Reality Check: What Is the Latest Paradigm for Cytoreductive
Nephrectomy vs Targeted Therapy in mRCC?
ave we reached an inflection point in the debate over
the role of cytoreductive nephrectomy (CN) in metastatic
renal cell carcinoma (RCC)? Controversy remains
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regarding the sequencing of CN and targeted therapy
in mRCC, and this controversy has been heightened with the
availability of new and more promising agents for the treatment
of metastatic renal cancers. The current literature also
points toward an improved understanding of the most appropriate
selection criteria for determining the best candidates
for CN using prognostic and predictive factors to optimize clinical
outcomes. Overall, there still remains a role for upfront
CN in appropriately selected candidates.
From the early landmark papers in the cytokine era to
recent analyses of retrospective observational data and
additional studies of CN in the era of targeted therapy,
the role of cytoreductive nephrectomy has undergone
virtually continuous reevaluation and considerable confusion
persists over the appropriate selection of surgical
candidates for cytoreductive nephrectomy. Without
question, the role of CN will continue to be modified by
the evolution of new and more effective systemic therapies
including the use of targeted therapies which have
dramatically reshaped the evidence-based paradigm of
advanced RCC treatment. Therefore, with the introduction
of these new systemic therapies, the widely accepted
rationale for the use of CN (either as an initial or
delayed therapy) has been reexamined and upgraded. In
addition, more information regarding the importance of
prognostic risk factors and predictive markers that are associated
with the value of CN has continued to evolve.
Within the last few years, the debate over CN in metastatic
RCC has been reassessed, largely due to the publication
of two trials (the CARMENA and SURTIME
trials). Furthermore, the debate over the validity of data
76 Kidney Cancer Journal
from these two trials has dominated the narrative on CN
and targeted therapy. Therefore, the controversy surrounding
these trials – particularly the limitations and
flaws of each – has become a focus of the recent literature.
The CARMENA trial, a phase 3 study, concluded that
overall survival (OS) in patients treated with sunitinib
alone is not inferior to those treated with CN followed
by sunitinib.1 Another pivotal trial, the European Organization
for Research and Treatment of Cancer
(EORTC) SURTIME trial explored a period of sunitinib
prior to CN as an alternative approach to immediate CN.
In this trial, the sequence of CN and sunitinib did not
affect the progression-free rate, but higher OS was seen
for deferred CN.2
These trials were also preceded by a long list of studies
on the use of CN, beginning in the cytokine era. A brief
chronicle of the highlights from these earlier studies offers
important perspectives on how the rationale for the
use of CN has evolved over the last 20 years. Furthermore,
a review of the findings from these earlier studies
offers a valuable vantage point from which to analyze
the results of more recent reports.
Cytoreductive nephrectomy in the Cytokine Era
At the beginning of the cytokine era, surgery was the
main treatment for localized RCC, but the use of nephrectomy
for metastatic disease was controversial and generally
considered not of value. Two pivotal studies from
the cytokine era addressed the question of whether combined
treatment with CN followed by systemic interferon
alfa lengthens time to progression and confers a
survival benefit in patients with metastatic RCC, and, secondarily,
whether nephrectomy before immunotherapy
increases the response rate to immunotherapy.3,4 In one
of these studies, by Flanigan et al, the median survival
of 120 eligible patients assigned to surgery followed by
interferon was 11.1 months, compared to was 8.1
months in 121 patient assigned to interferon alone.(4)
In patients with PS0, OS with CN was 17.4 mo vs. 11.7
mo without CN. This data was supported by another
study by Mickisch et al3 which demonstrated that time
Petar Bajic, MD
Fellow, Division of Urology
Rush University Medical Center
Chicago, Illinois
Robert C. Flanigan, MD
Professor, Department of Urology
Loyola University Chicago Stritch
School of Medicine
Maywood, Illinois
Keywords: cytoreductive nephrectomy, metastatic renal cell
carcinoma, targeted therapy, tyrosine kinase inhibitor, SURTIME,
CARMENA, interferon-alpha.
Corresponding Author: Petar Bajic, MD. Rush University Medical
Center, 1725 W Harrison St, Suite 352, Chicago, IL 60612
Email: pbajicmd@gmail.com
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