Renal Cell Carcinoma
Introduction
Background
Renal cell carcinoma accounts for approximately 3% of
adultmalignancies and 90-95% of neoplasms arising from the
kidney. It is characterized by a lack of early warning signs,
diverse clinical manifestations, and resistance to radiation
and chemotherapy.
Increasingly, renal cell cancers are diagnosed at an earlier
stage, and nephron-sparing surgery and thermal ablation are
gaining acceptance as a treatment of choice for smaller
tumors. Radical nephrectomy is the standard for larger and
central tumors.
Recent clinical trials have established the role of targeted
therapy as the first line of therapy in patients with metastatic
disease. While the optimal treatment strategy continues to
evolve, three agents that target angiogenesis (sunitinib,
bevacizumab, and pazopanib) and an mTOR-targeted therapy
(temsirolimus) have been approved as front-line agents.
These have largely replaced cytokines (immunotherapy) in
treatment-naive patients. Current clinical trials are testing
newer agents, combinations of approved agents, and the
optimal sequencing of these agents.
Pathophysiology
The tissue of origin for renal cell carcinoma is the proximal
renal tubular epithelium. Renal cancer occurs in both a
sporadic (nonhereditary) and a hereditary form, and both
forms are associated with structural alterations of the short
arm of chromosome 3 (3p). Genetic studies of the families at
high risk for developing renal cancer led to the cloning of
genes whose alteration results in tumor formation. These
genes are either tumor suppressors (VHL, TSC) or oncogenes
(MET).
At least 4 hereditary syndromes associated with renal cell
carcinoma are recognized: (1) von Hippel-Lindau (VHL)
syndrome, (2) hereditary papillary renal carcinoma (HPRC),
(3) familial renal oncocytoma (FRO) associated with BirtHogg-Dube syndrome (BHDS), and (4) hereditary renal
carcinoma (HRC).
von Hippel-Lindau disease is an autosomal dominant
syndrome that confers predisposition to a variety of
neoplasms, including the following:
1. Renal cell carcinoma with clear cell histologic features
2. Pheochromocytoma
3. Pancreatic cysts and islet cell tumors
4. Retinal angiomas
5. Central nervous system hemangioblastomas
6. Endolymphatic sac tumors
7. Epididymal cystadenomas
Renal cell carcinoma develops in nearly 40% of patients with
von Hippel-Lindau disease and is a major cause of death
among these patients. Deletions of 3p occur commonly in
renal cell carcinoma associated with VHL disease.
The VHL gene is mutated in a high percentage of tumors and
cell lines from patients with sporadic (nonhereditary) clear
cell renal carcinoma. Several kindreds with familial clear cell
carcinoma have a constitutional balanced translocation
between 3p and either chromosome 6 or chromosome 8.
Mutations of the VHL gene result in the accumulation of
hypoxia inducible factors (HIFs) that stimulate angiogenesis
through vascular endothelial growth factor and its receptor
(VEGF and VEGFR, respectively). VEGF and VEGFR are
important new therapeutic targets.
Hereditary papillary renal carcinoma is an inherited disorder
with an autosomal dominant inheritance pattern; affected
individuals develop bilateral, multifocal papillary renal
carcinoma. Germline mutations in the tyrosine kinase domain
of the MET gene have been identified.
Individuals affected with familial renal oncocytoma can
develop bilateral, multifocal oncocytoma or oncocytic
neoplasms in the kidney. Birt-Hogg-Dube syndrome is a
hereditary cutaneous syndrome. Patients with Birt-HoggDube syndrome have a dominantly inherited predisposition
to develop benign tumors of the hair follicle (ie,
fibrofolliculomas), predominantly on the face, neck, and
upper trunk, and are at risk of developing renal tumors,
colonic polyps or tumors, and pulmonary cysts.
Frequency
International
1. Deaths worldwide from kidney cancer exceeded 100,000
in 2001.
2. In most of Europe, the incidence of kidney cancer has
decreased or stabilized over the past decade, perhaps in
part because of reduced tobacco smoking in men.
Mortality from kidney cancer has also declined in most
of Europe, principally in Scandinavia and other western
European countries. In men, the mortality rate per
100,000 population fell from 4.8 in 1990-1994 to 4.1 in
2000-2004; in women, the rate fell from 2.1 to 1.8.3
Mortality/Morbidity
Renal cell carcinoma is the tenth leading cause of cancer
deaths in males in the United States. In men, deaths from
kidney cancer decreased 3.9% between 1990 and 2005; in
women, deaths decreased by 7.8% during that period.
Overall, 5-year relative survival increased from 51% to 67%
between 1975-1977 and 1996-2004.2 The 5-year survival
rates initially reported by Robson in 1969 were 66% for stage
I renal carcinoma, 64% for stage II, 42% for stage III, and only
11% for stage IV.4 Except for stage I, these survival statistics
have remained essentially unchanged for several decades.
Race
Renal cell carcinoma is more common in people of Northern
European ancestry (Scandinavians) and North Americans
than in those of Asian or African descent. In the United
States, its incidence is slightly higher among African
Americans than among whites: 21.3 versus 19.2 per 100,000
population in men, and 10.3 versus 9.9 per 100,000
population in women.1
Sex
Renal cell carcinoma has a m:f preponderance of 1.6:1.
Age
From 2002 – 2006, the median age at diagnosis was 64 years
of age1 ; however, the disease has been reported in younger
people who belong to family clusters.1
Clinical
History
Renal cell carcinoma may remain clinically occult for most of
its course. The classic triad of flank pain, hematuria, and flank
mass is uncommon (10%) and is indicative of advanced
disease. Twenty-five to thirty percent of patients are
asymptomatic, and their renal cell carcinomas are found on
incidental radiologic study.
1. Most common presentations
 Hematuria (40%)
 Flank pain (40%)
 Palpable mass in the flank or abdomen (25%)
2. Other signs and symptoms
 Weight loss (33%)
 Fever (20%)
 Hypertension (20%)
 Hypercalcemia (5%)
 Night sweats
 Malaise
 Varicocele, usually left sided, due to obstruction of the
testicular vein (2% of males)
3. Renal cell carcinoma is a unique and challenging tumor
because of the frequent occurrence of paraneoplastic
syndromes, including hypercalcemia, erythrocytosis, and
nonmetastatic hepatic dysfunction (ie, Stauffer
syndrome). Polyneuromyopathy, amyloidosis, anemia,
fever, cachexia, weight loss, dermatomyositis, increased
erythrocyte sedimentation rate, and hypertension also
are associated with renal cell carcinoma. (For more
information, see Paraneoplastic Syndromes.)
 Cytokine release by tumor (eg, IL-6, erythropoietin, nitric
oxide) causes these paraneoplastic conditions.
 Resolution of symptoms or biochemical abnormalities
may follow successful treatment of the primary tumor or
metastatic foci.
Physical
1. Gross hematuria with vermiform clots suggests upper
urinary tract bleeding.
2. Look for hypertension, supraclavicular adenopathy, and
flank or abdominal mass with bruit.
3. Approximately 30% of patients with renal carcinoma
present with metastatic disease. Physical examination
should include thorough evaluation for metastatic
disease. Organs involved include:
o Liver (18%)
 Lung (75%)
o Cutaneous sites (8%)
 Soft tissues (36%)
o CNS (8%)
 Bone (20%)
4.
Varicocele and findings of paraneoplastic syndromes
raise clinical suspicion for this diagnosis.
Causes
A number of environmental and genetic factors have been
studied as possible causes for renal cell carcinoma.
1. Cigarette smoking doubles the risk of renal cell
carcinoma and contributes to as many as one third of all
cases. The risk appears to increase with the amount of
cigarette smoking in a dose-dependent fashion.
2. Obesity is another risk factor, particularly in women;
increasing body weight has a linear relationship with
increasing risk.
3. Hypertension may be associated with an increased
incidence of renal cell carcinoma.
4. Phenacetin-containing analgesia taken in large amounts
may be associated with increased incidence of renal cell
carcinoma.
5. There is an increased incidence of acquired cystic disease
of the kidney in patients undergoing long-term renal
dialysis; this predisposes to renal cell cancer.
6. Tuberous sclerosis
7. Renal transplantation: Acquired renal cystic disease of
the native kidney also predisposes to renal cell cancer in
renal transplant recipients.
8. VHL disease: This inherited disease is associated with
renal cell carcinoma.
Differential Diagnoses
Pyelonephritis, Acute
Lymphoma, Non-Hod
Workup
Pyelonephritis, Chronic
Wilms Tumor
Laboratory Studies
1. Laboratory studies in the evaluation of renal cell
carcinoma should include a workup for paraneoplastic
syndromes. Initial studies are as follows:
o Urine analysis
o CBC with differential
o Electrolytes
o Renal profile
2. Liver function tests (AST and ALT)
3. Calcium
4. Erythrocyte sedimentation rate
5. Prothrombin time
6. Activated partial thromboplastin time
7. Other tests indicated by presenting symptoms
Imaging Studies
1. A large proportion of patients diagnosed with renal
cancer have small tumors discovered incidentally on
imaging studies. A number of diagnostic modalities are
used to evaluate and stage renal masses:
2.
 Excretory urography
 Arteriography
 CT scan
 Venography
 Ultrasonography
 MRI
Determining whether a space-occupying renal mass is
benign or malignant can be difficult. Radiologic studies
should be tailored to enable further characterization of
renal masses, so that nonmalignant tumors can be
differentiated from malignant ones.
3. Excretory urography is not used frequently in the initial
evaluation of renal masses because of its low sensitivity
and specificity. A small- to medium-sized tumor may be
missed by excretory urography.
4. Contrast-enhanced CT scanning has become the imaging
procedure of choice for diagnosis and staging of renal
cell cancer and has virtually replaced excretory
urography and renal ultrasound. In most cases, CT
imaging can differentiate cystic masses from solid
masses and supplies information about lymph node,
renal vein, and inferior vena cava involvement.
5. Ultrasound examination can be useful in evaluating
questionable cystic renal lesions if CT imaging is
inconclusive. Large papillary renal tumors are frequently
undetectable by renal ultrasound.
6. Renal arteriography is not used in the evaluation of a
suspected renal mass as frequently now as it was in the
past. When inferior vena cava involvement is suspected,
either inferior venacavography or MRI angiography is
used. MRI is currently the preferred imaging technique.
Knowledge of inferior vena cava involvement is
important in planning the vascular aspect of the
operative procedure.
7. A bone scan is recommended for patients with bony
symptoms and an elevated alkaline phosphatase level.
8. PET imaging remains controversial in kidney cancer. It
has better sensitivity for detecting metastatic lesions
than for determining the presence of cancer in the renal
primary site.
Procedures
Percutaneous cyst puncture and fluid analysis is used in the
evaluation of potentially malignant cystic renal lesions
detected by ultrasonography or CT imaging.
Histologic Findings
Renal cell carcinoma has 5 histologic subtypes, as follows:
clear cell (75%), chromophilic (15%), chromophobic (5%),
oncocytoma (3%), and collecting duct (2%).
1. Unusually clear cells with a cytoplasm rich in lipids and
glycogen characterize clear cell carcinoma, which is most
likely to show 3p deletion.
2. Chromophilic tumors tend to be bilateral and multifocal
and may have trisomy 7 and/or trisomy 17.
3. Large polygonal cells with pale reticular cytoplasm
characterize chromophobic carcinoma, which does not
exhibit 3p deletion.
4. Renal oncocytoma consists predominantly of
eosinophilic cells, in a characteristic nested or organoid
pattern, that rarely metastasize and do not exhibit 3p
deletion or trisomy 7 or 17.
5. Collecting duct carcinoma is an unusual variant
characterized by a very aggressive clinical course. This
tends to affect younger patients and may present as
local or widespread advanced disease. These cells can
have 3 different types of growth patterns, (1) acinar, (2)
sarcomatoid, and (3) tubulopapillary. The sarcomatoid
variant, which can occur with any histologic cell type, is
associated with a significantly poorer prognosis.
Table 1. Pathologic Classification of Renal Cell Carcinoma
Cell Type
Features
Clear cell
Most
common
Bilateral
and
multifocal
Indolent
course
Chromop
hilic
Chromop
hobic
Oncocyti
c
Collectin
g duct
Rarely
metastasiz
e
Very
aggressive
Growth
Pattern
Acinar
or
sarcomatoid
Papillary or
sarcomatoid
Cell
of
Origin
Proximal
tubule
Proximal
tubule
Cytogen
etics
3p-
Solid,
tubular, or
sarcomatoid
Tumor nests
Cortical
collecting
duct
Cortical
collecting
duct
Medullary
collecting
duct
Hypodipl
oid
Papillary or
sarcomatoid
+7, +17,
-Y
Undeter
mined
Undeter
mined
Staging
1. The Robson modification of the Flocks and Kadesky
system is uncomplicated and is used commonly in clinical
practice. This system was designed to correlate stage at
presentation with prognosis. The Robson staging system
is as follows:
Stage I - Tumor confined within capsule of kidney
Stage II - Tumor invading perinephric fat but still contained
within the Gerota fascia
Stage III - Tumor invading the renal vein or inferior vena cava
(A), or regional lymph-node involvement (B), or both (C)
Stage IV - Tumor invading adjacent viscera (excluding
ipsilateral adrenal) or distant metastases
2. The tumor, nodes, and metastases (TNM) classification is
endorsed by the American Joint Committee on Cancer
(AJCC). The major advantage of the TNM system is that it
clearly differentiates individuals with tumor thrombi
from those with local nodal disease. In the Robson
system, stage III disease includes both inferior vena caval
involvement (stage IIIA) and local lymph node
metastases (stage IIIB). Although patients with Robson
stage IIIB renal carcinoma have greatly decreased
survival rates, the prognosis for patients with stage
Robson IIIA renal carcinoma is not markedly different
from that for patients with Robson stage I or II renal
carcinoma. The TNM classification system is as follows:
Primary tumor (T)
 TX - Primary tumor cannot be assessed
 T0 - No evidence of primary tumor
 T1 - Tumor 7 cm or smaller in greatest dimension, limited
to the kidney
 T2 - Tumor larger than 7 cm in greatest dimension,
limited to the kidney

T3 - Tumor extends into major veins or invades adrenal
gland or perinephric tissues but not beyond the Gerota
fascia
 T3a - Tumor invades adrenal gland or perinephric tissues
but not beyond the Gerota fascia
 T3b - Tumor grossly extends into the renal vein(s) or
vena cava below the diaphragm
 T3c - Tumor grossly extends into the renal vein(s) or vena
cava above the diaphragm
 T4 - Tumor invading beyond the Gerota fascia
Regional lymph nodes (N) - Laterality does not affect the N
 NX - Regional lymph nodes cannot be assessed
 N0 - No regional lymph node metastasis
 N1 - Metastasis in a single regional lymph node
 N2 - Metastasis in more than 1 regional lymph node
Distant metastasis (M)
 MX - Distant metastasis cannot be assessed
 M0 - No distant metastasis
 M1 - Distant metastasis
 AJCC stages
 AJCC stage I - T1, N0, M0
 AJCC stage II - T2, N0, M0
 AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0
 AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1
 The division of patients with renal cell carcinoma into
low-, intermediate-, and high-risk groups with or without
metastases may be useful in choosing appropriate
therapy for them
Treatment
Medical Care
The therapeutic approach to renal cell carcinoma is guided by
the probability of cure, which is related directly to the stage
or degree of tumor dissemination. More than 50% of patients
with early-stage renal cell carcinoma are cured, but the
outcome for stage IV disease is poor. Thus, the approach is
curative for early-stage disease. Selected patients with
metastatic disease respond to immunotherapy, but many
patients with advanced disease can be offered only palliative
therapy.
1. The treatment options for renal cell cancer are surgery,
radiation therapy, chemotherapy, hormonal therapy,
immunotherapy, or combinations of these.
 Options for chemotherapy and endocrine-based
approaches are limited, and no hormonal or
chemotherapeutic regimen is accepted as a standard of
care. Objective response rates with chemotherapy,
either single-agent or combination, are usually lower
than 15%. Therefore, various biologic therapies have
been evaluated.
 Renal cell carcinoma is an immunogenic tumor, and
spontaneous regressions have been documented. Many
immune modulators have been tried, including
interferon, IL-2 (aldesleukin [Proleukin]), bacillus
Calmette-Guérin (BCG) vaccination, lymphokine-
2.
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activated killer (LAK) cells plus IL-2, tumor-infiltrating
lymphocytes,
and
nonmyeloablative
allogeneic
peripheral blood stem-cell transplantation.
Multikinase inhibitors
Sorafenib
Sorafenib (Nexavar), a small-molecule Raf kinase and
vascular endothelial growth factor (VEGF) multireceptor
kinase inhibitor, is approved by the U.S. Food and Drug
Administration for the treatment of patients with
advanced renal cell carcinoma. This indication was based
on the demonstration of improved progression-free
survival in a large, multinational, randomized doubleblind, placebo-controlled phase 3 study and a supportive
phase 2 study.
The sorafenib phase 3 study was conducted in patients
with advanced (unresectable or metastatic) renal cell
carcinoma who had received one prior systemic
treatment. Study endpoints included overall survival,
progression-free survival, and response rate.
Among 769 patients randomized, the median age was 59
years and 70% were male.
Baseline patient and disease characteristics were well
balanced. Regarding prior therapies, 93% had prior
nephrectomies; 99% had received prior systemic
therapies, including interleukin 2 (44%) and an interferon
(68%).
The median progression-free survival was 167 days in
the sorafenib group versus 84 days in the placebo
control group (HR 0.44; 95% CI for HR: 0.35-0.55, logrank
p <0.000001). Time-to-progression was similarly
improved. Tumor response was determined by
independent radiologic review according to Response
Evaluation Criteria in Solid Tumors (RECIST) criteria.
Overall, of 672 patients who were able to be evaluated
for response, 7 (2%) sorafenib patients and 0 (0%)
placebo patients had confirmed partial responses. 7
Final results of this trial established the efficacy and
safety of sorafenib in advanced renal cell carcinoma.
Once improved progression-free survival with sorafenib
had been demonstrated, patients assigned to placebo
were offered sorafenib. Although an analysis that
included patients who crossed over to sorafenib showed
no overall survival benefit with sorafenib, a secondary
analysis that did not include these patients showed
significantly improved overall benefit (17.8 v 14.3
months, P = .029).8
Sorafenib toxicities (based on an updated phase 3 study
database of 902 patients) included reversible skin rashes
in 40% and hand-foot skin reaction in 30%. Diarrhea was
reported in 43%, treatment-emergent hypertension in
17%, and sensory neuropathic changes in 13%. Alopecia,
oral mucositis, and hemorrhage also were reported more
commonly on the sorafenib arm. The incidence of
treatment-emergent cardiac ischemia/infarction events
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was higher in the sorafenib group (2.9%) compared with
the placebo group (0.4%).
Grade 3 and 4 adverse events were unusual; only handfoot skin reaction occurred at 5% or greater frequency in
the sorafenib arm. Laboratory findings included
asymptomatic hypophosphatemia in 45% versus 12%
and serum lipase elevations in 41% versus 30% of
sorafenib versus placebo patients, respectively. Grade 4
pancreatitis was reported in 2 sorafenib patients,
although both patients subsequently resumed sorafenib,
one at full dose.
Hypertension is a common side effect of sorafenib
treatment, and may be high grade.9Physicians should be
aware of the importance of frequent blood pressure
monitoring and management, especially during the first
6 weeks after starting sorafenib.
The recommended dose is 400 mg (two 200-mg tab)
twice daily taken either 1 hour before or 2 hours after
meals. Adverse events were accommodated by
temporary dose interruptions or reductions to 400 mg
once daily or 400 mg every other day.
Sorafenib targets serine/threonine and receptor tyrosine
kinases, including those of RAF; VEGFR-2,3; PDGFR-b;
KIT; FLT-3; and RET.
The safety and efficacy of sorafenib were also
demonstrated in a nonrandomized, open-label expanded
access program in which 2,504 patients from the United
States and Canada were treated with oral sorafenib 400
mg twice daily. Patients included those with no prior
therapy, nonclear cell renal cell carcinoma, brain
metastases, and prior bevacizumab treatment; and
elderly patients. Median overall survival was 50 weeks.10
Sunitinib (Sutent)
Sunitinib is another multikinase inhibitor approved by
the FDA for the treatment of metastatic kidney cancer
that has progressed after a trial of immunotherapy. The
approval was based on the high response rate (40%
partial responses) and a median time to progression of
8.7 months and an overall survival of 16.4 months.
The receptor tyrosine kinases inhibited by sunitinib
include VEGFR 1-3 and PDGFR a and b.
Major toxicities (grade II or higher) include fatigue (38%),
diarrhea (24%), nausea (19%), dyspepsia (16%),
stomatitis (19%), and decline in cardiac ejection fraction
(11%). Dermatitis occurred in 8%, and hypertension
occurred in 5% of patients.
In a phase 3 study in 750 patients with previously
untreated metastatic renal-cell carcinoma, PFS was
longer and response rates were higher in patients who
received sunitinib than in those receiving interferon
alfa.11 In final survival analyses, median overall survival
was greater in the sunitinib group than in the interferonalpha group (26.4 vs. 21.8 months; P=0.051), as was the
objective response rate (47% vs. 12%; P <0.001).12
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An expanded-access trial provided sunitinib on a
compassionate-use basis to 4,564 trial-ineligible patients
with renal cell carcinoma from countries where
regulatory approval had not been granted. Median
progression-free survival was 10.9 months (95% CI 10.311.2) and overall survival was 18.4 months (17.4-19.2).
These researchers concluded that the safety of sunitinib
in these patients was manageable and its efficacy was
encouraging, particularly in subgroups associated with
poor prognosis (eg, those with brain metastases, low
performance status, non–clear cell disease, and elderly
patients).13
Temsirolimus (Torisel)
Temsirolimus inhibits mTOR (mammalian target of
rapamycin), which is a serine/threonine kinase important
in the regulation of cell growth and division. Genes
involved with the response to hypoxia (HIF pathway
described above) are also upregulated by mTOR and are
believed to be central to the pathogenesis of kidney
cancers.
Temsirolimus has been tested alone and in conjunction
with interferon in patients with poor prognosis advanced
renal cell carcinoma. Temsirolimus monotherapy at a
dose of 25 mg IV weekly resulted in longer overall and
progression-free survival compared to interferon
(median survival 10.9 months versus 7.3 months, P=
0.008).14 There was no significant additive effect of
interferon combined with temsirolimus. A second study
combining temsirolimus and interferon over a range of
dose levels showed overall survival of 18.8 months and
progression-free survival of 9.1 months for the
combination. Partial response was observed in 8% and
stable disease in 36% of patients.15
Common toxicities of temsirolimus include asthenia,
rash, anemia, hypophosphatemia, and hyperlipidemia.
Temsirolimus has FDA approval for the treatment of
advanced renal cell carcinoma at a dose of 25 mg weekly
IV until progression.
Everolimus (Afinitor)
Everolimus (Afinitor) is a serine-threonine kinase
inhibitor of mTOR, an important regulatory protein in
cell signaling. Everolimus was approved by the US Food
and Drug Administration in March 2009 for advanced
renal cell carcinoma after failure of treatment with
sunitinib or sorafenib.
In a randomized, double-blind, placebo-controlled,
multicenter, phase 3 trial in patients with metastatic
renal cell carcinoma that had progressed during sunitinib
and/or sorafenib treatment, analysis showed
significantly longer median progression-free survival with
everolimus than with placebo. For everolimus, the
median overall survival was 14.8 months compared with
14.4 months for placebo (hazard ratio, 0.87; P = .162);
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3.
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4.
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80% of patients in the placebo arm crossed over to
everolimus.16
Other multikinase inhibitors undergoing investigation for
renal cell carcinoma
Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase
inhibitor that appears to have efficacy in the treatment
of tumors, including renal cell carcinoma, which
overexpress EGFR. A phase 3 study in patients with
advanced renal cell carcinoma who had failed prior
therapy found that lapatinib was well tolerated and had
overall efficacy equivalent to that of hormonal therapy. 17
The novel combination of bevacizumab (a neutralizing
monoclonal antibody to VEGF) and interferon has been
shown
to
have
activity
against
metastatic
RCC.18 Completion of this phase 3 trial by Escudier et al
found bevacizumab plus interferon alfa-2a effective as
first-line treatment in patients with metastatic RCC. 19
Chemotherapy
A phase 2 trial of weekly intravenous gemcitabine (600
mg/m2 on days 1, 8, and 15) with continuous infusion
fluorouracil (150 mg/m2/d for 21 d in 28-d cycle) in
patients with metastatic renal cell cancer produced a
partial response rate of 17%. No complete responses
were noted. Eighty percent of patients had multiple
metastases, and 83% had received previous treatment.
The mean progression-free survival duration of 28.7
weeks was significantly longer than that of historic
controls.20
Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol),
carboplatin, ifosfamide, gemcitabine, and anthracycline
(doxorubicin) all have been used. Floxuridine infusion
has a mean response rate of 12%, while vinblastine
infusion yielded an overall response rate of 7%. 5-FU
alone has a response rate of 10%, but when used in
combination with interferon, it had a 19% response rate
in some studies.
Renal cell carcinoma is refractory to most
chemotherapeutic agents because of multidrug
resistance mediated by p -glycoprotein. Normal renal
proximal tubules and renal cell carcinoma both express
high levels of p -glycoprotein. Calcium channel blockers
or other drugs that interfere with the function of p glycoprotein can diminish resistance to vinblastine and
anthracycline in human renal cell carcinoma cell lines.
Biologic therapies
The interferons are natural glycoproteins with antiviral,
antiproliferative, and immunomodulatory properties.
The interferons have a direct antiproliferative effect on
renal tumor cells in vitro, stimulate host mononuclear
cells,
and
enhance
expression
of
major
histocompatibility complex molecules. Interferon-alpha,
which is derived from leukocytes, has an objective
response rate of approximately 15% (range 0-29%).
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Preclinical studies have shown synergy between
interferons and cytotoxic drugs. In several prospective
randomized trials, combinations do not appear to
provide major advantages over single-agent therapy.
Many different types and preparations of interferons
have been used without any difference in efficacy.
IL-2 is a T-cell growth factor and activator of T cells and
natural killer cells. IL-2 affects tumor growth by
activating lymphoid cells in vivo without affecting tumor
proliferation directly.
In the initial study by the National Cancer Institute, bolus
intravenous infusions of high-dose IL-2 combined with
lymphokine-activated killer (LAK) cells produced
objective response rates of 33%. In subsequent
multicenter trials, the response rate was 16%.
Subsequent studies also showed that LAK cells add no
definite therapeutic benefit and can be eliminated from
the treatment.21 A high-dose regimen (600,000-720,000
IU/kg q8h for a maximum of 14 doses) resulted in a 19%
response rate with 5% complete responses. The majority
of responses to IL-2 were durable, with median response
duration of 20 months. 80% of patients who responded
completely to therapy with IL-2 were alive at 10 years.
Most patients responded after the first cycle, and those
who did not respond after the second cycle did not
respond to any further treatment. Therefore, the current
recommendation is to continue treatment with highdose IL-2 to best response (up to 6 cycles) or until toxic
effects become intolerable. Treatment should be
discontinued after 2 cycles if the patient has had no
regression. Combinations of IL-2 and interferon or other
chemotherapeutic agents such as 5-FU have not been
shown to be more effective than high-dose IL-2 alone.
Toxic effects associated with high-dose IL-2 are related
to increased vascular permeability and secondary
cytokine secretion (eg, IL-1, interferon gamma, tumor
necrosis factor, nitric oxide). The management of highdose IL-2 toxicities requires inpatient monitoring, often
in an intensive care unit.
The major toxic effect of high-dose IL-2 is a sepsislike
syndrome, which includes a progressive decrease in
systemic vascular resistance and an associated decrease
in intravascular volume due to capillary leak.
Other toxic effects are fever, chills, fatigue, infection,
and hypotension.
High-dose IL-2 has been associated with a 1-4%
incidence of treatment-related death and should be
offered only to patients with no cardiac ischemia or
significant impairment of renal or pulmonary functions.
Management includes judicious use of fluids and
vasopressor support to maintain blood pressure and
intravascular volume and at the same time to avoid
pulmonary toxicity due to noncardiogenic pulmonary
5.
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
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6.
edema from the capillary leak. This syndrome is normally
reversible.
Treatment strategies
For early stage renal cell carcinoma, an emerging
treatment strategy is to utilize these molecular
approaches earlier in the adjuvant setting in order to
improve overall survival rates. Indeed, a randomized
phase 3 trial of sunitinib versus sorafenib versus placebo
as adjuvant therapy in patients with resected renal cell
carcinoma is currently ongoing and open for patient
enrollment.22
The optimal sequence or combination of active agents in
advanced renal cell carcinoma is not yet defined. Based
on decisions derived from level 1 evidence, the following
may be considered as reasonable targeted therapy
choices in patients with metastatic renal cell carcinoma
who are not eligible for high-dose IL-2 therapy.
For previously untreated patients with clear cell renal
cell cancer of low or intermediate risk, sunitinib or the
combination of bevacizumab and interferon alpha
For patients with previously untreated clear cell renal
cell cancer with poor prognostic (high-risk)
characteristics, temsirolimus
For patients with previously treated clear cell renal cell
cancer, sorafenib; if standard doses fail, an increase in
dose may produce responses; patients in whom
sorafenib is failing may be treated with sunitinib if that
drug had not been previously used.
The treatment of metastatic renal cell carcinoma is
problematic, and, wherever possible, patients should be
directed to approved and controlled clinical trials. This
applies as well in the adjuvant treatment of surgically
resected renal cell carcinoma, for which no therapy has
yet been found to offer survival benefit.
High-dose interleukin-2 must be considered for robust
patients with excellent cardiopulmonary reserve, as it
remains the only treatment known to induce complete
and durable remissions, albeit in a minority of patients.
Prospective studies are underway to identify patients
more likely to respond to interleukin-2 immunotherapy
based on carbonic anhydrase IX expression in the
primary tumor and other assessments of immune
function and regulation. This study may help to resolve
the sequence and selection of available agents for
individual patients with metastatic disease.
Future treatment strategies for advanced renal cell
carcinoma will likely incorporate a combination of
molecular approaches, using multidrug regimens
consisting of small-molecule kinase inhibitors with
biologic therapies, immunomodulatory therapies, or
both.
Other experimental approaches for treatment include
immunomodulatory
drugs,
vaccines,
and

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7.
nonmyeloablative allogeneic peripheral blood stem-cell
transplantation.
The immunomodulator lenalidomide (Revlimid), a
derivative of thalidomide, inhibits VEGF, stimulates T and
NK cells, and inhibits inflammatory cytokines. It has been
evaluated extensively in hematologic malignancies. In
phase 2 studies of metastatic renal cell carcinoma, it
demonstrated an antitumor effect in some cases, with
disease stabilization or durable partial response.23,24
Vaccine trials are in early stages of development. Few
antigens have been identified that induce T-cell
responses from renal cell carcinoma. One example of
vaccine strategy is to induce the gene for granulocytemacrophage colony-stimulating factor (GM-CSF) into
autologous cultured renal cell cancer lines by retroviral
transduction. Patients then are immunized with
irradiated tumor cells secreting large amounts of GMCSF and are evaluated for immune responses and clinical
tumor regression. Other approaches to vaccination
include tumor lysates and dendritic cells. Autologous
vaccine therapy is now being tried in combination with
cytokine therapy. A pilot study of vaccinating with the
corresponding mutant von Hippel-Lindau peptides
demonstrated safety and proved efficacy in generating a
specific immune response in patients with advanced
renal cell carcinoma.25
Nonmyeloablative allogeneic stem cell transplantation is
another research approach. This can induce sustained
regression of metastatic renal cell carcinoma in patients
who have had no response to conventional
immunotherapy. In one trial, 19 patients with refractory
metastatic renal cell carcinoma who had suitable donors
received a preparative regimen of cyclophosphamide
and fludarabine, followed by an infusion of peripheral
blood stem cells from a human leukocyte antigen (HLA)identical sibling or a sibling with a mismatch of a single
HLA antigen. Patients with no response received as many
as 3 infusions of donor lymphocytes. Two patients died
of transplantation-related causes, and 8 died from
progressive disease. In 10 patients (53%), metastatic
disease regressed; 3 patients had a complete response,
and 7 had a partial response. The durations of these
responses continue to be assessed. Further trials are
needed to confirm these findings and to evaluate longterm benefits.
Multiple studies have been conducted using megestrol
(Megace) in the treatment of renal cell carcinoma. No
benefit has been shown except for appetite stimulation,
so megestrol is currently not recommended.
Antiestrogens such as tamoxifen (100 mg/m2/d or more)
and toremifene (300 mg/d) also have been tried, with a
response rate as low as that of most chemotherapeutic
agents.
Surgical Care
Surgical resection remains the only known effective
treatment for localized renal cell carcinoma, and it also is
used for palliation in metastatic disease.
1. Radical nephrectomy, which remains the most
commonly performed standard surgical procedure today
for treatment of localized renal carcinoma, involves
complete removal of the Gerota fascia and its contents,
including a resection of kidney, perirenal fat, and
ipsilateral adrenal gland, with or without ipsilateral
lymph node dissection. Radical nephrectomy provides a
better surgical margin than simple removal of the
kidney, since perinephric fat may be involved in some
patients. Twenty to thirty percent of patients with
clinically localized disease develop metastatic disease
after nephrectomy. Some surgeons believe that the
adrenal gland should not be removed because of the low
probability of ipsilateral adrenal metastasis and the
morbidity associated with adrenalectomy. In the absence
of distant metastatic disease with locally extensive and
invasive tumors, adjacent structures such as bowel,
spleen, or psoas muscle may be excised en bloc during
radical nephrectomy.
 Lymph nodes may be involved in 10-25% of patients. The
5-year survival rate in patients with regional node
involvement is substantially lower than in patients with
stage I or II disease. Regional lymphadenectomy adds
little in terms of operative time or risk and should be
included in conjunction with radical nephrectomy.
 Approximately 5% of patients with renal cell carcinoma
have inferior vena caval involvement. Tumor invasion of
the renal vein and inferior vena cava usually occurs as a
well-vascularized thrombus covered with its own intimal
surface. In patients with renal vein involvement without
metastases, radical nephrectomy is performed with early
ligation of the renal artery but no manipulation of the
renal vein. If the inferior vena cava is involved, then
vascular control of the inferior vena cava is obtained
both above and below the tumor thrombus, and the
thrombus is resected intact, with subsequent closure of
the vena cava. Patients with actual invasion of the
inferior vena caval wall have poor prognoses, despite
aggressive surgical approaches.
 At least 3 common approaches exist for removal of
kidney cancer, as follows: (1) the transperitoneal
approach, (2) the flank approach, and (3) the
thoracoabdominal approach. Approach depends on
tumor location and size and the body habitus of the
patient. The thoracoabdominal approach offers the
advantage of palpation of the ipsilateral lung cavity and
mediastinum, as well as the ability to resect solitary
pulmonary metastases.
2. Laparoscopic nephrectomy is a less invasive procedure,
incurs less morbidity, and is associated with shorter
3.
4.
5.
6.
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
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recovery time and less blood loss. The need for pain
medications is reduced, but operating room time and
costs are higher. Disadvantages include concerns about
spillage and technical difficulties in defining surgical
margins. Laparoscopic partial nephrectomy can be
considered at centers with experience in this procedure
for early stage renal cell cancer.
Palliative nephrectomy should be considered in patients
with metastatic disease for alleviation of symptoms such
as pain, hemorrhage, malaise, hypercalcemia,
erythrocytosis, or hypertension. Several randomized
studies are now showing improved overall survival in
patients presenting with metastatic kidney cancer who
have nephrectomy followed by either interferon or IL-2.
If the patient has good physiological status, then
nephrectomy should be performed prior to
immunotherapy. Reports have documented regression
of metastatic renal cell carcinoma after removal of the
primary tumor. Adjuvant nephrectomy is not
recommended for inducing spontaneous regression;
rather, it is performed to decrease symptoms or to
decrease tumor burden for subsequent therapy in
carefully controlled environments.
Renal artery embolization with ethanol and gelatin
sponge pledgets has been found effective for palliative
treatment in patients who are not candidates for
surgery, or who refuse surgery. A retrospective study in
8 patients with stage IV disease found that ethanol
ablation controlled hematuria and flank pain.26
About 25-30% of patients have metastatic disease at
diagnosis, and fewer than 5% have solitary metastasis.
Surgical resection is recommended in selected patients
with metastatic renal carcinoma. This procedure may not
be curative in all patients but may produce some longterm survivors. The possibility of disease-free survival
increases after resection of primary tumor and isolated
metastasis excision.
Radiation therapy may be considered as the primary
therapy for palliation in patients whose clinical condition
precludes surgery, either because of extensive disease or
poor overall condition.
A dose of 4500 centigray (cGy) is delivered, with
consideration of a boost up to 5500 cGy.
Preoperative radiation therapy yields no survival
advantage.
Controversies exist concerning postoperative radiation
therapy, but it may be considered in patients with
perinephric fat extension, adrenal invasion, or involved
margins. A dose of 4500 cGy is delivered, with
consideration of a boost.
Palliative radiation therapy is often used for local or
symptomatic metastatic disease, such as painful osseous
lesions or brain metastasis, to halt potential neurological
progression. Surgery also should be considered for
solitary brain or spine lesions, followed by postoperative
radiotherapy.
7. About 11% of patients develop brain metastasis during
the course of illness. Renal cell carcinoma is a
radioresistant tumor, but radiation treatment of brain
metastasis improves quality of life, local control, and
overall survival duration. Patients with untreated brain
metastasis have a median survival time of 1 month,
which can be improved with glucocorticoid therapy and
brain irradiation. Stereotactic radiosurgery is more
effective than surgical extirpation for local control and
can be performed on multiple lesions.
Medication
The goals of pharmacotherapy are to induce remission,
reduce morbidity, and prevent complications.
Antineoplastic agents
Few options are available for the systemic therapy of renal
cell carcinoma, and no hormonal or chemotherapeutic
regimen is accepted as a standard of care to treat renal cell
carcinoma. Objective response rates, either for single or
combination chemotherapy, usually are lower than 15%.
Multikinase inhibitors induce objective responses in up to
40% of patients, but they are not known to cure patients with
metastatic disease.
Aldesleukin (Proleukin)
IL-2; T-cell growth factor and activator of T cells and natural
killer cells. Affects tumor growth by activating lymphoid cells
in vivo, without affecting tumor proliferation directly.
Adult: 600,000-720,000 IU/kg q8h for as many as 5 d or per
protocol
Vinblastine (Velban, Alkaban-AQ)
Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to
specific site on tubulin, prevents polymerization of tubulin
dimers, and inhibits microtubule formation.
Gemcitabine (Gemzar)
Cytidine analog. After intracellular metabolism to active
nucleotide, inhibits ribonucleotide reductase and competes
with deoxycytidine triphosphate for incorporation into DNA.
5-fluorouracil (Adrucil)
Fluorinated pyrimidine antimetabolite that inhibits
thymidylate synthase (TS) and interferes with RNA synthesis
and function. Has cell-cycle specificity with activity in S phase.
Inhibits thymidylate synthase by 5-FU metabolite F-dUMP.
Metabolite FUTMP incorporates into RNA and F-dUTP
incorporates into DNA, resulting in alteration of RNA
processing and inhibition of DNA synthesis.
Sorafenib (Nexavar)
First oral multikinase inhibitor that targets serine/threonine
and tyrosine receptor kinases in both the tumor cell and the
tumor vasculature. Targets kinases involved in tumor cell
proliferation and angiogenesis, thereby decreasing tumor cell
proliferation. These kinases included RAF kinase, VEGFR-2,
VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced
renal cell carcinoma.
Adult: 400 mg PO bid 1 h ac or 2 h pc
Sunitinib (Sutent)
Mulitkinase inhibitor that targets several tyrosine kinase
inhibitors implicated in tumor growth, pathologic
angiogenesis, and metastatic progression. Inhibits plateletderived growth factor receptors (ie, PDGFR-alpha, PDGFRbeta), vascular endothelial growth factor receptors (ie,
VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT),
Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor
receptor type 1 (CSF-1R), and the glial cell-line–derived
neurotrophic factor receptor (RET). Indicated for advanced
renal cell carcinoma.
Adult
Standard dose: 50 mg PO qd on a schedule of 4 wk on
treatment followed by 2 wk off treatment, then repeat cycle
Dose modification: Increase or reduce dose in 12.5-mg
increments based on individual safety and tolerability
Coadministration with potent CYP4503A4 inhibitors:
Minimum dose of 37.5 mg PO qd during treatment phase of
cycle
Coadministration with CYP4503A4 inducers: Maximum dose
of 87.5 mg PO qd during treatment phase of cycle
Temsirolimus (Torisel)
Water soluble ester of sirolimus. Binds with high affinity to
immunophilin FKBP (FK506 binding protein). This complex
inhibits mammalian target of rapamycin (mTOR) kinase, a key
protein in cells that regulates gene translation responsible for
cell cycle regulation. mTOR also reduces cell growth factors
(eg, vascular endothelial growth factor) involved in new
blood vessel development. Indicated for advanced renal cell
carcinoma.
Adult: 25 mg IV qwk infused over 30-60 min
Everolimus (Afinitor)
Rapamycin-derivative kinase inhibitor. Indicated for
advanced renal cell carcinoma after failure of treatment with
sunitinib or sorafenib. Reduces cell proliferation and
angiogenesis by inhibition of mTOR pathway.
Adult
10 mg PO qd Hepatic impairment (ie, Child-Pugh class B): 5
mg PO qd Coadministration with strong CYP3A4 inducers:
Increase dose by 5-mg increments, not to exceed 20 mg/d
Treatment interruption and/or dose reduction to 5 mg/d may
be required to manage adverse drug effects
Interferon alfa 2a (Roferon A) and 2b (Intron A)
Interferons are natural glycoproteins with antiviral,
antiproliferative, and immunomodulatory properties.
They have direct antiproliferative effect on renal tumor cells,
stimulate host mononuclear cells, and enhance expression of
major histocompatibility complex molecules.
Adult: 6 million IU/m2 SC in combination with low-dose IL-2
or per protocol
Pazopanib (Votrient)
Multityrosine kinase inhibitor. Indicated for advanced renal
cell carcinoma.
Adult: 800 mg PO qd on empty stomach (at least 1 h ac or 2 h
pc) Baseline moderate hepatic impairment: 200 mg PO qd
Do not crush or chew (increases bioavailability and
absorption rate, with possible increased toxicity)
Food also increases bioavailability, possibly resulting in
increased toxicity
Follow-up
Further Outpatient Care
For stage I and II disease, complete history, physical
examination, chest radiographs, liver function tests, BUN and
creatinine, and calcium are recommended every 6 months
for 2 years, then annually for 5 years. Abdominal CT scan is
recommended once at 4-6 months and then as indicated.
For stage III renal cell carcinoma, physical examination, chest
radiographs, liver function tests, BUN and creatinine, and
calcium are recommended every 4 months for 2 years, every
6 months for 3 years, and then annually for 5 years.
Abdominal CT scan should be performed at 4-6 months, then
annually or as indicated.
Spontaneous regression has been reported anecdotally in
renal cell carcinoma. As many as 10% of patients with
metastatic disease show no progression for more than 12
months. All systemic therapies are associated with
treatment-related toxicity and low response, so close
observation is an option for asymptomatic metastatic
disease. Once evidence of progression or symptoms appears,
appropriate therapy should be initiated.
Careful surveillance of patients with end-stage renal disease
by ultrasonography and CT scan is recommended.
Deterrence/Prevention
Avoidance of causative factors such as smoking, obesity, and
other factors as described in Causes is recommended.
Careful surveillance of patients with end-stage renal disease
or VHL disease, those who have undergone renal
transplantation,
and
other
high-risk
groups
by
ultrasonography and CT scan is recommended.
Complications
Excruciating, sharp, bandlike back pain may be an early
warning for spinal cord compression due to metastatic renal
cell carcinoma and should not be ignored. Urgent MRI should
be performed to rule out cord compression, and high-dose
dexamethasone therapy should be started.
Prognosis
1. Five-year survival rates are as follows:
 After radical nephrectomy for stage I renal cell
carcinoma, the 5-year survival rate is approximately 94%.
Patients with stage II lesions have a survival rate of 79%.
A tumor confined to the kidney is associated with a
better prognosis.

The 5-year disease-specific survival rate in patients with
T1 renal carcinoma is 95% and in those with stage T2
disease, 88%. Patients with T3 renal carcinoma have a 5year survival rate of 59%, and those with T4 disease had
a 5-year disease-specific survival rate of 20%.
 Patients with regional lymph node involvement or
extracapsular extension have a survival rate of 12-25%.
Although renal vein involvement does not have a
markedly negative effect on prognosis, the 5-year
survival rate for patients with stage IIIB renal cell
carcinoma is 18%. In patients with effective surgical
removal of the renal vein or inferior vena caval
thrombus, the 5-year survival rate is 25-50%.
 Five-year survival rates for patients with stage IV disease
are low (0-20%).
2. Motzer et al identified 5 prognostic factors for predicting
survival in patients with metastatic renal-cell
carcinoma.27 These factors were used to categorize
patients with metastatic renal cell carcinoma into 3 risk
groups. Patients in the favorable-risk group (zero risk
factors) had a median survival of 20 months. Patients
with intermediate risk (1 or 2 risk factors) had a median
survival of 10 months, while patients in the poor-risk
group (3 or more risk factors) had a median survival of
only 4 months. The prognostic factors were as follows:
I.
Low Karnofsky performance status (<80%)
II.
High serum lactate dehydrogenase level (>1.5 times
upper limit of normal)
III.
Low hemoglobin (below lower limit of normal)
IV.
High "corrected" serum calcium (>10 mg/dL)
V.
No prior nephrectomy
3. Factors associated with increased survival in patients
with metastatic disease are as follows: (1) a long diseasefree interval between initial nephrectomy and the
appearance of metastases, (2) the presence of only
pulmonary metastases, (3) good performance status,
and (4) removal of the primary tumor.
Miscellaneous
Medicolegal Pitfalls
1. In 25-30% of patients, renal cell carcinoma is
asymptomatic and found incidentally on a radiologic
study.
2. A renal mass of indeterminate etiology should be
monitored periodically by imaging study; intravenous
pyelography (IVP), ultrasound, or CT scan. A cystic mass
can be simply observed. Patients with a solid mass
should have a complete workup, including evaluation for
metastatic disease and vascular extension of the primary
tumor.
3. As many as one third of patients with clinically localized
disease may develop metastatic disease after
nephrectomy, so they should be monitored carefully.
4. The major medical pitfall is ignoring a solid renal mass
and failing to provide appropriate follow-up care.
Special Concerns
Renal cell carcinoma develops in nearly 40% of patients with
VHL disease and is a major cause of death in patients with
VHL disease. VHL disease and other hereditary forms are
transmitted in an autosomal dominant manner. Family
members of patients with these syndromes should be
educated about familial multiple-cancer syndrome, and
genetic counseling should be offered to the patients and
family members.