EURURO Vol. 73 No. 1

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grade 2, and performance status 1; or T4 stage and/or
nodal involvement and Fuhrman grade 3/4.
The additional 10 mo of follow-up data did not allow
detection of an improvement in OS with sunitinib, but no
detrimental effect on OS should be expected. The authors
argue that the study population is underpowered and that
OS data are not mature 9 yr after initiation of the study,
given that the life expectancy after nephrectomy in locally
limited but high-risk RCC is nearly 40% at 10 yr Therefore
the authors conclude that given the challenges of measuring
survival prolongation for diseases for which many subse-
quent therapies are available or survival is long, adjuvant
sunitinib should be approved on the basis of the DFS benefit.
S-TRAC and the other adjuvant trials with VEGF inhibitors
in ccRCC have raised several questions concerning the
generalized approval of an adjuvant treatment. As the
principal mode of action of these VEGF inhibitors is limiting
the blood supply to tumor masses, the relevance of such
effects on micrometastatic disease remains unclear and may
not depend on angiogenesis for viability. This is reflected by
the heterogeneous outcomes observed among these trials.
Furthermore, it has been shown that VEGF inhibition in
metastatic ccRCC is a short-lived effect, followed by
progression after treatment discontinuation or even the
development of resistance. Therefore, we do not know the
optimal duration of adjuvant treatment for high-risk
disease. Is it a finite period of time or should patients be
treated for life? Another consideration is whether temporal
or indefinite treatment is acceptable given the high rate of
toxicities associated with VEGF inhibition and the related
costs. It is true that VEGF inhibitors may be more acceptable
than other antitumoral agents, but patients with no residual
disease [7_TD$DIFF]are [8_TD$DIFF]less willing to accept the side effects of
prolonged adjuvant therapy[9_TD$DIFF] than patients with incurable
metastases. For example, patients with adjuvant sunitinib
in S-TRAC reported more skin toxicities than patients with
metastatic disease on sunitinib (16% vs 5%)
Patients with a high risk of relapse will be more likely to
accept an effective adjuvant treatment and associated
toxicities, maybe even life-long therapy, but accurate
patient selection is needed to define high-risk populations.
The clinical tools currently available for stratifying patients
are not satisfactory and partly explain differences in the
adjuvant trial results. We believe that future adjuvant trials
are urgently needed, including trials with novel compounds
such as checkpoint inhibitors given the promising
results for PD-1/PD-L1 inhibitors in metastatic ccRCC
. However, the design of future studies should ideally
be guided by molecular signatures to treat only the patients
who are most likely benefit to from the adjuvant therapy.
Despite the positive message of the S-TRAC study,
conflicting results from the other adjuvant trials underscore
the current limitations of these trials conceived in the era of
stratified medicine. We are now advocating precision
medicine, so research on disease pathophysiology and
optimal patient selection guided by molecular markers are
indispensable to further the promising prevention of
metastatic RCC in patients with high-risk disease.
Conflicts of interest: The authors have nothing to disclose.
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[10]
E U R O P E A N U R O L O GY 7 3 ( 2 0 18 ) 6 9 – 7 0 70