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Cross et al. J Cancer Metastasis Treat 2021;7:55 https://dx.doi.org/10.20517/2394-4722.2021.99 Page 3 of 9

was overall survival with a secondary endpoint of tumor response to treatment. Similar to the EORTC
counterpart, the SWOG study showed a statistically significant improvement in overall survival in patients
undergoing cytoreductive nephrectomy, though the observed improvement in survival in the SWOG study
was less, 11 months vs. 8 months.

Three years later, in 2004, a combined analysis of both of the preceding randomized cytoreductive
[6]
nephrectomy trials was published by Flanigan et al. in The Journal of Urology. This combined effort by
SWOG and EORTC analyzed the combined 331 patients randomized in both studies to upfront
cytoreductive nephrectomy followed by interferon alfa vs. interferon alfa monotherapy. The primary
endpoints of overall survival and secondary endpoints of response to therapy were evaluated. The combined
analysis showed an overall median survival of 13.6 months for patients undergoing nephrectomy followed
by interferon alfa vs. 7.8 months for interferon alone. It represented a 31% decrease in the risk of death in
the surgery arm. The Kaplan-Meier estimate of 1-year survival was 51.9% in the study group (nephrectomy
plus interferon) vs. 37.1% in the control group (interferon alone). Figure 1 shows the unadjusted survival
curves for the 2 treatment regimens.

While these trials are mainly considered from a historical perspective in the current treatment landscape of
patients presenting with upfront mRCC, their importance cannot be overstated, as they cemented
cytoreductive nephrectomy as a part of the treatment algorithm for patients with synchronous mRCC for
nearly 20 years. They were the only randomized level 1 data on which treating physicians had to rely on
making treatment decisions.

CHANGING LANDSCAPE OF SYSTEMIC THERAPY
In the mid-2000s, an improved understanding of the molecular pathways of RCC carcinogenesis led to the
FDA approval of several new targeted therapies, including vascular endothelial growth factor neutralizing
[7,8]
antibodies, tyrosine kinase inhibitors, and mammalian target of rapamycin inhibitors . It led some
physicians to question the continued need for upfront cytoreductive nephrectomy prior to initiation of
systemic therapy, particularly in light of these dramatic improvements in the systemic treatment of these
patients.

In response to this shift away from interferon and IL-2-based immunotherapy toward systemic therapy
targeting the biology of RCC tumorigenesis, numerous multi-institutional retrospective trials were
undertaken to evaluate the benefit of cytoreductive nephrectomy again. While there are far too many
retrospective studies to cover concisely in this review, a few warrant discussions.

[9]
In 2011, Choueiri et al. published a multi-institutional retrospective trial from 7 different oncology
treatment centers across the United States and Canada, analyzing overall survival in 314 patients with
metastatic RCC receiving VEGF-target therapy with either sunitinib, sorafenib, or bevacizumab. Of the 314
patients included in the analysis, 201 underwent cytoreductive nephrectomy, and 113 did not. The median
time from surgery to the start of targeted therapy was 5 months. Not surprisingly, patients who underwent
cytoreductive nephrectomy were overall younger with better performance status. On univariable analysis,
cytoreductive nephrectomy was associated with a median overall survival of 19.8 months compared to 9.4
months for patients who did not undergo surgery. On multivariable analysis, patients with poor-risk criteria
based on Memorial Sloan Kettering (MSKCC) and International Metastatic RCC Database Consortium
(IMDC) criteria [10,11] and those with poor performance status (Karnofsky performance status < 80) seemed to
have marginal survival benefit from cytoreductive nephrectomy.