The CARMENA (Clinical Trial to Assess the Importance of Nephrectomy) noninferiority trial evaluated the outcomes of patients with mRCC receiving first-line sunitinib compared with those receiving CRN followed by sunitinib.5 There was a trend towards longer OS (18.4 months vs 13.9 months) in the sunitinib-only treatment arm compared with the CRN with sunitinib arm (HR mortality, 0.89; 95% CI, 0.71-1.1). Response rates (29.1% vs 27.4%, P =.02) and progression-free survival (PFS) (HR, 0.82; 95% CI, 0.67-1.00 for sunitinib alone) were similar between the sunitinib vs CRN with sunitinib group, respectively.

Therefore, these data were not as supportive of CRN as were previous trials, although the authors still concluded that CRN could continue to have a role in lower-risk disease as well as for patients with mRCC with symptomatic primary tumors. It is important to note that the CARMENA trial was stopped early based on slow recruitment and because it did not meet the target enrollment of 576 patients.

The SURTIME trial (Immediate Surgery or Surgery after Sunitinib Malate in Treating Patients with Metastatic Kidney Cancer trial) data were published in December 2018.6 In this clinical trial, patients were randomized to either immediate CRN followed by sunitinib, or 3 cycles of 4 weeks of sunitinib followed by 2 weeks off (then followed by CRN).


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In comparison to the CARMENA trial, SURTIME had more strict inclusion criteria, therefore “sicker” patients were excluded if they did not have more than 3 surgical risk factors such as low serum albumin, metastasis-related symptoms, subdiaphragmatic or retroperitoneal lymphadenopathy, or stage cT3 to stage cT4 disease. This study also stopped early based on poor recruitment.  The intention-to-treat (ITT) progression-free rate (PFR) at 28 weeks was similar between the 2 groups: with immediate CRN it was 42%; with deferred CRN it was 43% (HR, 0.88; 95% CI, 0.56-1.37, P =.569). Patients in the deferred CRN group did have longer median OS compared with the immediate CRN group (HR, 0.57; 95% CI, 0.34-0.95, P =.32), which equated to an approximately 17-month survival advantage (32.4 months vs 15 months).

It is important to note that at the time of publication of both of these studies in 2018, the most recent guidelines at that time were from 2016, which recommended CRN in patients with mRCC whom had good performance status, or for those with solitary or oligometastatic disease as they as they did not have poor-risk features.7 Interestingly, these guidelines were subsequently updated and published in December 2018 in order to incorporate newer data that had accumulated since 2016, namely the CARMENA and SURTIME trials.8

These updated 2018 guidelines advised against considering performing CRN in poor-risk patients, as well as performing immediate CRN in intermediate-risk patients who have an asymptomatic synchronous primary tumor and require systemic therapy with

vascular endothelial growth factor receptors and tyrosine kinase inhibitors. These same intermediate-risk patients should start sunitinib without CRN and have a discussion with their oncologist regarding the role of delayed CRN in those patients with minimal residual metastatic burden and potential for long-term sustained benefit. The final recommendation supported the performance of an immediate CRN in patients with good performance who do not require systemic therapy.

Another key point to consider is that in both the CARMENA and SURTIME clinical trials, as well as in the 2018 European Association of Urology guidelines, the recommendations were only incorporating data in patients with clear cell mRCC (cc-mRCC). Therefore, although non–cc-mRCC is significantly less common, there are limited data on the true role of CRN in this specific patient population. One of the larger studies that evaluated outcomes in patients with non–cc-mRCC showed that these patients undergoing CRN had overall worse outcomes compared with those with cc-mRCC. Multivariate analyses showed that median disease-specific survival was significantly worse in patients with non–cc-mRCC compared with those with cc-mRCC (9.7 months vs 20.3 months, P =.026).9

To further evaluate the role of CRN in mRCC, new prospective and retrospective studies evaluating its role in the setting of immunotherapy will be necessary in the future. The guidelines will likely require another update after these data on immunotherapeutic agents such as PD-1 and CTLA-4 inhibitors are incorporated.

References

  1. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: kidney and renal pelvis cancer. Accessed June 20, 2019.
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  3. 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.
  4. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R; 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;358(9286):966-970.
  5. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Eng J Med. 2018;379:417-427.
  6. 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 [published online December 13, 2018]. JAMA Oncol. doi: 10.1001/jamaoncol.2018.5543
  7. Bex A, Ljungberg B, van Poppel H, Powles T; European Association of Urology. The role of cytoreductive nephrectomy: European Association of Urology recommendations in 2016. Eur Urol. 2016;70(6):901-905.
  8. 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.
  9. Kassouf W, Sanchez-Ortiz R, Tamboli P, et al. Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology[RH1] . J Urol. 2007;178(5):1896-1900.