Kidney Cancer Journal 47
tients, found that delay in initiation of therapy was not
independently associated with overall survival. The conclusion:
in carefully selected patients, outcomes might
not be compromised with initial observation.
A retrospective analysis by Bimbatti et al,22 studying
52 patients with RCC over 9 years, examined whether
IMDC risk class, number of metastatic sites, and tumor
burden (TB) changed over time, whether these factors affected
survival and how using such data could influence
the decision about when it is appropriate to initiate systemic
therapy. TB was defined as the sum in millimeters
of the longest tumor diameter of each lesion.
Seen through the lens of IMDC prognostic classes, the
median time on AS was 20.4 months in the favorable risk
group, 17.8 months in the intermediate-risk group, and
5 months in the poor-risk group. Baseline IMDC class
was the only factor to independently predict time on AS.
An increased number of metastatic sites during AS and
an increase in TB adversely affected overall survival. The
“take-home” messages from Bimbatti et al are:
• AS could be considered a safe option in managing
selected patients with asymptomatic good- or inter-
mediate-risk status in oligometastatic RCC.
• An increase in TB during the AS time reflects a need
to consider initiating fist-line systemic therapy, based
on the post-surveillance overall survival results.
Do the results from Rini et al, Bimbatti et al and similar
findings suggest that AS is underutilized and should
be integrated more widely in the treatment algorithm?
An Editorial Commentary by Ficarra et al23 suggests not
necessarily. For these authors, AS is a cautionary tale, of
value in a well-selected subset of patients with indolent,
asymptomatic, and good-risk. They conclude that delaying
systemic treatment does not seem to have negative
consequences on overall survival but questions persist.
They suggest that there is a dilemma as to whether cancer
control in patients managed with an initial AS protocol
vs immediate systemic therapy is compromised,
and to what extent initial debulking is also critical. They
leave open the question whether AS in oligometastatic
RCC should be considered an option or an exception
until further studies clarify the risks and benefits.
SBRT: Widening the Net for Local Control
of Oligometastatic RCC
Advances in imaging and precision of modern radiation
delivery has enabled the development and adoption of
SBRT for the treatment of both primary tumors and
metastatic sites.24 High local control rates have been observed
with SBRT in RCC tumors once thought to be radioresistant,
and is increasingly utilized for treatment of
oligometastatic disease. In select de novo oligometastatic
and oligorecurrent patients, SBRT offers the potential
to delay the onset of a new line of systemic therapy that
may be associated with adverse side effects.24 Recent
studies have demonstrated the advancement of SBRT in
comparison to earlier studies of conventional fractionated
radiotherapy (CF-EBRT). Reports have suggested
that SBRT leads to greater and more durable radiographic
responses and improved local control compared to CFEBRT
with minimal toxicity.
In addition to the editorial commentary by Beckham
et al, recent reports have illustrated the integration of
SBRT into the treatment algorithm25-29 and have addressed
a broad spectrum of issues related to its use to
improve outcomes for enlarging or anatomically problematic
masses.28 In 2019, the National Comprehensive
Cancer Network (NCCN) included the use of SBRT for recurrent
and metastatic RCC into its guidelines.25 In their
meta-analysis of 28 studies, Zaorsky et al. found that
SBRT is safe and effective for RCC oligometastases, with
local control at 90% and any significant toxicity at 1%.
One of the caveats to emerge from this meta-analysis—
and confirmed by other studies—concerns the worse survival
rates observed among patients with intracranial
RCC oligometastases vs those with extracranial disease.
SBRT has the potential to promote an anti-tumor immune
response through multiple mechanisms, including
the promotion of neoantigen expression and activation
of cytotoxic CD8+ T cells. This effect has been explained
as dependent on type 1 interferon induction in the irradiated
tumor .25 Although hypothesis generating, the
concept that SBRT appears to be immunostimulatory for
historically radioresistant tumors argues for a plausible
biological rationale to combine stereotactic ablative radiotherapy
with immunotherapy. This point was enlarged
upon in the report by Dengina et al26 who also
explored the immunogenic aspects of RCC. In their report
on the use of extracranial SBRT with TKI or checkpoint
inhibitors, they offered further insights on the
mechanisms of action of stereotactic radiotherapy. The
clinical response in lesions outside of the radiation
field—known as abscopal effect—is worthy of further
study and has been previously noted. Overall, Dengina
et al suggest that SBRT can safely be administered to patients
concomitantly receiving TKI or checkpoint inhibitors.
The addition of SBRT to systemic therapy led to
a rapid regression of the target lesions in 13 of 177 subjects,
thus offering further proof of the benefit of such
localized therapy.
As SBRT continues to evolve and its use better delineated,
one of the underlying questions concerns its relationship
to cytoreductive nephrectomy. Singhet al30
pursued this issue in a single-arm feasibility study in patients
who underwent CN 4 weeks after SBRT. They
found that SBRT followed by nephrectomy was safe and
patients benefited from significant changes to their immune
status. Patient tumors had increased expression of
the immunomodulatory molecule calreticulin, tumor,
tumor-associated antigen, and a higher percentage of
proliferating T cells compared with archived RCC tumors.
Two phase II trials have been presented evaluating the
combination of SBRT and checkpoint inhibition. The
Nivolumab Plus SBRT in 2nd and 3rd Line Patients with
Metastatic Renal Cell Carcinoma (NIVES) Study suggested
the safety and tolerability of SBRT with the
nivolumab, an anti-PD-1 checkpoint inhibitor, with an
objective response rate (ORR) of 17.4%, a complete response
rate (CRR) of 1.4%, and disease control rate (DCR)
of 58%. Of note, the ORR and DCR were 26.9% and 82%
in irradiated sites of disease. However, the primary endpoint,
improvement in ORR from 25% to 40%, was not