For more than 20 years, cytoreductive nephrectomy (CN) has been the standard of care as a first-line treatment for patients with metastatic renal cell cancer (mRCC)-this norm was based on the results of two prospective randomized trials conducted in the era of interferon immunotherapy[1-2].The use of CN before starting systemic therapy in selected mRCC patients eliminates the primary tumor and diminishes the potential of the tumor for bleeding and causing pain during systemic treatment. Removing the primary tumor might also excludes the secretion of immunosuppressants and tumor growth promoters, and enhances clinical response to therapy.
However, with the recent approval of therapeutic agents that target vascular endothelial growth factor(VEGF) signalling-including the VEGF receptor tyrosine kinase inhibitors(sunitinib and pazopanib),anti-VEGF monoclonal antibody(bevacizumab)-and the mammalian target of rapamycin(mTOR) inhibitor(temsirolimus), have muddied the exact role and timing of CN as a pre-treatment to therapy using these agents: while CN is still typically recommended as a prior procedure whenever it is clinically feasible and justifiable, limited level 1 evidence exists that is based on retrospective studies and meta-analysis and that shows direct benefits of CN prior to treatment with the targeted therapy[6-8].
Results of the CARMENA (Cancer of the Rein Metastatique Nephrectomie et Antiangiogéniques) trial were presented at a plenary session at the American Society of Clinical Oncology (ASCO)2018 and were simultaneously published in the New England Journal of Medicine(NEJM) - these findings argue against the combined use of CN and targeted therapies. The CARMENA trial was a prospective, randomized, phase III non-inferiority trial of 450 patients with mRCC. Patients were enrolled at more than 79 centers in Europe over a period of 8 years, and were randomly assigned (1:1 ratio) to CN followed by sunitinib(226 patients) treatment, or to treatment with sunitinib alone(224 patients). mRCC patients were randomized according to prognostic risk(intermediate or poor) according to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic model. Baseline demographics were wellbalanced between the groups: approximately 75% of the patients in each group were men, and the median age was 63 in the CN plus sunitinib group, and 62 in the sunitinib-alone group. Slightly more than half of each group had an intermediate MSKCC risk score, and the remainder had an MSKCC poor-risk score.
With a median follow-up of 50.9 months and 326 observed deaths, the study met its primary endpoint, and documented that sunitinib alone is not inferior to CN plus sunitinib with regard to overall survival (OS). The median OS with CN plus sunitinib was 13.9 months [95%CI, 11.8 to 18.3] compared to 18.4 months [95%CI, 14.7 to 23.0] with the use of sunitinib alone. The hazard ratio for death in the analysis of OS, stratified according to MSKCC risk score, was 0.89(95%CI, 0.71 to 1.10). In both the intermediate-risk and poor-risk groups of patients, the median OS was longer in the sunitinib group than in the nephrectomy plus sunitinib group: for MSKCC intermediate-risk patients, the median OS was 19.0 months with CN and 23.4 months without it (HR, 0.92, 95% CI[0.68, 1.24]), and for MSKCC poor-risk patients, the median OS was 10.2 months and 13.3 months, respectively (HR 0.86, 95% CI[0.62, 1.17]).
Data analysis revealed no significant differences in response rate or progression-free survival (PFS). The median PFS was 7.2 months (95% CI[6.7, 8.5]) with CN plus sunitinib and 8.3 months with sunitinib alone (95%[6.2, 9.9]) and the objective response rate was 27.4% with CN and 29.1% without it. But interestingly, the clinical benefit rate, defined as disease control beyond 12 weeks, was 36.6% with the combination treatment and 47.9% with sunitinib alone(p=0.02).
Thus results of the CARMENA study seem to have flipped the existing paradigm for managing the mRCC. Sunitinib alone was found to be not inferior to CN followed by sunitinib, leading to the conclusion that intermediate and poor-risk patients with mRCC should be treated with sunitinib, without necessarily removing the kidney. However, this conclusion needs to be investigated further, and the data obtained from it should be analysed more deeply, because the trial was explicitly designed to detect the non-inferiority of sunitinib when compared to CN plus sunitinib, rather than the superiority of sunitinib alone. This is underscored by the commentary on the study by Robert Motzer and Paul Russo of the MSKCC in New York- they point out that the study reached the noninferiority endpoint because the population was heavily biased towards poor-risk patients, who represented 43% of the cohort - these poor-risk individuals are less likely to benefit from surgery(and more likely to be damaged) because they are less robust in enduring the invasive procedure and potential complications. Furthermore, the mRCC patients from the sunitinib only group recorded better surgical outcomes than those in the CN plus sunitinib, due to a high percentage of locally advanced disease in the sunitinib plus surgery group (70.1% versus 51.0%).
Problems of interpretation of the results may also be due to some anomalies related to overlap of the treatment modalities. In the sunitinib only group, 17%(n=38) of the patients required emergency CN for management of haemorrhage and necrosis of the tumors, and thus underwent delayed surgery whereas 4.9%(n=11) did not receive the drug. In the CN plus sunitinib group, 17%(n=40) did not received the drug while 7%(n=16) did not undergo surgery. These patients form a statistically significant number that may alter the results of the study. On further analysis, a relatively larger number of patients from the CN plus sunitinib group received subtherapeutic doses of the drug hence had worse outcomes, whereas another large number of patients from the sunitinib only group received an extra form of treatment, and thus recorded better results.
Given the above caveats, the CARMENA study does not convincingly advocate for abandoning CN altogether in clinical practice; instead, it highlights the importance of carefully selecting patients that are submitted to intervention based on published risk models, and of carefully timing the interventions in order to reap maximum benefits.
Thus, CN remains the management of choice for favourable-risk mRCC patients, who have a good performance status and a resectable primary tumor with low tumor burden outside the tumor; on the contrary, CN is not ideally suited for poor-risk patients and bad performance status. For patients with mRCC, a performance status of 0 or 1, and limited metastatic tumor burden, the management modality of choice remains at the discretion of the clinician, based on the risk before treatment, the resectability of the primary tumor, and the presence of other comorbidities.
An additional benefit of the CARMENA study is that it paves the way for similar studies aimed at verifying whether CN is beneficial or not in the context of immune therapies with checkpoint inhibitor. Recently, results of the phase III CheckMate-214 trial showed that the combined use of nivolumab plus ipilimumab reduces the risk of death by 32% compared to use of sunitinib. The risk reduction was 37% among patients with intermediate or poor risk, who constituted approximately 75% of the population . Also, in the CABOSUN phase II study, use of cabozantinib as a frontline treatment reduced the risk of progression or death by 34% compared to use to sunitinib, and median PFS was 8.2 months with cabozantinib versus 5.6 months with sunitinib (HR 0.66 95%CI 0.46-0.95,p=0.012). Given the advent of these more recent therapies, sunitinib should be obsolete, and it is clear that new trials need to be redesigned to study the need or lack thereof for CN in the era of targeted therapy and immunotherapy.
- 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 Dec 6;345(23):1655-9.
- Mickisch GH, Garin A, van Poppel H et al. European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001 Sep 22;358(9286):966-70.
- Russo P. Multi-modal treatment for metastatic renal cancer: the role of surgery. World J Urol. 2010 Jun;28(3):295-301.
- Marcus SG, Choyke PL, Reiter R et al. Regression of metastatic renal cell carcinoma after cytoreductive nephrectomy. J Urol. 1993 Aug;150(2 Pt 1):463-6.
- Choueiri TK, Motzer RJ. Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med. 2017 Jan 26;376(4):354-366.
- Culp SH. Cytoreductive nephrectomy and its role in the present-day period of targeted therapy. Ther Adv Urol. 2015 Oct;7(5):275-85.
- García-Perdomo HA, Zapata-Copete JA, Castillo-Cobaleda DF. Role of cytoreductive nephrectomy in the targeted therapy era: A systematic review and meta-analysis. Investig Clin Urol. 2018 Jan;59(1):2-9.
- Bhindi B, Habermann EB, Mason RJ et al. Comparative Survival following Initial Cytoreductive Nephrectomy versus Initial Targeted Therapy for Metastatic Renal Cell Carcinoma. J Urol. 2018 Mar 21.
- Méjean A, Ravaud A, Thezenas S et al. Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma. N Engl J Med. 2018 Jun 3.
- Motzer RJ, Russo P. Cytoreductive Nephrectomy - Patient Selection Is Key. N Engl J Med. 2018 Jun 3.
- Motzer RJ, Tannir NM, McDermott DF et al.Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018 Apr 5;378(14):1277-1290.
- Choueiri TK, Halabi S, Sanford BL et al. Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol. 2017 Feb 20;35(6):591-597.
- Will the results of the CARMENA trial change the clinical practice for mRCC patients?
- Should CN be dismissed in intermediate-risk and poor-risk mRCC patients who have been deemed candidates for the targeted therapy? Which patients should be given CN and when should this occur?
- What could be the role of CN in mRCC patients after the future approval of immunotherapy?