OS benefit for the deferred CN arm be identified (15 vs 32 months, HR 0.57; 95% CI, 0.34-0.95; P = .03) in the ITT population. This difference was not maintained in the per-protocol analysis.

The SURTIME cohort was 88% MSKCC intermediate risk, which would seem to make it more generalizable to a typical candidate for CN, but very poor accrual limits the interpretation of the results. The study was not powered to detect an OS difference, so conclusions cannot be drawn from their exploratory analysis.

How should CARMENA and SURTIME alter my practice?

These important studies should be viewed as practice-confirming rather than practice-altering. Appropriate patient selection using objective criteria has always been paramount in managing mRCC with CN. The European Association of Urology updated its guidelines⁹ for managing mRCC to reflect the findings of these randomized trials by stating that MSKCC poor-risk patients should not undergo CN. However, I venture that most urologic oncologists would not have offered an MSKCC poor-risk patient CN prior to the publication of CARMENA. Importantly, these guidelines also state that MSKCC intermediate-risk patients should be considered for upfront systemic therapy. This key point highlights the need for objective scoring criteria to evaluate patients suitable for surgical cytoreduction. Any patient suspected to be high risk for disease progression or perioperative morbidity should be considered for upfront systemic therapy, and this likely includes many intermediate-risk patients. Initial systemic therapy can serve as a litmus test for the clinician—a favorable response may prompt a re-evaluation for CN. The goal of CN should be to prolong survival, and therefore clinicians must endeavor to minimize time spent off of systemic therapy.

Risk stratification for CN

Multiple studies and guideline panels utilize the MSKCC criteria to risk-stratify patients with mRCC. It should be noted that the MSKCC criteria were initially published to stratify predicted survival outcomes for mRCC patients receiving therapy with interferon.7 They were never intended to incorporate surgical risk and perioperative morbidity and mortality into their model. The International mRCC Database Consortium (IMDC) has published a risk model,¹⁰ which has been validated in cytoreductive nephrectomy patient cohorts and includes 6 easily measured preoperative variables. These include Karnofsky perfoxqrmance status less than 80%, hemoglobin less than 12 g/dL, corrected serum calcium higher than 10.2 mg/dL, neutrophils higher than 7 x109/L, and platelets higher than 400k cells/μL. This model was also published during the targeted therapy era, so it likely represents a more generalizable application to modern mRCC patients. However, because this model includes “less than 1 year from diagnosis to systemic therapy” as the sixth risk factor, it automatically excludes all patients presenting with de novo mRCC from the favorable risk category. For this reason, these criteria may not be ideally suited for clinical application in surgical candidates.

The University of Texas MD Anderson Cancer Center criteria (MD Anderson), recently published in Cancer (as an update from a prior study¹¹), provides clinicians with 9 objective preoperative clinical variables by which patients with mRCC can be stratified into 3 tiers of risk for increased likelihood of death following CN (Table).¹² Patients are considered low, intermediate, and high risk for poor survival outcomes following CN if they have 0-1, 2-3, and 4 or more risk factors, respectively. The risk groups not only directly correlated with survival outcomes but also with adverse features on pathology and adverse perioperative outcomes. These findings suggest that the model can predict those patients in whom increased surgical risk may exist outside of their tumor biology. The cohort was derived from consecutive patients undergoing CN in the targeted therapy era and are therefore generalizable to a typical patient with mRCC presenting to a urologist’s office. Notably, median survival in the poor risk group in the MD Anderson cohort was 19 months as compared with 13.9 months in the combined arm (sunitinib + CN) of CARMENA. It seems that when appropriately selected, even poor risk patients receiving CN fare better than those enrolled in CARMENA.

On the basis of the MD Anderson study, patients who fall into a good risk category can be considered for CN and those who are poor risk should not be offered upfront CN. For intermediate-risk patients, careful patient selection based on these risk factors, individual performance status, and other patient comorbid conditions should be undertaken to individualize recommendations. Those patients who elect to receive upfront systemic therapy should be restaged and risk-stratified for CN once a favorable response is documented. Again, the goal should be to prolong survival and CN should only be undertaken when it can be reasonably expected that the patient can resume/begin systemic therapy in a timely fashion post operatively. As the therapeutic landscape continues to evolve and shift to rely more heavily on immuno-oncology therapy, we must be diligent in continuing to develop tools to appropriately risk-stratify patients with mRCC for CN.

McIntosh is assistant professor of urology, University of Oklahoma Stephenson Cancer Center, and acting section chief of urology, VA Medical Center, Oklahoma City.

References

1. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659. doi:10.1056/NEJMoa003013

2. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970. doi:10.1016/s0140-6736(01)06103-7

3. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185(1):60-66. doi:10.1016/j.juro.2010.09.012

4. 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. Eur Urol. 2019;75(1):111-128. doi:10.1016/j.eururo.2018.09.016

5. Hanna N, Sun M, Meyer CP, et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a national cancer data base study. J Clin Oncol. 2016;34(27):3267-3275. doi:10.1200/JCO.2016.66.7931

6. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427. doi:10.1056/NEJMoa1803675

7. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289-296. doi:10.1200/JCO.2002.20.1.289

8. 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. 2019;5(2):164-170. doi:10.1001/jamaoncol.2018.5543

9. 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. Eur Urol. 2018;74(6):805-809. doi:10.1016/j.eururo.2018.08.008

10. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014;66(4):704-710. doi:10.1016/j.eururo.2014.05.034

11. Culp SH, Tannir NM, Abel EJ, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer. 2010;116(14):3378-3388. doi:10.1002/cncr.25046

12. McIntosh AG, Umbreit EC, Holland LC, et al. Optimizing patient selection for cytoreductive nephrectomy based on outcomes in the contemporary era of systemic therapy. Cancer. 2020;126(17):3950-3960. doi:10.1002/cncr.32991