Kidney Cancer Journal 57
(17.7%) never received sunitinib. In the sunitinib-alone
group, 11 patients (4.9%) never received sunitinib and
38 (17.0%) underwent subsequent nephrectomy a median
of 11.1 months after randomization for the control
of symptoms.
SURTIME
The SURTIME (Immediate Surgery or Surgery After Sunitinib
Malate in Treating Patients With Metastatic Kidney
Cancer) was originally a randomized, multicenter, openlabel
phase III trial conducted during a similar time period
as CARMENA that randomized (1:1 fashion) a total
of 99 patients with untreated, clear-cell mRCC to immediate
CN followed by sunitinib (50 mg daily 4 weeks on,
2 weeks off) or 3 cycles of sunitinib followed by CN (sunitinib
was stopped day before nephrectomy) and resumption
of sunitinib (delayed CN arm) (8). Sunitinib was
started in both arms 4 weeks after surgery, and in the case
of systemic progressive disease (PD) in the deferred CN
arm, CN was not recommended and left to the discretion
of the investigator. The primary endpoint was the 28-
week progression-free rate (PFR). Of note, the trial was
originally powered for 458 patients, but suffered from
poor accrual resulting in a downsizing to 98 patients. At
a median follow-up of 3.3 years (range 0-6.2 years), a
total of 87 (88%) met MSKCC intermediate risk criteria,
and the 28-week PFR in the ITT population was 42%
(90% CI 30-55%) in the immediate CN arm vs. 43% (90%
CI 31-56%) in the deferred CN arm (1-sided Fisher test
p=0.61). The PFS HR for deferred vs. immediate CN was
0.88 (95% CI 0.56-1.37, P=0.57), while for OS the HR for
deferred vs. immediate CN was 0.57 (95% CI 0.34-0.95,
P=0.03). The median OS was 32.4 months (95% CI 14.5-
65.3 months) in the deferred CN arm vs. 15.0 months
(95% CI 9.3-29.5 months) in the immediate CN arm. In
the per-protocol population, OS was higher in the deferred
CN arm than the immediate CN group (HR 0.71,
95% CI 0.40-1.24), but the difference was not statistically
significant (P=0.23).
Delayed Cytoreductive Nephrectomy
The results of SURTIME, when placed in the context of
CARMENA, appear to support that upfront CN does not
result in additional survival benefit with potential to
even be harmful in patients with primary clear cell
mRCC who require treatment with sunitinib. Instead,
there was evidence to suggest that deferred CN conferred
a greater survival benefit than immediate CN, particularly
in those who are MSKCC intermediate risk. SURTIME,
however, suffered from poor accrual and was
ultimately grossly underpowered and therefore its results
should be considered exploratory. To further provide evidence
in support of deferred CN in mRCC, 2 large studies,
albeit retrospective, using prospectively collected
data were recently conducted.10,11
The first was a retrospective pooled analysis of 3 single
arm prospective phase II studies (12-14) and n=20 patients
from the deferred CN experimental arm of
SURTIME.11 The goal was to compare patients with
MSKCC intermediate-risk primary clear cell mRCC receiving
presurgical VEGF-TKIs (sunitinib or pazopanib)
followed by delayed CN in the absence of systemic PD
vs. upfront CN followed by VEGF-TKIs where treatmentnaïve
patients received VEGF-TKIs 12-18 weeks prior to
planned CN. This deferred CN cohort was compared to
a European upfront CN cohort from 4 centers planned
to receive VEGF-TKI after surgery between 2006-2016.
The pooled deferred CN included 189 patients (57% received
sunitinib and 43% pazopanib) where 144 (76%)
patients were MSKCC intermediate risk and 42 (22%)
poor risk. From 244 patients who received upfront CN,
a final 149 patients were included after excluding favorable
risk and non-clear cell mRCC. Of these, 131 patients
(88%) were intermediate risk and 18 (12%) were poor
risk, while the majority (76%) of patients received sunitinib.
For intermediate-risk patients, OS in the deferred
CN cohort was 33.0 months (95% CI 25.0-51.0) vs. 22.8
months (95% CI 17.9-30.6) in the upfront CN cohort
(HR for death 0.72, 95% CI 0.52-0.996, P = 0.047). In the
overall cohort, OS was 24.3 months (95% CI 20.8-34.8)
vs. 18.4 months (95% CI 14.4-26.9, P=0.09) in the deferred
CN and upfront CN arms, respectively. Notably,
66 (35%) patients in the deferred CN cohort did not undergo
CN (24% in the intermediate-risk and 52% in the
poor-risk group), while following nephrectomy in the
upfront CN group, 34 MSKCC intermediate-risk patients
(25.9%) had a short cancer-specific survival of <6 months
with 10 (7%) never going on to receive a VEGF-TKI, 8
due to rapid PD.
To further evaluate the benefit of deferred CN in
mRCC using International mRCC Database Consortium
(IMDC) risk criteria, a retrospective analysis of the
prospectively maintained IMDC database was conducted
for patients with mRCC diagnosed between 2006-2018
across 33 international centers (10). Patients with mRCC
whose first systemic therapy was sunitinib were included
whereas patients were excluded if first treatment (sunitinib
or upfront CN) occurred >12 months after diagnosis,
patients were on surveillance for >6 months after
upfront CN (i.e., sunitinib given >6 months after upfront
CN), and timing of deferred CN was unknown. Patients
were stratified by receipt of upfront CN followed by sunitinib,
sunitinib alone, or deferred CN (defined as any CN
after receipt of upfront sunitinib) with primary outcome
being OS. A final 1541 patients with newly diagnosed
mRCC were included, 805 received upfront CN followed
by sunitinib, 651 received sunitinib alone, and 85 received
sunitinib followed by delayed CN at a median of
7.8 months (interquartile range or IQR 4.8-12.6) from
the date of initiation of sunitinib. A majority 85% were
clear-cell with 40% of cases being IMDC poor-risk.
With a median follow-up from first treatment initiation
of 25 months (IQR 10-49), the median OS for patients
treated with sunitinib alone, CN followed by
sunitinib, and sunitinib followed by CN were 10 (IQR 4–
20), 19 (IQR 9–46), and 46 (IQR 25–67) months, respectively.
On multivariable analysis, upfront CN followed
by sunitinib was significantly associated with improved
OS vs. sunitinib alone (HR 0.60, 95% CI 0.53-
0.68, P<0.001), as did deferred CN vs. sunitinib alone (HR
0.45, 95% CI 0.33-0.60, P<0.001. Among CN-treated patients,
deferred CN was associated with improved OS vs.
upfront CN followed by sunitinib (HR 0.52, 95% CI 0.39-
0.70, P<0.001). Similar findings were seen with time to