EURURO Vol. 73 No. 1

Platinum Opinion

New Insights into Adjuvant Renal Cell Carcinoma Treatment with

Vascular Endothelial Growth Factor Inhibitors: What Have We

Learned So Far?

Bernard Escudier

a , * , Michael Staehler b

Gustave Roussy Cancer Institute, Villejuif Cedex, France;

Department of Urology, University of Munich, Klinikum Grosshadern, Munich, Germany

The incidence of renal cell carcinoma (RCC) has increased

worldwide by

30% during 1990

–

2013

[1]

and continues to

contribute to the global burden of cancer. Owing to

improvements in imaging and subsequent diagnosis, this

rise in RCC incidence has largely been due to the increased

diagnosis of locoregional disease. Locoregional disease is

typically treated with surgery, followed by observation.

Overall, 27.6% of patients undergoing curative surgery for

nonmetastatic RCC will have tumour recurrence within 5 yr

[2]

. Surveillance protocols are variable, and there has been

intensive research to better differentiate between patients

with low-risk tumours that will have a largely indolent

course and those with tumours that are more aggressive

and more likely to recur.

Accordingly, several risk scores based on clinical features

such as tumour stage and Fuhrman grade have been

identified and clinically validated, including the Mayo clinic

stage, size, grade, necrosis (SSIGN) and University of

California Los Angeles Integrated Staging System (UISS)

scores

[2,3]

. More recently, molecular scores, such as those

based on gene expression, have also been developed and

validated

[4]

. The commonly used UISS score, based on

tumour, node, metastasis stage, Fuhrman grade, and Eastern

Cooperative Oncology Group performance status, has

shown vast discrepancy in the 5-yr recurrence rate between

low-risk tumours (at 9.6%) and high-risk tumours (at 58.1%)

[2]

Awareness of this variability in recurrence between

high-, intermediate- and low-risk patients has prompted

research into adjuvant treatments that could prevent

recurrence by abolishing oligometastatic disease. This is

especially important in high-risk patients and currently

represents an unmet therapeutic need. Following the

success of translating effective treatments in the metastatic

setting to the adjuvant setting in tumour types such as breast

cancer and gastrointestinal stromal tumours

[5]

, this

approach has been investigated in RCC. However, despite

the established efficacy and availability of several treatments

in the metastatic setting, trials with agents of the pre-

vascular endothelial growth factor (pre-VEGF) era in the RCC

adjuvant setting failed to meet their primary endpoint

[6]

. Subsequently, despite the success of paradigm-changing

VEGF inhibitors in metastatic RCC, anticipation of the results

of trials with these agents in the adjuvant setting was

tempered by the failure of antiangiogenic treatments in

other diseases, such as breast and colon cancer

[7] .

In this

context, the S-TRAC trial of sunitinib versus placebo in high-

risk patients with clear cell renal cell carcinoma met its

primary endpoint of improving disease-free survival (DFS)

in sunitinib versus placebo-treated patients

( Table 1 ) [8]

Together with the ASSURE trial (which did not meet its

primary endpoint) and the recently presented PROTECT trial,

these results have reignited the debate around efficacy of

VEGF inhibitor adjuvant treatment in RCC

[9,10] .

On the surface, ASSURE, S-TRAC, and PROTECT may seem

similar: all enrolled patients with RCC and treated patients

with VEGF inhibitors. On closer inspection, however, there

are numerous distinctions between these trials, including

study design and conduct. Three of the key differences are

patient characteristics (including tumour histology and

recurrence risk), assessment of progression (blind indepen-

dent review vs investigator review), and dosing

( Table 2

With respect to patient inclusion criteria, ASSURE

enrolled patients with any histological subtype of RCC,

whereas PROTECT and S-TRAC limited inclusion to clear cell

histology only

( Table 2 )

. Clear cell RCC comprises 90% of all

E U R O P E A N U R O L O GY 7 3 ( 2 0 18 ) 1 – 3

ava ilable at

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journal homepage:

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* Corresponding author. Department of Oncology, Gustave Roussy, 114 rue Edouard Vaillant, Villejuif, France. Tel.

+331 4211 5410

E-mail address:

escudier@gustaveroussy.fr

(B. Escudier).

http://dx.doi.org/10.1016/j.eururo.2017.08.020