Original Article
© JNCCN–Journal of the National Comprehensive Cancer Network | Volume 9 Number 9 | September 2011
997
Key Words
Carcinoma, renal cell, genetics, pathology, therapy, kidney neo-
plasms, non–clear cell renal cell carcinoma, clear cell renal cell
carcinoma
Abstract
Advanced renal cell carcinoma (RCC) is a heterogeneous disease
with variable histology, biology, and response to treatment. In
the past 5 years, 6 new agents have been approved for the treat-
ment of RCC, and many more are in clinical development. With
an ever-increasing number of treatment options, selecting among
them for a particular patient can be a daunting task for clinicians.
This article describes how treatment choice can be guided by the
disease setting and histology, as well as patient characteristics, co-
morbidities, and preference within the context of available data.
Results from clinical trials are combined with practical consider-
ations to make recommendations for first-line and subsequent
treatment of patients with clear cell and non–clear cell RCC.
These recommendations should supplement the current NCCN
Clinical Practice Guidelines in Oncology (NCCN Guidelines) for the
treatment of advanced RCC. (JNCCN 2011;9:997–1007)
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All other clinicians completing this activity will be issued a cer-
tificate of participation. To participate in this journal CME ac-
tivity: (1) review the learning objectives and author disclosures;
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Release date: September 6, 2011; Expiration date: September
6, 2012.
From the Department of Medical Oncology, Fox Chase Cancer Center,
Philadelphia, Pennsylvania
Submitted April 26, 2011; accepted for publication July 13, 2011.
The authors have disclosed that they have no financial interests, arrange-
ments, or affiliations with the manufacturers of any products discussed in
this article or their competitors.
Correspondence: Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center,
333 Cottman Avenue, Philadelphia, PA 19111-2497.
E-mail: elizabeth.plimack@fccc.edu
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National
Comprehensive Cancer Network
Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial
relationships.
AUTHORS AND CREDENTIALS
Elizabeth R. Plimack, MD, MS, Department of Medical Oncology, Fox
Chase Cancer Center, Philadelphia, Pennsylvania
Disclosure: Elizabeth R. Plimack, MD, MS, has disclosed no relevant
financial relationships.
Gary R. Hudes, MD, Department of Medical Oncology, Fox Chase Cancer
Center, Philadelphia, Pennsylvania
Disclosure: Gary R. Hudes, MD, has disclosed no relevant financial
relationships.
CME AUTHOR
Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial
relationships.
Selecting Targeted Therapies for Patients
With Renal Cell Carcinoma
Elizabeth R. Plimack, MD, MS, and Gary R. Hudes, MD, Philadelphia, Pennsylvania

Original Article
Plimack and Hudes
© JNCCN–Journal of the National Comprehensive Cancer Network | Volume 9 Number 9 | September 2011
998
Learning Objectives
Upon completion of this activity, participants will be able to:
• Describe currently available and new agents (approved
in the past 5 years) for the treatment of RCC
• Describe first-line therapy of metastatic clear cell RCC
• Describe second-line management of patients with
metastatic clear cell RCC
In the past 5 years, 6 new agents were approved for
the treatment of renal cell carcinoma (RCC). These
can be broadly categorized into 2 groups: vascular en-
dothelial growth factor (VEGF)–directed therapies
(sorafenib, sunitinib, pazopanib, and bevacizumab)
and mammalian target of rapamycin (mTOR) inhibi-
tors (temsirolimus and everolimus). With such a large
number of treatment options, selecting among them
for a particular patient can be daunting for clinicians.
This article describes how treatment choices can be
guided by the disease setting, histology, patient char-
acteristics and comorbidities, and patient preference.
Adjuvant or Neoadjuvant Therapy
for Localized Disease
Adjuvant therapy has been shown to improve surviv-
al in patients with breast and colon cancer. With the
advent of active targeted therapy for RCC, research-
ers have questioned whether treatment with targeted
agents in the postnephrectomy setting can prevent
recurrence. The first 2 adjuvant studies (ASSURE
and S-TRAC) have closed to accrual; however, as is
typical with adjuvant studies, results are expected to
take years to report. In the meantime, several other
adjuvant studies are open in both the United States
and Europe. The NCCN Clinical Practice Guide-
lines in Oncology (NCCN Guidelines) for Kidney
Cancer recommends adjuvant treatment be given in
the context of a clinical trial (in this issue; to view
the most recent version of these guidelines, visit the
NCCN Web site at www.NCCN.org).1 Adjuvant
treatment outside a clinical trial is not recommend-
ed until it can be supported by prospective data.
In select cases of locally advanced disease, surgical
resection with curative intent may be technically chal-
lenging because of tumor bulk or proximity to major ves-
sels. Data from several small series suggest that targeted
therapy can result in tumor shrinkage in the primary
tumor, sometimes enough to make surgery feasible.2–5
The largest reported experience in this setting is with
sunitinib, which has been shown to produce a mean of
10% to 20% shrinkage of the primary tumor, with ap-
proximately 90% of patients showing some degree of
tumor reduction while on therapy.3,5 Another potential
advantage of the neoadjuvant approach is the use of tar-
geted therapy as a “litmus test” for patients with bulky
local disease. If metastases appear during treatment with
targeted therapy, a technically challenging resection
may not be warranted because the goal of surgery would
no longer be cure but rather cytoreduction.
Metastatic Clear Cell RCC:
First-Line Treatment
Most patients with RCC for whom targeted thera-
py is considered have metastatic disease. Of these,
clear cell histology is the most common, accounting
for 80% of RCCs, and has the most data available.
Cytoreductive nephrectomy should be considered
for patients with clear cell histology and good per-
formance status who are appropriate surgical candi-
dates. This recommendation is based on 2 random-
ized trials conducted in the 1990s involving patients
treated with interferon.6,7 This paradigm is being re-
evaluated in the era of targeted therapy, and studies
are ongoing.8 In the NCCN Guidelines for Kidney
Cancer, 6 options are given for first-line treatment of
clear cell RCC, 4 of which are supported by category
1 data.1 Although all may be acceptable choices,
certain considerations may weigh in the decision to
choose one over another.
Stratifying Risk: Selecting Appropriate Treatment
for Poor-Risk Patients
The Memorial Sloan-Kettering Cancer Center
(MSKCC) risk criteria, first published in 1999 and
revised in 2002, categorize RCC into 3 risk catego-
ries: good, intermediate, and poor based on 5 clini-
cal characteristics: hemoglobin, serum calcium, lac-
tate dehydrogenase, performance status, and length
of disease-free interval (Table 1).9,10 The phase III
clinical trials supporting the approval of sorafenib,
sunitinib, bevacizumab plus interferon, and pazo-
panib included 10% or fewer patients with poor-risk
disease. The only agent that has been studied specifi-
cally in the poor-risk population is temsirolimus. In
the randomized 3-arm trial comparing temsirolimus
with temsirolimus plus interferon or interferon alone
in patients with poor-risk RCC, temsirolimus pro-
duced a 3.6-month improvement in median overall