EURURO Vol. 73 No. 1

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1. Introduction
The prognosis for renal cell carcinoma (RCC) depends on
stage and on additional tumor and patient-specific risk
factors obtained at diagnosis. Nearly 20% of all patients with
RCC are diagnosed with locoregional disease , and up to
40% of these patients experience relapse after nephrectomy
and develop metastasis . Adjuvant therapies to
decrease relapse after nephrectomy are needed. A decision
to adopt a new adjuvant therapy in standard clinical
practice depends on consideration of a patient’s estimated
risk of recurrence, the clinical benefit of the additional
treatment, and the additive treatment related morbidity.
In the phase 3 S-TRAC study, sunitinib (50 mg once daily)
was administered on a 4-wk on/2-wk off treatment
schedule to patients with locoregional RCC at high risk of
tumor recurrence after nephrectomy . Adjuvant sunitinib
significantly improved disease-free survival (DFS) versus
placebo (median 6.8 vs 5.6 yr) according to blinded
independent central review (hazard ratio [HR] 0.76, 95%
confidence interval [CI] 0.59–0.98; p = 0.03) . At 5 yr, the
DFS rate gain was 8% in favor of sunitinib over placebo.
Overall survival (OS) data were not mature at data cutoff
. The most common (>5% of patients) grade 3,
all-causality adverse events (AEs) in the sunitinib group
were palmar-plantar erythrodysesthesia (16%), neutropenia
(8.5%), hypertension (7.8%), and thrombocytopenia (6.2%)
In the present study, we examined treatment outcomes
for subgroups of patients defined according to baseline
characteristics, and report here the sites of tumor recur-
rence in the two treatment arms. Updated OS data, based on
an additional 10 mo of follow-up, are also provided.
2. Patients and methods
2.1. Patients and treatment
As described previously key inclusion criteria in the S-TRAC study
included: nonmetastatic locoregional RCC defined as T3 or T4, no or
undetermined nodal involvement, or any T stage with local nodal
involvement; and for all patients, any Fuhrman grade and any Eastern
Cooperative Oncology Group performance status (ECOG PS). In addition,
patients had to have clear cell histology, no previous systemic therapy,
ECOG PS 2 before nephrectomy, no evidence of macroscopic residual
disease/metastasis (confirmed by blinded independent central review),
and treatment initiation within 3–12 wk after nephrectomy. Patients
were randomized to receive treatment with sunitinib or placebo for nine
cycles ( 1 yr) until recurrence, second cancer, significant toxicity, or
consent withdrawal.
2.2. Analyses
Disease recurrence was determined via centrally confirmed imaging
and/or histological findings. Prespecified subgroup analyses of DFS by
baseline risk factors were conducted using a Cox proportional hazards
model. The baseline risk factors were as follows: University of California
Los Angeles integrated staging system (UISS) criteria age; gender;
ECOG PS before first dose (as opposed to ECOG PS in risk groups before
nephrectomy); weight; and neutrophil-to-lymphocyte ratio). Post hoc
analyses of DFS by Fuhrman grade were also performed. Interaction
terms (treatment baseline factors) were analyzed to investigate
possible interactions between treatment and the baseline factors in a
univariate model. All subgroup analyses were exploratory, and no
adjustments for multiplicity were made.
Patients were followed for survival status (regardless of treatment
duration) every 12 wk until the time of the final analysis. OS was defined
as the time from the date of randomization to the date of death due to
any cause. In the absence of confi rmation of death, survival time was
censored at the last date on which the patient was known to be alive. OS
was estimated using the Kaplan-Meier method, and data were compared
using a two-sided log-rank test, stratifi ed by UISS risk group.
3. Results
3.1. Patients and treatment
Overall, 615 patients (n = 309 sunitinib; n = 306 placebo)
were enrolled from 97 sites, including 73 in Europe, 15 in
Asia, and nine in the Americas. Of these patients, 306 were
treated with sunitinib and 304 with placebo. Patient
characteristics, summary of treatment, and treatment
outcome are summarized in Overall, 71% of patients
received sunitinib for six or more cycles (8 mo) and 56%
completed the full 1-yr treatment. It should be noted
that the trial permitted a dose decrease to 37.5 mg/d, but
not to 25 mg/d. The most common reasons for treatment
discontinuation in the sunitinib group included AEs (28%),
relapse (7.2%), and patient refusal to continue treatment for
reason other than AEs (4.6%). In the placebo-treated
patients, the most common reasons for treatment discon-
tinuation included relapse (19%), AEs (5.9%), and patient
refusal to continue treatment for a reason other than
AEs (2.6%).
nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55– 0.99; p = 0.04),
NLR 3 (HR 0.72, 95% CI 0.54–0.95; p = 0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55–
0.98; p = 0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity
were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66– 1.28; p = 0.6);
67 and 74 patients died in the sunitinib and placebo arms, respectively.
Conclusions: A benefit of adjuvant sunitinib over placebo was observed across subgroups.
The results are consistent with the primary analysis, which showed a benefit for adjuvant
sunitinib in patients at high risk of recurrent RCC after nephrectomy.
Patient summary: Most subgroups of patients at high risk of recurrent renal cell carcinoma
after nephrectomy experienced a clinical benefit with adjuvant sunitinib.
Trial registration: ClinicalTrials.gov NCT00375674.
© 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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