The Landscape of Adjuvant Therapy:
A Controversy in Search of a Consensus
umerous studies have taken aim at what still appears
to be a moving target—optimal use of adjuvant therapy.
The volume of literature on this treatment setting
has grown rapidly in the past several years and ongoing
studies will soon add to the wealth of information—often discordant—
on the clinical dilemma in this disease space. A review
of the key studies suggests overarching issues and the
salient questions still to be addressed. Studies of immune
checkpoint inhibitors provide a potential path forward.
Clinical decision making in the adjuvant therapy setting
for renal cell carcinoma (RCC) remains challenging. Despite
a dramatic evolution in therapy that has ushered in
novel approaches in metastatic disease with the promise
of improving outcomes in the adjuvant setting, it remains
a hotbed of controversy with the results of pivotal trials
decisively at odds with one another. The discrepancy in
the results of these trials has not helped to resolve the
unmet need for an effective strategy for high risk locoregional
kidney cancer. There is still clinical equipoise as to
whether targeted therapy improves outcomes significantly,
highlighted by the placebo comparator (as opposed
to sunitinib) in recently designed adjuvant trials.
The topic of adjuvant therapy for high risk localized RCC
remains a controversy in search of a consensus.
The 5-year survival rate is 53% for locoregional (stage
III) disease and 8% for metastatic (stage IV) disease.1 Overall,
locoregional disease is diagnosed in 16% of patients
with RCC, and the unmet need is plainly evident when
one considers that up to 40% of these patients have a relapse
with metastasis after nephrectomy.2,3 This relapse
risk has been assessed with validated models, including
the University of California Los Angeles Integrated Staging
System (UISS). One of the challenges in validating an
effective adjuvant therapy is the relatively long duration
88 Kidney Cancer Journal
to observe a benefit in disease-free survival: the S-TRAC
Trial, for example, required a median of 5.4 years follow
up before a benefit became apparent. Practically speaking,
this means that patients were enrolled to the study
from September 2007 to April 2011. The study was presented
at a scientific congress and published simultaneously
in October 2016, and sunitinib received FDA
approval in November 2017.
Initial Results in Cytokine Era Disappointing
Initial efforts to improve the prognosis in the adjuvant
setting began in the cytokine era. Prior to the approval of
targeted agents, IFN-alpha was used as a reference standard
for phase III studies in metastatic (mRCC). IL-2 was
approved for mRCC in 1992, and in comparison with
IFN-alpha, the agent had greater potential for inducing
durable responses (occurring in roughly 5-10% of treated
patients.4 However, the use of IL-2 has generally been restricted
to younger patients with good performance status
and more limited metastases.5
These earlier efforts in the cytokine era, however, met
with a lack of success.5 A study led by the Cytokine Working
Group, for example, is typical of the disappointing
results: the study was prematurely closed after an interim
analysis suggested futility for the primary endpoint—2-
year DFS. One of the earlier trials of a targeted approach
for adjuvant therapy was ARISER.6 It examined a carbonic
anhydrase IX inhibitor (girentuximab), a chimeric monoclonal
antibody that binds a cell surface glycoprotein
ubiquitously expressed in clear cell RCC. Adjuvant girentuximab
failed to improve disease-free or overall survival
vs placebo in a cohort of patients with fully resected,
high-risk clear cell renal cell carcinoma. Although ARISER
was disappointing, it signified a transition to a new generation
of studies and an evolution in the rationale for
treatment as cytokine therapy, at least in the adjuvant setting,
began to fade because of a lack of efficacy. As the cytokine
era was brought to a close by the emergence of
novel targeted therapies, signaling the beginning of the
targeted therapy era in 2006, investigations turned toward
the use of antiangiogenic strategies. The proven ef-
Michael R. Harrison, MD
Associate Professor of Medicine
Division of Medical Oncology
Duke Cancer Institute
Duke University Health System
Durham, North Carolina
N
Keywords: adjuvant therapy, locoregional, cytokine therapy, S-TRAC,
ARISER, ASSURE, PROTECT, disease-free survival, sunitinib, pazopanib.
Corresponding Author: Michael R. Harrison, MD, Duke Cancer Center
20 Duke Medicine Circle Durham, NC 27710
Email: michael.harrison@duke.edu
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