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Figure 1. Duration of survival in combined SWOG and EORTC trails. Unadjusted survival curves for nephrectomy followed by interferon
[6]
vs. interferon alone for patients with synchronous mRCC. O: Observation; N: nephrectomy. From Flanigan et al. , J Urol March 2004.

Three years later, in 2014, Heng et al. published their results from the IMDC. Also retrospective in nature,
[12]
this study analyzed the overall survival benefit of cytoreductive nephrectomy in patients treated with
targeted therapies. Retrospective data were analyzed from patients at 20 international cancer centers from
Canada, the United States, Belgium, South Korea, Japan, Denmark, Greece, and Singapore. Included
patients diagnosed with mRCC and treatment with a VEGF or mTOR targeted therapy (sunitinib, sorafenib,
axitinib, bevacizumab, temsirolimus, pazopanib, or everolimus). In total, 1658 patients met inclusion
criteria, including 982 who underwent nephrectomy vs. 676 who did not. The median overall survival for
patients undergoing cytoreductive nephrectomy was 20.6 months vs. 9.6 months for those who did not have
surgery. Progression-free survival was also improved in the nephrectomy group, 7.6 months vs. 4.5 months.
As discussed in the prior study, when stratified by IMDC risk criteria, those poor-risk patients with multiple
adverse prognostic factors (> 3) did not seem to derive benefit from cytoreductive nephrectomy.

[13]
More recently, in 2016, Hanna et al. published a review of the National Cancer Database analyzing 15,390
patients with metastatic RCC treated with targeted therapy, 5374 (35%) of whom underwent cytoreductive
nephrectomy. Patients undergoing cytoreductive nephrectomy were younger (< 50 years) with minimal
comorbidities (Charlson comorbidity index 0). Meantime to death was 32.5 months for patients undergoing
nephrectomy vs. 14.9 months for those not undergoing surgery.

These are but three of the numerous retrospective studies undertaken after the advent of improved systemic
therapies aimed at defining the role of cytoreductive nephrectomy in the targeted therapy era. While
cytoreductive nephrectomy had been cemented in the treatment algorithm of patients with mRCC since the
immunotherapy era (1992-2004) based on level 1 data, all treating physicians had to rely upon these
retrospective data to decide if nephrectomy was still beneficial. While these studies were well-done and
provided valuable information, retrospective case-control studies suffer from nearly insurmountable
selection bias. Patients undergoing cytoreductive nephrectomy included in retrospective studies were likely
younger, healthier, and with better risk profile, which may skew the results to favor cytoreductive
nephrectomy.