Figure 2. A 66 year old male post right nephrectomy with recurrent tumor and metastatic renal
carcinoma. Axial fused Whole Body FDG PET CT Scan following intravenous administration of
9.7 mCi of 18-FDG reveal confluent metabolically active tumor in retroperitoneum in the
retrocaval region, para-aortic and aortocaval space.
value for CN. Abern et al9 employed the Surveillance,
Epidemiology, and End Results (SEER) database, describing
the primary outcome of OS in patients with metastatic
RCC. Out of 7,143 mRCC cases, they reported
that 37% underwent CN. Patients who underwent CN
were more likely to be younger, white, male, married,
and to have stage T3 tumors. Patients who underwent
CN had an improved one-year survival (61% vs 22%).
Although this report favored the role of CN in the management
of metastatic RCC, the authors acknowledged
limitations and confounding factors in the analysis. This
analysis was not able to control for prognostic variables,
the location or number or volume of metastatic sites
(shown by other studies to be of prognostic significance).
10,11 In addition, other prognostic factors, including
serum hemoglobin, lactate dehydrogenase (LDH),
calcium and albumin were also unavailable from their
dataset and could have varied between the groups receiving
CN or not.
Another study reported on a large and robust sample
cohort from the National Cancer Data Base reviewed between
2006 and 2013. The report by Hanna et al12 also
found an OS benefit when CN was combined with targeted
therapy: the median OS of CN vs non-CN patients
was 17.1 months vs 7.7 months respectively. CN was also
found to be associated with (Figures 3, 4) a lower risk of
any death (HR, 0.45, P<.001).
Two Pivotal Randomized Trials (the SURTIME and
CARMENA trials): Are They a Turning Point in
Debate Regarding CN?
The CARMENA Trial This phase 3, randomized study
attempted to delineate the value of CN and systemic therapy
in the era of targeted therapy – specifically sunitinib.
78 Kidney Cancer Journal
In this study, the median
OS was 18.4 months in the
sunitinib only arm versus
13.9 months in the CN/ sunitinib
arm. Thus, the CARMENA
trial did not support
the conclusions of previously
reported retrospective and database
studies of CN as it failed
to show an overall OS
benefit with CN in patients
treated with sunitinib therapy.
However, over the last
two years, the validity and application
of CARMENA’s results
have been questioned
based on widely ranging criticisms.
One of the criticisms is
related to this trial’s slow and
likely incomplete recruitment,
as noted in a report by
Arora et al.13 During 8 years of
accrual to this study, 450 patients
were enrolled at 79 centers,
considerably short of the
target of 576 patients. This
fact raised questions about
whether the recruitment process
was biased, especially since patients with a lower metastatic
burden were “selectively treated outside the
trial.” The extent to which the results from CARMENA
can be generalized to all patients with metastatic RCC
has also been scrutinized. For example, the 18.4-month
OS in the sunitinib arm is lower than in other recently
published studies.14 Arora et al further criticized CARMENA
because the trial recruited patients with a higher
number of metastatic sites than in the National Cancer
Data Base trial. There is a strong suggestion that candidates
for CARMENA (due to their lower metastatic burden)
underwent a nephrectomy outside the trial.
Perhaps most importantly, there was a sizeable degree
of crossover in the trial which utilized intention to treat
criteria. Specifically, 17% of patients who were randomized
to sunitinib alone actually underwent CN and 7% of
the patients in the CN arm did not undergo CN. IN addition,
he higher percentage of patients with advanced
disease in the CN/sunitinib arm(70% vs 51%) could have
also influenced outcomes.15
The SURTIME Trial This randomized phase 3 trial attempted
to evaluate whether a period of sunitinib therapy
before CN might improve outcomes in patients
with metastatic renal cancer compared with immediate
CN followed by sunitinib therapy. The objective of the
SURTIME trial was also to investigate whether pretreatment
with sunitinib before planned surgery improves
outcome by identifying patients with inherent resistance
to VEGF-TKI therapy who are unlikely to benefit from
CN. SURTIME also examined whether a deferred approach
to CN could reduce cancer-related morbidity, primary
tumor size, and neovascularization, which, in turn,
may decrease surgical risk and morbidity. Very impor-