EURURO Vol. 71 No. 5

695 844

Platinum Opinion
Adjuvant Treatment of High-risk Renal Cell Carcinoma:
Leaving the Desert?
Nils [5_TD$DIFF]Kroeger Arnulf Stenzl Martin Burchardt Jens Bedke
a Department of Urology, Ernst[1_TD$DIFF]-Moritz-Arndt-University, Greifswald, Germany; bDepartment of Urology, Eberhard Karls University, Tu¨bingen, Germany
Surgery is the gold standard treatment for patients with
localized and locally advanced renal cell carcinoma (RCC)
. However, up to 30% of RCC patients will ultimately
experience disease recurrence Despite the possibility of
identifying high-risk RCC using clinical and molecular
classification tools,[2_TD$DIFF] there has not been any effective way
to treat patients with high-risk RCC with adjuvant agents to
prevent disease relapse. In the past, several trials with
mainly unspecific (IL-2 or IFN-a) immunology-based
treatment approaches have failed to improve disease-free
survival (DFS) or overall survival (OS) .
Since 2006, tyrosine kinase inhibitors (TKIs) have
dramatically improved progression-free survival (PFS)
and OS among patients with metastatic RCC. Up to now,
TKI treatment has not been available for adjuvant therapy
following nephrectomy. The first trial by Haas et al.
(ASSURE; NCT00326898) used sunitinib and sorafenib in
comparison to placebo in patients with intermediate- to
high-risk RCC according to the University of California–Los
Angeles Integrated Staging System[6_TD$DIFF] and was not restricted to
any RCC subtype . The primary endpoint did not differ
between the groups, with[7_TD$DIFF] a median DFS of 5.8 [8_TD$DIFF](yr[9_TD$DIFF]) for
sunitinib (hazard ratio [HR] 1.02, 97.5% confidence interval
[CI] 0.85–1.23; p = 0 8038), 6.1 yr for sorafenib (HR 0.97,
97.5% CI 0.80–1.17; p = 0 7184) and 6.6 yr for placebo. The
authors concluded that antiangiogenic therapy in the
adjuvant setting for patients with primary resected RCC
is not advised, as the underlying biology of disease
recurrence in RCC is probably independent of angiogenesis
.
Most recently, Ravaud et al published results for a
phase 3 trial (S-TRAC; NCT00375674) that investigated
administration of sunitinib versus placebo in the adjuvant
setting for clear-cell (cc)RCC patients with locoregional
high-risk disease ( T3 and/or N1–2). The [3_TD$DIFF] primary outcome[10_TD$DIFF]
was DFS as assessed via centralized review was reached,
with[7_TD$DIFF] a DFS of 59.3% and 51.3% in the sunitinib and placebo
groups, respectively, at 5 yr, with 113 (36.6%) and 144
(47.1%) disease relapses. The median DFS was 6.8 yr (95% CI
5.8 to not reached) in the sunitinib group and 5.6 yr (95% CI
3.8–6.6) in the placebo group. This difference resulted in a
24% lower chance of disease relapse (HR 0.761, 95% CI
0.594–0.975; p = 0.030) for patients treated with sunitinib
. This is the first report of a DFS advantage in high-risk
ccRCC[11_TD$DIFF] after adjuvant treatment. Will the data from the S-
TRAC trial lead to a paradigm shift in adjuvant treatment for
RCC patients?
The ASSURE and S-TRAC trials have fundamentally
different results. Some explanations discussed by Ravaud
et al include higher maximum dose reductions in
ASSURE than in S-TRAC (25 vs 37.5 mg), different patient
populations (RCC vs ccRCC), and different assessment
methods (centralized vs investigator assessment). As
demonstrated inmetastatic RCC, higher dosages of sunitinib
induce a better tumor response In addition, patients in
the S-TRAC trial were treated some years later than in the
ASSURE study, and uro-oncologists have[12_TD$DIFF] better learned how
to[4_TD$DIFF] handle side effects and to keep patients on treatment
over the past years. Different patient populations (eg ccRCC
only and high-risk disease) may have contributed to the
different results, but subgroup [13_TD$DIFF]analyses of the ASSURE data
revealed that neither sunitinib nor sorafenib demonstrated
any benefit over placebo in these subcohorts.
The mode of action of TKIs is cytostatic rather than
cytotoxic, as demonstrated in preclinical tumor models and
as known from treatment of RCC patients TKIs are not
only antiangiogenic agents, although they are directed
against the VEGF receptor. VEGF receptors are also
ava ilable at
journal homepage:
* Corresponding author. Department of Urology, University Hospital Tu¨ bingen, Hoppe-Seyler-Strasse 3, 72076 Tu¨ bingen, Germany. Department of
Urology, University Medicine Greifswald, F. Sauerbruch Strasse, 17475 Greifswald, Germany. Tel. +49 38 34865979.
E-mail addresses: (N. Kroeger), (J. Bedke).
0302-2838/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.