Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432

Seminar article
Targeted therapies for kidney cancer in urologic practice
Naomi B. Haas, M.D.a, Robert G. Uzzo, M.D.b,*
a
Department of Medical Oncology, Fox Chase Cancer Center, Temple University School of Medicine, Philadelphia, PA 19111, USA
b
Department of Urologic Oncology, Fox Chase Cancer Center, Temple University School of Medicine, Philadelphia, PA 19111, USA

Abstract
Renal cell carcinoma (RCC) is the most lethal of all genitourinary malignancies with nearly half of all patients presenting with locally
advanced or metastatic disease. Systemic treatments such as chemo- or immunotherapy have historically been associated with overall
response rates of 5–15% with very few durable responses. The basis of newly approved, more effective targeted therapies for metastatic
RCC are based on a fundamental knowledge of the molecular mechanisms that give rise to RCC. We review the clinical data for targeted
therapies in RCC and discuss the pertinent biology, side effects, and targets important to the practicing clinician. © 2007 Elsevier Inc. All
rights reserved.

Keywords: Kidney; Renal; Cancer; Targeted therapy; Angiogenesis

Introduction patients with early, localized disease, radical nephrectomy

Kidney cancer accounts for 3% of all solid tumors with
an estimated 36,160 new cases and 12,660 deaths per year,
making renal cell carcinoma (RCC) the most lethal of all
genitourinary neoplasms [1]. Like most malignancies, RCC
is a heterogeneous disease. This heterogeneity is reflected in
its presentation, pathology, molecular biology, and clinical
course. Although most patients are completely asymptom-
atic, many may exhibit a variety of symptoms at presenta-
tion, including any of the classic triad of flank pain, hema-
turia, and a palpable abdominal mass. Other nonspecific
presenting symptoms include fatigue, weight loss, or ane-
mia [2]. The widespread use of body imaging modalities has
led to an increased detection of incidental renal masses over the
last two decades [3]. Pathologic heterogeneity is illustrated by
several distinct histological subtypes, which exhibit varying
degrees of biological aggressiveness [4] and by variations in
tumor grade [5]. Emerging data from molecular analyses indi-
cate that RCCs express a variety of molecular tumor markers
and unique patterns of gene expression [6,7]. Clinically, the
disease behaves quite heterogeneously, with courses ranging
from indolent [8] to highly aggressive.
For most cases of RCC, surgical monotherapy or as part
of a multimodal approach remains the standard of care. In
* Corresponding author. Tel.: ⫹1-215-728-3501; fax: ⫹1-215-214-
1734.
E-mail address: Robert.Uzzo@fccc.edu (R.G. Uzzo).
is associated with a 5-year cancer-specific survival (CSS) as
high as 97% for pT1a lesions and 87% for pT1b tumors,
while nephron-sparing surgery (NSS) is associated with 5-
and 10-year CSS of 96% and 90%, respectively, for tumors
ⱕ4 cm [9]. Early data regarding laparoscopic partial ne-
phrectomy is similarly favorable, albeit with more limited
follow-up [10]. Minimally invasive ablative technologies
are emerging as potential treatment options for localized
RCC with excellent initial outcomes [11].
Unfortunately, 20% of patients have either locally ad-
vanced or node positive (N⫹) RCC while another 22% have
metastatic RCC (mRCC) at presentation [1]. Unlike the
outcomes in early localized disease, survival rates for N⫹
patients are poor and patients with mRCC are rarely cured
despite aggressive multimodal therapy. Classic cytotoxic
chemotherapy has repeatedly been shown to have little
effect in RCC [12,13]. Cytoreductive nephrectomy with
systemic immunotherapy is associated with few cures and
poor CSS outcomes with median survivals of 12 to 24
months [14]. Moreover, only 5% to 20% of patients with
mRCC respond to biological agents such as interferon
and/or interleukin [15,16]. A recent meta-analysis of 53
published randomized clinical trials that stratified 6,117
patients with advanced RCC to an immunotherapeutic agent
in at least one arm demonstrated an overall chance of partial
or complete response to immunotherapies of only 12.9%
compared with 4.3% in the placebo arm with a median
survival of 13 months [16].

1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.urolonc.2007.05.009
 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
Despite this rather poor track record in the management
of advanced RCC, recent advances in our understanding of
the molecular origins and pathways of RCC have led to the
development of more effective targeted therapies. Here we
review the molecular pathways that define the pertinent
therapeutic targets in RCC and the clinical data for these
new and promising approaches.
Genetics, pathways, and targets in RCC
Our understanding of the genetics and molecular pathways
in RCC is perhaps more advanced than for any other solid
malignancy. Unraveling these pathways has been possible only
through a series of sentinel observations made over the course
of the last three decades. Some knowledge of the basic biology
of RCC is essential for clinicians who manage this disease,
particularly in this new era of targeted therapies.
Basic molecular biology
The study of hereditary forms of RCC has been essential
in understanding the molecular origins of this disease. Iden-
tification of affected family pedigrees has led to the discov-
ery of germline mutations in genes that predispose individ-
uals to tumor development. To date, several inherited forms
of RCC have been described, including von Hippel Lindau
(VHL), hereditary papillary renal carcinoma (HPRC), the
Birt-Hogg Dubet syndrome (BHD), and hereditary leiomy-
oma renal cell carcinoma (HLRCC) [17]. The specific mu-
tations involved are distinct and may involve a loss of
function event (tumor suppressor) such as in VHL, or a gain
of function event (oncogene) as in HPRC. Most tumor
suppressor genes (including VHL) follow Knudson’s “two
hit” theory of tumorigenesis, which postulates that certain
genes encode proteins responsible for the negative regula-
tion of cell growth [18]. Mutations causing loss of function
of these proteins result in uninhibited cell growth and ma-
lignant transformation. Mutation of a tumor suppressor gene
on one chromosome is insufficient to induce tumorigenesis;
however, if both alleles are affected, tumor formation will
ensue. Because patients with familial cancers such as VHL
inherit a germline mutation, they only require one “hit” to
inactivate the remaining tumor suppressor gene. However,
patients with sporadic tumors require two “hits,” which
occur less frequently [19]. For this reason, patients with
familial cancers typically present at an earlier age with
multifocal and/or bilateral disease.
In contrast to mutations of tumor suppressors, mutated
proto-oncogenes (oncogenes) are responsible for gain of
function processes leading to increased cellular growth,
differentiation or proliferation through the accumulation of
normal signaling proteins, or creation of a mutant activating
protein as in the case of the met gene in HPRC [20]. Unlike
tumor suppressor genes, oncogenes may only require a
single mutating event to promote malignant transformation.
421
A small number of established genetic mechanisms are
responsible for the majority of known mutations in kidney
cancer related tumor suppressors or oncogenes. These in-
clude loss of heterozygosity (LOH), homozygous deletion,
rearrangement, point mutation, and promoter hypermethyl-
ation [21]. Loss of heterozygosity (LOH) involves the loss
of specific chromosomal regions that contain known or
presumptive tumor suppressor genes. LOH may be achieved
through a deletion, gene conversion, mitotic recombination,
translocation, chromosome breakage and loss, chromosomal
fusion or telomeric end-to-end fusions, or whole chromo-
some loss. LOH is a useful diagnostic marker because of its
high level of specificity for transformed cells. Point muta-
tions occur at the level of individual nucleotides where
substitutions, insertions, and deletions may result in frame-
shift, missense, and nonsense mRNA transcripts, and ulti-
mately truncated or non-functional proteins. Promoter hy-
permethylation is another point of genetic control and
counter-control [22]. In most somatic cells, the CpG dinu-
cleotide “islands” in the controlling or promoter region of a
gene are normally protected from methylation. Although
not a distinct genetic event, promoter hypermethylation is
an epigenetic event capable of silencing expression. One or
more of these mechanisms may be responsible for an inher-
ited (germline) or acquired (somatic) mutation in tumor
suppressor or oncogenes; however, LOH and hypermethyl-
ation are not typically associated with oncogenes.
Genetics of histologic subtypes of RCC
Clear cell carcinoma
The VHL gene was initially mapped to the short arm of
chromosome 3 (3p) by Seizinger et al. in 1988 following
reports of 3p deletions in sporadic RCC [23]. Genetic link-
age and in situ hybridization studies subsequently mapped it
to the 3p25 locus with LOH observed in greater than 95% of
cases of both early- and late-stage sporadic clear cell car-
cinoma [24]. Isolation of the VHL gene was ultimately
accomplished using a positional cloning strategy. It is now
known that differences in phenotype between patients with
VHL are due to variable mutations in a single gene rather
than multiple genes. Therefore, allelic heterogeneity rather
than locus heterogeneity is responsible for differences in the
clinical manifestations of VHL [25].
The VHL gene is small and is composed of 3 exons with
852 coding nucleotides [26]. Recent studies have demon-
strated somatic mutations of the VHL gene in approxi-
mately 50% to 75% of cases of sporadic clear cell renal
carcinoma [27]. Most sporadic clear cell cancers have either
point mutations of the VHL gene, hypermethylation of the
promoter region, or rearrangement of the gene. Notably,
genetic “hotspots” exist where individual mutations cluster,
principally at the 3= end of exon 1 and the 5= end of exon 3;
however, specific mutations at nucleotides 712 and 713
(codon 238) may account for nearly half of all mutations in
patients with VHL associated pheochromocytoma [26].
422 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432

Table 1
Molecular targets of current targeted therapies
Target Sunitinib Sorafenib AG013736 GW786034 ABT-869 PTK-787 Bevacizumab Temsirolimus/
[34] [35] [36] [37,38] everolimus

Vascular endothelial growth N N N N N N Y N

factor (VEGF)
VEGFR1 (Flt-1) Y N Y Y Y Y N N
VEGFR2 N Y Y Y Y Y N N
(Flk-1/KDR)
VEGFR3 (FLT-4) Y Y Y Y N N
Platelet derived growth factor N N Y N N N
receptor ␣
PDGFR-␤ Y Y Y Y Y N N N
c-kit Y Y Y Y Y N N N
FLT-3 Y Y Y U Y N N N
Receptor stem cell factor (SCF) Y N U U N N N
RET Y N Y N U N N N
FAK (focal adhesion kinase) N N N N U N N N
Basic fibroblast growth factor Y Y Y Y Y N N N
(b-FGF)
B-raf kinase N Y N N N N N N
c-raf kinase N Y N N N N N N
Mammalian target of rapamycin N N N N N N N Y
(MTOR)

Y ⫽ inhibits target; N ⫽ no inhibition; U ⫽ unknown.

Other genetic alterations in clear cell RCC include frequent
LOH of chromosomes 8p, 14q, and 9p (p16) among others
[28], suggesting other unknown tumor suppressors may be
important in renal cell tumorigenesis.
Papillary RCC
The most common genetic events associated with pap-
illary renal cancer are trisomy of chromosomes 7 and 17
and loss of Y [28]. Linkage analyses in families with
HPRC have localized the site for the HPRC gene to 7q31.
The HPRC gene has been identified as the c-met proto-
oncogene. Mutations of the met oncogene are perhaps
best studied in familial papillary renal cancer with occa-
sional mutations found in apparently sporadic cases. Ac-
tivating missense mutations in the important intracellular
signaling tyrosine kinase domain of the met gene may be
responsible for the gain of function events in papillary
renal carcinoma [29].
Chromophobe and collecting duct carcinoma
Chromophobe carcinoma is associated with multiple
chromosomal losses, most commonly monosomy of multi-
ple chromosomes, including 1, 2, 6, 10, 13, 17, and 21.
Frequent LOH of chromosomal arms 3p, 5q, 17p, and 17q
has been identified in chromophobe tumors as has loss of
chromosomes 1 (100% of cases), 2 (95% of cases), 6, 10,
13, 17, and 21 [30]. Van den Berg et al. found the more
frequent aberrations to be polysomy 7 and trisomies of 12,
16, 18, and 19, structural abnormalities on 11q and telo-
meric association involving chromosome 7 [31]. Genetic
deletions on chromosome 3 have been reported in 25% of
chromophobe tumors, but VHL gene mutations are absent
[32]. Therefore, the finding of LOH on numerous chromo-
somes supports the diagnosis of chromophobe carcinoma.
Collecting duct carcinomas or Bellini tumors are un-
common and clinically very aggressive cancers [33]. The
cytogenetics of three collecting duct cancers have been
characterized [32]. Each was consistently monosomic for
chromosomes 1, 6, 14, 15, and 22. Trisomy 17, tri- or
tetrasomy 7, or deletion of chromosome 3p were not ob-
served by cytogenetic analysis, thus differentiating these
tumors from papillary and clear cell carcinoma, respec-
tively. Monosomy of chromosome 1 appears to be a com-
mon finding in collecting duct carcinoma [33].
VEGF and pertinent pathways in RCC
Transcription and translation of mutated tumor sup-
pressor genes or oncogenes ultimately lead to malignant
transformation through aberrant protein expression.
While it was once believed that there was a precise
relationship between a gene and its protein product, it is
now known that through a process known as alternative
splicing, there is significant redundancy in gene expres-
sion such that one gene may be responsible for any
number of protein products and their isoforms. This has
hampered the study of cellular proteins responsible for
the malignant transformation of renal epithelium. None-
theless, a number of known proteins are believed to be
under the control of mutated genes implicated in the
development of RCC. These proteins represent rationale
targets for new therapies in RCC (Table 1).
Transformation may result from abnormal expression of
normal cellular proteins, normal expression of abnormal
 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
proteins, or both. Ordinarily, the VHL gene product (pVHL)
forms a multimer (VEC) with Elongin B and C, Cullin 2,
and Rbx1, which binds to the ␣ subunits of HIF1, a tran-
scription factor that allows cells to grow and survive under
hypoxic conditions. Under normal oxygen conditions, hy-
droxylation of HIF allows subsequent binding to VEC,
which marks it for ubiquitination and degradation. Under
low oxygen states or in the presence of mutated pVHL,
HIF1␣ cannot bind VEC, which is then free to translocate
into the nucleus and up-regulate production of its targeted
genes, including VEGF and other hypoxia inducible pro-
teins such as TGF-␣, PDGF-␤, CAIX (G250), and the
glucose transporter Glut-1 [39,40].
Many of the receptors for HIF inducible factors exhibit
tyrosine binding activity, which, upon ligand binding, acti-
vate downstream signaling pathways such as the Raf/MEK/
ERK pathway. This process of signal transduction through
the receptor forms a link between extracellular signals on
endothelial cells (VEGFR), pericytes (PDGFR), and tumor
cells (EGFR), and intracellular events contributing to cell
differentiation, proliferation, and survival [39]. Activation
of tyrosine kinases is a central event in the development of
RCC, a finding that is currently being exploited for thera-
peutic benefit.
Targeted therapy in RCC
More than 10 agents have recently demonstrated activity
in renal cell carcinoma, reflecting the success of identifying
targets in critical pathways. Most of these agents have been
studied in advanced RCC with clear cell features, as this is
the predominant subtype. Experiences in the non-clear cell
populations are anecdotal; however, Phase II trials for tar-
gets specific to pathways such as c-met are currently under-
way. The molecular targets important in clear cell RCC
include VEGF receptors, the mammalian target of rapamy-
cin, and the VEGF molecule itself (Table 1). Two novel
agents, sorafenib and sunitinib, have recently been approved
by the FDA for use in advanced renal cell carcinoma, with
more approvals anticipated.
Sunitinib
Sunitinib malate is an oral multitargeted tyrosine kinase
inhibitor with antitumor and antiangiogenic activity directed
through inhibition of PDGFR, VEGFR 1 and 3, KIT, FLT3,
the receptor stem cell factor (SCF), and RET [41– 45]. FDA
approval of this agent was based on Phase III data from
treatment of gastrointestinal stromal tumors and two Phase
II trials in metastatic RCC [46 – 48]. In the first RCC study,
63 patients received sunitinib orally at 50 mg daily for 4
weeks with a 2-week rest period. Entry criteria included
patients with measurable disease and disease progression on
one prior cytokine-based therapy. Ninety-two percent of
patients had prior nephrectomy. The results of this study
423
demonstrated 40% partial response as assessed strictly with
RECIST [49] criteria and a median duration of response of
8.7 months. The second Phase II RCC trial enrolled a
similar population of 106 patients with identical dosing and
demonstrated a response rate of 44% with one complete
response by RECIST, and a median time to progression of
8.1 months. A randomized Phase III trial of interferon-␣
(IFN-␣) (9 million units TIW) vs. the same schedule of
sunitinib in 690 patients with first-line metastatic clear cell
RCC (presented at ASCO in 2006) showed a median pro-
gression-free survival (PFS) of 47.3 weeks for sunitinib vs.
24.9 weeks for IFN-␣. The objective response rate (ORR)
by third-party independent review was 24.8% for sunitinib
vs. 4.9% for IFN-␣. Thus, this trial demonstrated a signif-
icant improvement in PFS and ORR for sunitinib over
IFN-␣ in first-line treatment of patients with metastatic
RCC and is now indicated as first-line treatment for meta-
static RCC [50]. Additional schedules are being explored. A
randomized trial of a continuous dose protocol of 37.5 mg
daily sunitinib vs. standard 50 mg daily for 4 weeks fol-
lowed by a 2-week rest is underway.
Sorafenib
Sorafenib is an oral small molecule inhibitor of multiple
kinases including raf, the VEGFR2 and VEGFR3 receptor
tyrosine kinases, PDGFR-␤, FLT-3, and c-kit [51]. A Phase
II randomized discontinuation trial of sorafenib 400 mg BID
in patients with solid tumors at five participating centers
was completed with over 484 patients accrued (202 patients
with RCC) [52]. All patients were treated in an open-label
fashion with sorafenib for 3 months and responses were
measured. Patients who had a reduction in tumor volume of
25% or more by WHO criteria continued on sorafenib in an
open-label fashion until disease progression. Patients with-
out progression and less than 25% reduction were random-
ized to continue sorafenib or initiate placebo in a double-
blinded fashion. These patients were restaged every 6
weeks. Upon progression, the treatment assignment was
unblinded and patients on the observation arm were permit-
ted to resume sorafenib until subsequent progression.
During the run-in period of this trial, 73 of 202 patients
had tumor shrinkage of 25% or more. Sixty-five patients
with stable disease at 12 weeks were randomly assigned to
take either sorafenib [32] or placebo [33]. At 24 weeks, 50%
of the patients on sorafenib had stable disease and 18% of
placebo treated patients remained stable with a significantly
longer median PFS of 24 weeks vs. 6 weeks (placebo) (P ⫽
0.0087). A randomized Phase III trial of sorafenib vs. pla-
cebo in patients with advanced RCC who had failed one
prior systemic treatment in the past 8 months was recently
completed, and results of the first 769 (384 sorafenib/385
placebo) of a total of 905 patients randomized were pre-
sented at ASCO 2005 [53]. Over 81% of patients in both
arms had received prior cytokine therapy and over 93% in
both arms had prior nephrectomy. Fifty-seven percent of
424 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
patients in each arm had greater than two organ sites of
metastatic disease. The median PFS was 24 weeks in the
sorafenib group compared with 12 weeks in the placebo
group. Discontinuation of drug occurred in 9% of patients
on sorafenib compared with 6% on placebo due to adverse
events. A Phase III trial of first-line sorafenib vs. IFN-␣ in
advanced RCC has recently been completed and is under-
going survival analysis. Anticipating these results, sor-
afenib, like sunitinib, has replaced interferon as first-line
therapy for advanced RCC.
Other multitargeted tyrosine kinase receptor inhibitors
Other agents, including AG013736 (axitinib) [34],
GW786034 (pazopanib) [50], ABT-869 [36], and AZD2171
[54] have demonstrated striking activity in Phase I or II
trials. The specific targets of some of these agents are
reviewed in Table 1. The use of multiple agents with mul-
tiple and overlapping targets has helped identify targets or
combinations of targets that may be most important for
disease control. Investigation of these agents is ongoing at
multiple sites worldwide.
Temsirolimus
Inhibition of the mammalian target of rapamycin
(mTOR/FRAP), a pathway with a serine/threonine kinase
that regulates mRNA translation, is another treatment strat-
egy in metastatic RCC [55,56]. Both the rapamycin analog
temsirolimus and rapamycin bind to FK506 binding protein,
which inhibits mTOR [57]. Temsirolimus’ interaction with
mTOR prevents phosphorylation of 4E-BP1 (PHAS-I), al-
lowing this protein to bind to eIF4E and thus inhibiting
mRNA translation. In addition to causing G1 arrest, there
are data that temsirolimus inhibits HIF by these mechanisms
[58 – 60].
A randomized Phase II trial of temsirolimus treating 111
patients with mRCC at 25, 75, or 250 mg i.v. weekly [61]
demonstrated a median survival of 15 months in patients
with intermediate and unfavorable Motzer risk factors [62].
This led to a Phase III trial of temsirolimus (25 mg i.v.
weekly) vs. temsirolimus (15 mg i.v. weekly) and interferon
␣ (6 million units subcutaneously TIW) vs. interferon alpha
alone (up to 18 million units subcutaneously TIW) first-line
in 626 patients with poor-risk features [63]. The results of
this trial presented at ASCO 2006 demonstrated a signifi-
cant improvement in median overall survival (OS) in pa-
tients in the temsirolimus arm alone of 10.9 months (vs. 7.3
months interferon alone) and less toxicity. This trial was the
first to demonstrate an improvement in OS for a targeted
agent in RCC. Since patients with predominantly poor risk
features were included in this trial, it is likely that this agent
will be further developed for this population. Indeed, data
exists that demonstrates expression of mTOR pathway tar-
gets in poor risk groups such as sarcomatoid subtype his-
tology [64].
Other mTOR inhibitors are currently in development or
in trial, including everolimus (RAD001). In a recent Phase
II study, 7of 25 patients with mRCC with some clear cell
features had partial responses to everolimus (RAD001)
[65]. Multiple everolimus and temsirolimus combination
trials are ongoing.
Bevacizumab
Although not currently approved by the FDA for use in
RCC, bevacizumab was the first antiangiogenic agent
shown to have activity in this disease. High-dose bevaci-
zumab (10 mg/kg), a neutralizing antibody to vascular en-
dothelial growth factor, improved PFS in a Phase II trial and
heightened awareness of the importance of the HIF-1 ␣
pathway and angiogenesis in the regulation of RCC. In a
randomized, placebo-controlled, double-blind trial, bevaci-
zumab was administered at 3 or 10 mg/kg every 2 weeks in
116 patients with mRCC (40 to placebo, 37 to low-dose
antibody, and 39 to high-dose antibody) [66]. A significant
prolongation in time to progression of disease based on
WHO criteria was observed in the high-dose antibody group
compared with the placebo group (4.8 vs. 2.5 months).
There was a small difference, of borderline significance,
between the time to progression of disease in the low-
dose antibody group (3.0 months) and that in the placebo
group. There were four partial responses (10% response
rate) and a prolongation of time to tumor progression in
patients who received the higher dose of bevacizumab.
This trial by Yang et al. also validated the use of pro-
gression free survival as an index of activity for the
antiangiogenic drugs in this disease [66].
Based on these findings, two randomized Phase III trials
of interferon with and without bevacizumab were completed
in Europe and the United States. These include the
AVOREN Phase III trial of IFN ␣-2a ⫹ placebo vs. IFN
␣-2a ⫹ bevacizumab in metastatic RCC results conducted
in Europe and the CALGB trial of interferon- ␣ or interfer-
on-␣ plus anti-VEGF antibody conducted in the United
States [67]. The results of these trials are expected to be
reported at ASCO 2007.
Toxicities of targeted therapies
Multi-targeted tyrosine kinase inhibitors
As a class, the multi-targeted receptor tyrosine kinases
have characteristic side effects. These include fatigue, skin
and hair, cardiovascular, endocrine, gastrointestinal and
metabolic effects. As more patients are treated with these
agents, more is known about the extent of each side effect.
An ongoing study, E1Y03, sponsored by the Eastern Coop-
erative Oncology Group (ECOG), is characterizing the pres-
ence of pharmacogenetic cyp3A4 polymorphisms and phar-
macokinetics of sunitinib and sorafenib within populations
 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432 425

Table 2
Toxicities of targeted therapies
Toxicity [68,69] Sunitinib (n ⫽ 169) Sorafenib (n ⫽ 451) Bevacizumab (n ⫽ 39) Temsirolimus (n ⫽ 212)
10 mg/kg

Fatigue Likely Likely Less likely Likely

Hand-foot syndrome Less likely Likely ND ND
Other rash Less likely Likely Likely Likely
Hypertension Less likely Less likely Likely ND
Edema Less likely ND ND Less likely
Dyspnea Less likely Less likely ND Likely
LVEF decline Rare ND ND ND
Prolonged QT interval Rare ND ND ND
Anorexia Likely Less likely ND Likely
Diarrhea Likely Likely ND Likely
Stomatitis Likely Less likely ND Likely
Nausea Likely Less likely ND Likely
Fever Less likely Less likely Less likely Less likely
Bleeding Less likely Less likely Less likely Rare
Thrombosis Rare Rare Rare ND
Hypothyroidism Less likely ND ND ND
High AST/ALT Less likely Less likely Less likely Less likely
High amylase/lipase Less likely Less likely ND ND
High cholesterol ND ND ND Likely
High triglycerides ND ND ND Likely
Low phosphorus Less likely Less likely ND Likely
Neutropenia Less likely Less likely ND Likely
Thrombocytopenia Less likely Less likely ND Likely
Lymphopenia Less likely Less likely ND Likely
GI perforation Rare Rare Rare ND

Likely ⬎20%; less likely ⱕ20%; rare but serious ⬍3%.

ND ⫽ not described.

of patients treated with these agents to help determine if Sunitinib

subsets of populations are more prone to side effects. Many
side effects can be attributed to specific receptors targeted.
The most commonly reported side effects, occurring in
more than 10% of patients are depicted in Table 2.
Hypertension is a common side effect for both the mul-
titargeted tyrosine kinase inhibitors and VEGF inhibitors,
but has not been correlated to response or to elevation in
VEGF levels [70]. A rare but serious complication is re-
versible posterior leukoencephalopathy syndrome [71],
characterized by hypertension, headache, lethargy, altered
mental status, and visual loss. The cardiac effects of this
class have not been well characterized but may be similar to
other agents such as imatinib and traztuzimab [72,73].
There are numerous skin manifestations of the tyrosine
kinase inhibitors [74]. The most troubling of these is the
hand-foot syndrome. Hand-foot syndrome is a different
variety than that reported with chemotherapy agents such as
the fluorodeoxyuridines [75]. It is characterized by an initial
discomfort in the palmar and plantar surfaces followed by
painful callus formation, often at pressure points and the
appearance of sores underneath the calluses. A diffuse mac-
ular rash can also occur, which tends to improve with time.
Another side effect that appears to be commonly associated
with both drugs is splinter hemorrhages in the nailbeds [76].
Additionally, either curling or lightening of the hair and
changes in skin tone can occur [77].
The most commonly reported side effects of sunitinib are
nausea, rash, fatigue, hypertension, diarrhea, and stomatitis
[68]. There is a higher incidence of myelosuppression re-
ported with sunitinib than sorafenib. Two side effects are
specific to inhibition of stem cell factor and c-kit, and thus
reported with sunitinib (as well as GW786034 and
AG013736) [77]. These include a yellowish discoloration to
the skin and/or lightening of hair. Additionally, altered
thyroid function tests, including hypothyroidism, have been
reported in one publication to be as high as 62% and 36%,
respectively [78]. This is most likely related to sunitinib
targeting of the RET proto-oncogene.
A toxicity sometimes seen with sunitinib is left ventric-
ular dysfunction. The left ventricular ejection fraction
(LVEF) was measured in a number of sunitinib trials con-
ducted and the overall incidence of this abnormality was
10% with only 1% of these grade 3. As this potential side
effect has not been analyzed in sorafenib trials, it is un-
known if this is a class effect [79]. A Phase IV cardiac study
is ongoing in the ASSURE Trial, which will prospectively
characterize the incidence of decline in LVEF as well as any
relationship to congestive heart failure, hypertension, or
other toxicities to sorafenib, sunitinib or placebo. A rare
side effect is seizure, reported in 1% of patients on sunitinib.
This can occur from drug interaction affecting anticonvul-
426 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
sant therapy serum levels, in the presence of previously
undetected brain metastases and idiopathically. Other rare
side effects are thrombotic and bleeding complications,
which are listed as rare but serious in Table 2.
Sorafenib
The most frequently observed sorafenib-related toxicities
include hand-foot skin reaction, rash, anorexia, diarrhea,
fatigue, and hypertension [68]. Other common side effects
include pruritis, joint pain, and liver function abnormalities.
Neutropenia, thrombocytopenia, and anemia are uncom-
mon, but not rare. The incidence of bleeding, thrombosis,
and other serious side effects such as myocardial infarction
are reported as rare. A side effect specific to sorafenib is
curling of the hair. Alopecia is also more common with
sorafenib than sunitinib. Additionally, the incidences of
hypertension and hand-foot appear to be more common with
sorafenib than with sunitinib.
Bevacizumab
Most of the toxicity data reported for bevacizumab is
reported from trials that incorporate bevacizumab with cy-
totoxic chemotherapy [68]. As such, many side effects may
have been reported in both chemotherapy alone and chemo-
therapy plus bevacizumab arms and can be attributed to
both the chemotherapy and antiangiogenic agents. Side ef-
fects specific to bevacizumab alone can be singled out in a
small Phase II trial. In the Phase II trial of high dose
bevacizumab vs. low dose bevacizumab vs. placebo in ad-
vanced RCC, toxic effects were minimal, with hypertension
(35%) and proteinuria (64%) reported as the most substan-
tial events in the high dose arm [66].
Potential side effects of bevacizumab plus chemotherapy
include gastrointestinal perforation, hemorrhage, impaired
wound healing, and arterial thrombosis. The incidence of
gastrointestinal perforation (2%) was best characterized in
the colorectal cancer population [68]. Hemorrhage has been
classified as minor, usually epistaxis, and major, including
hemoptysis in squamous cell lung cancer (31%), hemopty-
sis in adenocarcinoma of the lung (4%), CNS bleeding
(hemorrhagic stroke and subarachnoid hemorrhage, uncom-
mon) [80]. Arterial thrombotic events (cerebral infarction,
transient ischemic attacks, myocardial infarction, angina,
and others), pooled from 1,745 patients in randomized trials
of chemotherapy with and without the bevacizumab label,
had an incidence of 1.9% vs. 4.4%, respectively [68].
mTOR inhibitors
The rapamycin analogs have some class-specific side
effects as well. The most common side effects of the tem-
sirolimus in a Phase 2 study of 110 patients with RCC are
rash (72%), mucositis (65%), asthenia (39%), nausea
(36%), and acne (30%) [61]. Treatment related adverse
events in the Phase II trial of everolimus were similar and
included mucositis, skin rash, pneumonitis, hypophos-
phatemia, hyperglycemia, thrombocytopenia, anemia, and
elevated LFTs [65]. Hypersensitivity reactions including
facial flushing and, rarely, difficulty breathing or speaking,
usually during the initial intravenous infusion have been
reported for temsirolimus [69].
Similar to organ-transplant patients receiving sirolimus,
pneumonitis/pulmonary infiltrates and alveolitis has been
reported among patients receiving intravenous temsirolimus
[81]. Some patients have been asymptomatic with pneumo-
nitis detected on CT scan or chest X-ray, while others have
had symptoms of dyspnea, cough, and fever. This side effect
appears to respond to steroid treatment and discontinuation
of the temsirolimus.
Hyperlipidemia and hypophosphatemia are additional
class-specific toxicities of these agents secondary to mTOR
inhibition [82,83]. Interference with insulin signaling path-
ways, as a consequence of mTOR inhibition, appears to be
the mechanism responsible for these side effects [84]. The
hyperlipidemia usually requires treatment with a lipid-low-
ering agent. Additionally, myelosuppression occurs com-
monly when this agent is combined with cytotoxic agents.
Targeted adjuvant strategies in RCC
Between the extremes of early incidental RCC and
mRCC exists a gradation of risk. Twenty to 40% of patients
undergoing surgical resection for localized RCC experience
recurrence, suggesting that there are some individuals in
whom surgical excision is necessary but insufficient [4]. In
these patients, the development of effective adjuvant strat-
egies is imperative. The use of adjuvant therapies to treat
patients with high-risk malignancies has been explored for
many different solid tumors. These efforts seek to eradicate
micrometastatic disease that has escaped surgical control
using systemic therapies. Due to poor outcomes for patients
with mRCC, studies have been undertaken to determine the
potential utility of various forms of adjuvant therapy for
those patients at high risk for recurrent disease. Historically,
postoperative adjuvant therapies have not been shown to
have significant clinical benefit for these patients [85]. In
spite of this, the initial time after surgical resection holds
promise as a period with minimal tumor bulk corresponding
with a newly “unsuppressed” immune system whereby ad-
juvant strategies may be successful.
Published adjuvant trials in RCC
Agents that have been studied as adjuvant treatment for
high risk RCC include radiotherapy, hormonal therapies,
and immunotherapies. Unfortunately, nearly all the trials
examining the use of local or systemic therapies have failed
to demonstrate any benefit in the adjuvant setting [85].
Among these trials, the most significant failures have all
 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
been using immunotherapeutic strategies, which for nearly
two decades has been the standard of care for patients with
mRCC. Multiple trials examining the effects of adjuvant
interferon-␣, recombinant interferon ␣-2b, autologous irra-
diated tumor cells mixed with BCG, IL-2, subcutaneous
cytokines with 5-FU, and combination IL-2/FN-2␣/5-FU
have all failed to show any survival advantages over obser-
vation alone [85,86].
To our knowledge there has only been a single positive
prospective adjuvant randomized trial in RCC. In a multi-
center Phase III trial using individually prepared autologous
renal tumor cell vaccine injected intradermally at 55 Ger-
man centers following radical nephrectomy, 5-year PFS was
77.4% following vaccine vs. 67.8% in the observation arm
(P ⫽ 0.02, log-rank test) [87]. Importantly, 32% of enrolled
patients (174/553) were lost after randomization with a
disproportionate number of losses from the treatment group.
Moreover, OS differences were not analyzed, raising sig-
nificant questions regarding the interpretation and applica-
bility of these results.
Adjuvant targeted trials in RCC
Several important trials currently underway are examin-
ing adjuvant, primarily targeted agents in high risk but fully
surgically resected RCC. The European Organization for
Research and Treatment of Cancer (EORTC) has coordi-
nated a Phase III adjuvant trial to further evaluate interleu-
kin-2, interferon-␣, and 5-fluorouracil for patients with high
risk of relapse after surgical treatment for RCC (EORTC
protocol 30955). In this study, 550 patients have been ran-
domized to either treatment or observation after surgery.
Now closed to recruitment, analysis will determine disease-
free survival and overall survival in each arm [86].
RCC is highly vascular with disordered angiogenesis.
Due to its antiangiogenic effects, thalidomide has been
studied in mRCC in a Phase III trial for patients with stage
IV disease randomized patients to receive interferon-␣ with
or without thalidomide. This study demonstrated an im-
provement in progression-free survival using thalidomide
[88]. Based on these findings, an adjuvant study was initi-
ated at M.D. Anderson for patients with high risk RCC
comparing thalidomide to controls after nephrectomy. This
Phase II trial had an accrual goal of 220 patients but has
closed due to poor accrual.
A currently ongoing clinical trial involves the use of a
monoclonal antibody against G250, a transmembrane pro-
tein associated with RCC, which is identical to CAIX [74].
cG250 (WX-G250, Rencarex®; Wilex Pharmaceuticals,
Munich, Germany) is a monoclonal IgG1 antibody admin-
istered intravenously that binds to CAIX on clear cell RCC
and may recruit effector cells or activate complement to
result in cell death [86]. In 2004, an international random-
ized, Phase III trial termed ARISER (adjuvant rencarex
immunotherapy trial to study efficacy in nonmetastatic
RCC) opened to accrual to evaluate cG250 vs. placebo after
427
nephrectomy for 612 patients with high-risk nonmetastatic
clear cell RCC. This trial is currently accruing patients.
On the basis of the aforementioned favorable data in
patients with mRCC using the oral tyrosine kinase inhibitors
sorafenib and sunitinib, a Phase III trial is currently under-
way randomizing patients to receive either sorafenib,
sunitinib, or placebo after definitive resection of localized or
locally advanced RCC. The study, termed ASSURE (adju-
vant sorafenib sunitinib for unfavorable renal cell carci-
noma), is sponsored by ECOG and hopes to accrue 1,332
patients over 4 years. Eligible patients must have fully
resected, locally advanced, nonmetastatic disease with or
without lymph node involvement. Progression-free survival
is the primary endpoint. Patients are registered for this trial
based on unfavorable pathologic findings after surgical re-
section or preoperatively based on high-risk radiographic
findings, thus allowing for tissue correlative studies. Sec-
ondary endpoints include overall survival and toxicity in the
adjuvant setting.
Another Phase III trial examining the prolonged use of
sorafenib in the adjuvant setting sponsored by the Medical
Research Council (MRC) is currently planned. SOrafenib in
Renal CEll (SORCE) is a randomized controlled study com-
paring sorafenib administered for 3 years or 1 year with
placebo in patients with resected primary renal cell carci-
noma at high or intermediate risk of relapse. This study aims
to recruit approximately 331 patients per year for each of 5
years with an additional 3 years of follow-up. The primary
endpoint is metastasis-free survival and secondary measures
include CSS, overall survival, cost effectiveness, and tox-
icity [85,86] (Table 3).
Surgical considerations of targeted therapies in RCC
As targeted therapies in RCC have been introduced into
urologic clinics, several practical and biologically relevant
surgical issues have been raised as the collective experience
with these agents grows. For example, since these agents
target tissue vascularity, do they have any definable adverse
effects on intra- or postoperative bleeding? What are the
implications of these agents on perioperative wound heal-
ing? How should patients taking these agents be advised of
management prior to elective surgery? Are there other clin-
ical urologic concerns? Whereas these agents have only
been approved for use outside of clinical trials since De-
cember 2005, data of this nature remain limited.
Neoadjuvant targeted therapies and the role of
cytoreduction
Since nearly 4 in 10 patients with RCC present with
locally advanced or metastatic disease [1], the role of sur-
gical removal of the primary tumor in advanced disease has
been debated and reviewed [89]. Arguments for cytoreduc-
tion include a small body of literature demonstrating spon-
 428
Table 3
Current adjuvant trials for high-risk RCC
Trial Sponsor Study groups Route Study design Treatment Accrual Inclusion criteria Status
duration goal

N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
ARISER, Rencarex (G250 mAb) Wilex G250 mAb vs. i.v. Phase III, double- 24 weeks 600 ● Histologically confirmed primary Open and accruing
placebo blind, placebo- clear cell RCC
controlled ● Meets one of the following stage
criteria:
- stage T3a, T3b, T3c, or T4 and
No/NxMo
- any T stage and N⫹ M0
- T1bN0/NXM0 or T2N0/NXM0
with microscopic vascular inva-
sion and grade ⱖIII or T3aN0/
NX°M0 with grade ⱖIII
● Fully resected within 12 weeks
● No evidence of macroscopic or
microscopic residual disease
ASSURE, sorafenib/sunitinib ECOG Sunitinib vs. sorafenib PO Phase III, randomized, 1 year 1,332 ● Patients with high-grade (G3) Open and accruing
vs. placebo for 1 double-blind, T1b and any grade with a higher
year placebo-controlled T stage (T2-4)
● Patients with Nx, N0, N1, or N2
if all positive nodes were
removed
● Patients must be M0
● Patients can have a laparoscopic
or open, partial or radical
● No more than 3months since
surgery
● No evidence of residual or
recurrent disease
● Clear cell and non-clear cell
tumors eligible
SORCE, sorafenib MRC Sorafenib (for 1 or 3 PO Phase III, three-arm, 3 years 1,650 ● Intermediate- or high-risk disease Activated May 2007
years) vs. placebo double-blind, RCC (clear cell and non-clear
controlled cell)
● No more than 3 months prior to
treatment start date
● No evidence of residual
macroscopic disease after
resection
 N.B. Haas, R.G. Uzzo / Urologic Oncology: Seminars and Original Investigations 25 (2007) 420 – 432
taneous regression of metastatic sites upon removal of the
primary tumor, reduction of the overall tumor burden in an
effort to make systemic therapies more effective, alleviation
of symptoms or the prevention of future symptoms due to
the primary tumor, and removal of tissues for clinical trials.
Arguments against radical nephrectomy in the setting of
metastatic disease include the definable morbidity and mor-
tality of surgery in elderly, higher risk patients and the
associated postsurgical delay in beginning systemic thera-
pies.
Nonetheless, current practice is to perform cytoreduc-
tive nephrectomy when possible. This is based primarily
on the results of two randomized clinical trials demon-
strating a statistically significant 6 month survival benefit
to cytoreduction and IFN vs. IFN alone [14,90]. It is
therefore important to note that there has not been a
demonstrated benefit to cytoreduction in the targeted
therapy era. Recently a RAND appropriateness survey
was performed to evaluate data regarding treatment of
mRCC including the role of cytoreduction [91]. A total of
22 controlled trials were reviewed (20 prospective) in-
cluding 4,289 patients with mRCC. Cytoreduction was
deemed most appropriate for patients with good surgical
risk, symptoms related to the primary tumor, and limited
metastatic burden. For patients with planned immuno or
targeted therapy and good surgical risk status, cytoreduc-
tion was also deemed appropriate in patients with limited
metastatic burden and no primary tumor-related symp-
toms. In good surgical risk patients with extensive tumor
burden with symptoms, cytoreduction was deemed ap-
propriate in patients who were planning postoperative
immunotherapy, but its role was uncertain in those same
patients planning postoperative targeted therapy. The role
of cytoreductive nephrectomy was considered uncertain
or inappropriate for poor surgical risk patients and those
without primary tumor-related symptoms who had exten-
sive metastatic burdens [91]. These findings underscore
the uncertainty associated with primary tumor responses
following targeted therapy, particularly for asymptom-
atic, poor risk patients with extensive metastatic burdens.
Although several institutionally based clinical trials are
currently underway examining the clinical and biological
responses of the primary tumor and their associated me-
tastases to targeted therapies, until these data become
available, the clinician should select patients for cytore-
duction carefully in the targeted therapy era.
Wound healing and other concerns following targeted
therapies
The risks of bleeding, hemorrhage, and gastrointestinal
perforation have best been characterized in bevacizumab,
but data are emerging for the multitargeted tyrosine kinase
inhibitors. Several publications have emerged addressing
the safety of the use of bevacizumab in association with
surgical procedures [92,93]. The serum half-lives (bevaci-
429
zumab 20 days, sunitinib and sorafenib 5 days, temsirolimus
15 hours) are helpful in planning surgical procedures, and it
is generally recommended to discontinue bevacizumab 4
weeks prior to surgery. The reported incidence of wound
healing complications in patients who had taken bevaci-
zumab 28 to 60 days prior to surgery was 1.3% vs. 0.5% in
non-bevacizumab treated patients and 13% vs. 3.4%, re-
spectively, for complications from surgery while on therapy
in one series [92]. The same series reported surgical com-
plications in patients receiving bevacizumab within less
than 30 and 30 to 60 days after surgery. The authors con-
cluded that receiving bevacizumab within 28 days of sur-
gery was safe and feasible. Another study recommended a
window of 6 to 8 weeks postoperatively following bevaci-
zumab therapy [93].
Information in the product labels and PDR for sorafenib
and sunitinib is limited and recommends physician discre-
tion. Clearly, there are anecdotes of delayed wound healing
with minor injuries such as abrasions using these agents,
and the common entry criterion for both sunitinib and sor-
afenib based trials includes a minimum of 4 weeks post
major surgery prior to initiating therapy; however, given the
shorter half-lives of these agents, the use of these agents
preceding or following surgery may be more permissive.
Little data exist for the impact of temsirolimus on wound
healing or surgical complications. Given that this target is
upstream to the immediate VEGF pathways, it is possible
that the wound and surgical issues are of less importance
with this agent. More data are needed with temsirolimus as
well as the other agents in this class.
Future directions
The use of targeted therapies for RCC is a direct result of
refinements in basic science techniques and our understand-
ing of the complexities of the VEGF pathway. Ongoing
Phases I and II trials will address the use of these agents in
combination as parallel or sequential targeted agents. From
these studies, more data will be compiled about the rele-
vance of the particular targets to toxicities as well as to
response. Ongoing studies hope to refine the use of these
agents in appropriate populations. Many questions remain.
Nonetheless, as the pathways responsible for RCC are better
understood, the role of targeted therapies in RCC will con-
tinue to expand.
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