Sequencing of Cytoreductive Nephrectomy
in Metastatic Renal Cell Carcinoma During
the VEGF-TKI and Immunotherapy Era
Abstract
The survival benefit of cytoreductive nephrectomy (CN)
was demonstrated in patients with metastatic renal cell
carcinoma (mRCC) in randomized control trials of interferon
alfa. Since 2005, the development of targeted therapies
with vascular endothelial growth factor tyrosine
kinase inhibitors (VEGF-TKIs) has prompted investigations
into the benefit of CN in patients treated with these
standard agents in mRCC. With the advent of immune
checkpoint inhibitors (ICIs) that have now been approved
as new first-line treatments in mRCC, the role of
CN in this population remains even more undefined. In
this review, we highlight seminal studies of CN in mRCC
patients treated with VEGF-TKIs. We also discuss early
evidence on the impact of CN in patients with mRCC in
the immunotherapy era. We end with a discussion on
factors that could potentially aid the selection of mRCC
candidates for CN.
Introduction
Renal cell carcinoma (RCC) is among the top 10 most
frequently diagnosed cancers in men and women worldwide
with >140,000 RCC-related deaths yearly.1 Although
the majority of RCC cases are diagnosed at a
localized stage, nearly one third of cases present with regional
or distant metastases where the 5-year survival is
53% for patients with locoregional (stage III) disease and
a dismal 8% for metastatic disease.2 Two randomized
control trials demonstrated the survival benefit of cytoreductive
nephrectomy (CN) followed by interferon alfa
over interferon alfa alone in patients with metastatic
RCC (mRCC) in the cytokine era.3,4 In a pooled analysis
of these studies including a total of 331 patients with
mRCC and primary tumors deemed resectable, the median
overall survival (OS) was 13.6 months for CN plus
interferon vs. 7.8 months for interferon alone (31% reduced
risk of death, P=0.002).5
56 Kidney Cancer Journal
Since 2005, the advent of targeted therapies involving
vascular endothelial growth factor (VEGF) tyrosine kinase
inhibitors (TKIs) and mammalian target of rapamycin
(mTOR) inhibitors led to a paradigm shift in
the systemic treatment of mRCC with improvements in
OS to nearly 40 months for targeted therapy in the contemporary
era compared to a median OS of 10 months
in the cytokine era.6,7 To provide level 1 evidence on the
role of CN for mRCC in the targeted therapy era, 2 randomized
controlled trials CARMENA and SURTIME were
conducted.8,9
CARMENA
The CARMENA (Cancer du Rein Metastatique Nephrectomie
et Antiangiogéniques) trial was a randomized,
multicenter, open-label phase III trial randomizing (1:1
fashion) 450 treatment-naïve patients with metastatic
clear-cell RCC to receive CN within 28 days of randomization
followed by sunitinib treatment (3-6 weeks after
nephrectomy) or sunitinib alone (50 mg daily for 4
weeks on, 2 weeks off) within 21 days of randomization.9
The primary endpoint was OS and 226 patients were randomized
to the CN plus sunitinib arm and 224 to the
sunitinib alone arm. At a median follow-up of 50.9
months (95% confidence interval or CI 44.0-56.9), the
sunitinib-alone group had a longer median OS (18.4
months, 95% CI 14.7-23.0) than those in the CN-sunitinib
group (13.9 months, 95% CI 11.8-18.3) in the intention
to-treat (ITT) population with a hazard ratio (HR)
for death of 0.89 (95% CI 0.71-1.10). Given that the
upper boundary of the 95% CI for the HR did not exceed
the fixed noninferiority limit of 1.20, sunitinib alone was
deemed not inferior to CN followed by sunitinib. In the
CN-sunitinib group, 55.6% and 44.4% were in the Memorial
Sloan Kettering Cancer Center (MSKCC) intermediate
risk and poor-risk groups, respectively, while in the
sunitinib-alone group, the corresponding values were
58.5% and 41.5%. In both intermediate-risk and poorrisk
groups, the median OS was longer in the sunitinibalone
group than in the CN-sunitinib group (23.4 vs.
19.0 months in the intermediate-risk subgroup and 13.3
vs. 10.2 months in the poor-risk group). Notably, 16 patients
(7.1%) did not undergo nephrectomy and 40
Jun Gong, MD
Department of Medicine
Division of Hematology and Oncology
Cedars-Sinai Medical Center
Los Angeles, California
Keywords: Cytoreductive nephrectomy, metastatic renal cell
carcinoma, VEGF therapy, TKI therapy, CARMENA trial, SURTIME
trial, IMDC risk criteria, ADAPT trial, immunotherapy.
Corresponding Author: Jun Gong, MD, Samuel Oschin Cancer Center,
8700 Beverly Blvd., Los Angeles, CA 90048.
Email address: jun.gong@cshs.org
link