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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 5 of 9

CONTEMPORARY CYTOREDUCTIVE NEPHRECTOMY TRIALS
In response to the lack of high-quality data to guide treatment decisions regarding cytoreductive
nephrectomy in patients receiving VEGF and mTOR targeted therapy, prospective clinical trials evaluating
cytoreductive nephrectomy were sorely needed. CARMENA and SURTIME were two randomized
controlled trials initiated in 2010 to investigate the necessity of cytoreductive nephrectomy in the era of
VEGF tyrosine kinase inhibitors. Each of these warrants in-depth discussion.

SURTIME
The first of these two trials, the SURTIME (Immediate Surgery or Surgery After Sunitinib Malate in
Treating Patients With Metastatic Kidney Cancer) trial, was jointly conducted by the EORTC
GenitoUrinary Cancer Group, the National Cancer Research Institute Renal Clinical Studies Group/Wales
Cancer Trial Unit (United Kingdom), and the Canadian Uro-Oncology Group beginning in 2010 . The
[14]
open-label multicenter trial randomized patients 1:1 between immediate cytoreductive nephrectomy
followed by sunitinib therapy vs. treatment with 3 cycles of sunitinib followed by restaging at 16 weeks
followed by cytoreductive nephrectomy. In the case of progressive disease, proceeded decision with
nephrectomy was left at the discretion of each investigator.

The study had a goal accrual of 450 patients but fell well short of that goal, randomizing 99 patients over 6
years at 19 institutions throughout Europe and Canada. The primary endpoint was progression-free survival
(PFS), but this had to be altered to PFS at 28 weeks due to poor accrual. Fifty patients were randomized to
immediate nephrectomy vs. 49 to deferred nephrectomy. The median follow-up was 3.3 years. Patients were
predominantly MSKCC intermediate-risk (88%). The 28-week progression-free rate was 42% in the
immediate surgery group vs. 43% in the deferred surgery arm [Figure 2].

Although the study did not meet its primary endpoint, the investigators did note a difference in overall
survival, which served as a secondary endpoint. Patients in the deferred nephrectomy group had an overall
survival of 32 months, compared with 15 months for those in the immediate nephrectomy group. While the
study is likely underpowered to prove that delayed nephrectomy is beneficial, we can surmise that with the
TKIs, there will be patients who progress through systemic therapy and are clearly not going to do well with
upfront surgery. A course of upfront systemic therapy may identify these patients, and they can be spared
the morbidity and recovery of cytoreductive nephrectomy.

CARMENA
Parallel to SURTIME, the CARMENA trial (Cancer du Rein Metastatique Nephrectomie et Antiangiogé
niques), a phase 3 non-inferiority trial, was conducted between 2009 and 2017 at 79 centers, led by
[15]
European investigators . In this trial, 450 patients with confirmed metastatic clear-cell RCC and ECOG
performance status of 0-1 were randomized 1:1 to undergo nephrectomy and then receive sunitinib or to
receive sunitinib alone. All patients had MSKCC intermediate-risk (one or two prognostic factors) or poor-
risk disease (three or more prognostic factors). The primary endpoint of the trial was overall survival.

After about 50 months of follow-up, an interim analysis of the intention-to-treat population showed median
OS times of 18 months in the sunitinib-only group vs. 14 months in the cytoreductive nephrectomy group.
Based on this interim analysis and the trial’s slow accrual, the decision was made to close the trial early
[Figure 3].

One of the main criticisms of the study was that many of the patients in the CARMENA trial were not
treated as planned. In the cytoreductive nephrectomy arm, 7% of patients did not receive nephrectomy, and