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Platinum Opinion

Adjuvant Treatment of High-risk Renal Cell Carcinoma:

Leaving the Desert?




a , * ,

Arnulf Stenzl

b ,

Martin Burchardt

a ,

Jens Bedke

b , *


Department of Urology, Ernst


-Moritz-Arndt-University, Greifswald, Germany;


Department 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

[2] .

Despite the possibility of

identifying high-risk RCC using clinical and molecular

classification tools,


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-


) 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


and was not restricted to

any RCC subtype


. The primary endpoint did not differ

between the groups, with


a median DFS of 5.8




) for

sunitinib (hazard ratio [HR] 1.02, 97.5% confidence interval

[CI] 0.85–1.23;


= 0 8038), 6.1 yr for sorafenib (HR 0.97,

97.5% CI 0.80–1.17;


= 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


primary outcome


was DFS as assessed via centralized review was reached,



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



= 0.030) for patients treated with sunitinib


. This is the first report of a DFS advantage in high-risk



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

[6] .

In addition, patients in

the S-TRAC trial were treated some years later than in the

ASSURE study, and uro-oncologists have


better learned how



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


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

[7] .

TKIs are not

only antiangiogenic agents, although they are directed

against the VEGF receptor. VEGF receptors are also

E U R O P E A N U R O L O G Y 7 1 ( 2 0 1 7 ) 6 9 5 – 6 9 6

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).



2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.