Renal Cell Carcinoma cell lines from patients with sporadic (nonhereditary) clear
Introduction cell renal carcinoma. Several kindreds with familial clear cell
Background carcinoma have a constitutional balanced translocation
Renal cell carcinoma accounts for approximately 3% of between 3p and either chromosome 6 or chromosome 8.
adultmalignancies and 90-95% of neoplasms arising from the Mutations of the VHL gene result in the accumulation of
kidney. It is characterized by a lack of early warning signs, hypoxia inducible factors (HIFs) that stimulate angiogenesis
diverse clinical manifestations, and resistance to radiation through vascular endothelial growth factor and its receptor
and chemotherapy. (VEGF and VEGFR, respectively). VEGF and VEGFR are
Increasingly, renal cell cancers are diagnosed at an earlier important new therapeutic targets.
stage, and nephron-sparing surgery and thermal ablation are Hereditary papillary renal carcinoma is an inherited disorder
gaining acceptance as a treatment of choice for smaller with an autosomal dominant inheritance pattern; affected
tumors. Radical nephrectomy is the standard for larger and individuals develop bilateral, multifocal papillary renal
central tumors. carcinoma. Germline mutations in the tyrosine kinase domain
Recent clinical trials have established the role of targeted of the MET gene have been identified.
therapy as the first line of therapy in patients with metastatic Individuals affected with familial renal oncocytoma can
disease. While the optimal treatment strategy continues to develop bilateral, multifocal oncocytoma or oncocytic
evolve, three agents that target angiogenesis (sunitinib, neoplasms in the kidney. Birt-Hogg-Dube syndrome is a
bevacizumab, and pazopanib) and an mTOR-targeted therapy hereditary cutaneous syndrome. Patients with Birt-Hogg-
(temsirolimus) have been approved as front-line agents. Dube syndrome have a dominantly inherited predisposition
These have largely replaced cytokines (immunotherapy) in to develop benign tumors of the hair follicle (ie,
treatment-naive patients. Current clinical trials are testing fibrofolliculomas), predominantly on the face, neck, and
newer agents, combinations of approved agents, and the upper trunk, and are at risk of developing renal tumors,
optimal sequencing of these agents. colonic polyps or tumors, and pulmonary cysts.
The tissue of origin for renal cell carcinoma is the proximal International
renal tubular epithelium. Renal cancer occurs in both a 1. Deaths worldwide from kidney cancer exceeded 100,000
sporadic (nonhereditary) and a hereditary form, and both in 2001.
forms are associated with structural alterations of the short 2. In most of Europe, the incidence of kidney cancer has
arm of chromosome 3 (3p). Genetic studies of the families at decreased or stabilized over the past decade, perhaps in
high risk for developing renal cancer led to the cloning of part because of reduced tobacco smoking in men.
genes whose alteration results in tumor formation. These Mortality from kidney cancer has also declined in most
genes are either tumor suppressors (VHL, TSC) or oncogenes of Europe, principally in Scandinavia and other western
(MET). European countries. In men, the mortality rate per
At least 4 hereditary syndromes associated with renal cell 100,000 population fell from 4.8 in 1990-1994 to 4.1 in
carcinoma are recognized: (1) von Hippel-Lindau (VHL) 2000-2004; in women, the rate fell from 2.1 to 1.8.
syndrome, (2) hereditary papillary renal carcinoma (HPRC), Mortality/Morbidity
(3) familial renal oncocytoma (FRO) associated with Birt- Renal cell carcinoma is the tenth leading cause of cancer
Hogg-Dube syndrome (BHDS), and (4) hereditary renal deaths in males in the United States. In men, deaths from
carcinoma (HRC). kidney cancer decreased 3.9% between 1990 and 2005; in
von Hippel-Lindau disease is an autosomal dominant women, deaths decreased by 7.8% during that period.
syndrome that confers predisposition to a variety of Overall, 5-year relative survival increased from 51% to 67%
neoplasms, including the following: between 1975-1977 and 1996-2004. The 5-year survival
1. Renal cell carcinoma with clear cell histologic features rates initially reported by Robson in 1969 were 66% for stage
2. Pheochromocytoma I renal carcinoma, 64% for stage II, 42% for stage III, and only
3. Pancreatic cysts and islet cell tumors 11% for stage IV. Except for stage I, these survival statistics
4. Retinal angiomas have remained essentially unchanged for several decades.
5. Central nervous system hemangioblastomas Race
6. Endolymphatic sac tumors Renal cell carcinoma is more common in people of Northern
7. Epididymal cystadenomas European ancestry (Scandinavians) and North Americans
Renal cell carcinoma develops in nearly 40% of patients with than in those of Asian or African descent. In the United
von Hippel-Lindau disease and is a major cause of death States, its incidence is slightly higher among African
among these patients. Deletions of 3p occur commonly in Americans than among whites: 21.3 versus 19.2 per 100,000
renal cell carcinoma associated with VHL disease. population in men, and 10.3 versus 9.9 per 100,000
The VHL gene is mutated in a high percentage of tumors and population in women.
Sex 4. Varicocele and findings of paraneoplastic syndromes
Renal cell carcinoma has a m:f preponderance of 1.6:1. raise clinical suspicion for this diagnosis.
From 2002 – 2006, the median age at diagnosis was 64 years A number of environmental and genetic factors have been
of age ; however, the disease has been reported in younger studied as possible causes for renal cell carcinoma.
people who belong to family clusters. 1. Cigarette smoking doubles the risk of renal cell
Clinical carcinoma and contributes to as many as one third of all
History cases. The risk appears to increase with the amount of
Renal cell carcinoma may remain clinically occult for most of cigarette smoking in a dose-dependent fashion.
its course. The classic triad of flank pain, hematuria, and flank 2. Obesity is another risk factor, particularly in women;
mass is uncommon (10%) and is indicative of advanced increasing body weight has a linear relationship with
disease. Twenty-five to thirty percent of patients are increasing risk.
asymptomatic, and their renal cell carcinomas are found on 3. Hypertension may be associated with an increased
incidental radiologic study. incidence of renal cell carcinoma.
1. Most common presentations 4. Phenacetin-containing analgesia taken in large amounts
Hematuria (40%) may be associated with increased incidence of renal cell
Flank pain (40%) carcinoma.
Palpable mass in the flank or abdomen (25%) 5. There is an increased incidence of acquired cystic disease
2. Other signs and symptoms of the kidney in patients undergoing long-term renal
dialysis; this predisposes to renal cell cancer.
Weight loss (33%)
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.
Varicocele, usually left sided, due to obstruction of the
testicular vein (2% of males)
Pyelonephritis, Acute Pyelonephritis, Chronic
3. Renal cell carcinoma is a unique and challenging tumor
Lymphoma, Non-Hod Wilms Tumor
because of the frequent occurrence of paraneoplastic
syndromes, including hypercalcemia, erythrocytosis, and
nonmetastatic hepatic dysfunction (ie, Stauffer
1. Laboratory studies in the evaluation of renal cell
syndrome). Polyneuromyopathy, amyloidosis, anemia,
carcinoma should include a workup for paraneoplastic
fever, cachexia, weight loss, dermatomyositis, increased
syndromes. Initial studies are as follows:
erythrocyte sedimentation rate, and hypertension also
o Urine analysis
are associated with renal cell carcinoma. (For more
o CBC with differential
information, see Paraneoplastic Syndromes.)
Cytokine release by tumor (eg, IL-6, erythropoietin, nitric
o Renal profile
oxide) causes these paraneoplastic conditions.
2. Liver function tests (AST and ALT)
Resolution of symptoms or biochemical abnormalities
may follow successful treatment of the primary tumor or
4. Erythrocyte sedimentation rate
5. Prothrombin time
6. Activated partial thromboplastin time
1. Gross hematuria with vermiform clots suggests upper
7. Other tests indicated by presenting symptoms
urinary tract bleeding.
2. Look for hypertension, supraclavicular adenopathy, and
1. A large proportion of patients diagnosed with renal
flank or abdominal mass with bruit.
cancer have small tumors discovered incidentally on
3. Approximately 30% of patients with renal carcinoma
imaging studies. A number of diagnostic modalities are
present with metastatic disease. Physical examination
used to evaluate and stage renal masses:
should include thorough evaluation for metastatic
Excretory urography Arteriography
disease. Organs involved include:
CT scan Venography
Lung (75%) o Liver (18%)
Soft tissues (36%) o Cutaneous sites (8%)
2. Determining whether a space-occupying renal mass is
Bone (20%) o CNS (8%)
benign or malignant can be difficult. Radiologic studies
should be tailored to enable further characterization of tends to affect younger patients and may present as
renal masses, so that nonmalignant tumors can be local or widespread advanced disease. These cells can
differentiated from malignant ones. have 3 different types of growth patterns, (1) acinar, (2)
3. Excretory urography is not used frequently in the initial sarcomatoid, and (3) tubulopapillary. The sarcomatoid
evaluation of renal masses because of its low sensitivity variant, which can occur with any histologic cell type, is
and specificity. A small- to medium-sized tumor may be associated with a significantly poorer prognosis.
missed by excretory urography. Table 1. Pathologic Classification of Renal Cell Carcinoma
4. Contrast-enhanced CT scanning has become the imaging Cell Type Features Growth Cell of Cytogen
procedure of choice for diagnosis and staging of renal Pattern Origin etics
Clear cell Most Acinar or Proximal 3p-
cell cancer and has virtually replaced excretory common sarcomatoid tubule
urography and renal ultrasound. In most cases, CT Chromop Bilateral Papillary or Proximal +7, +17,
imaging can differentiate cystic masses from solid hilic and sarcomatoid tubule -Y
masses and supplies information about lymph node, multifocal
Chromop Indolent Solid, Cortical Hypodipl
renal vein, and inferior vena cava involvement. hobic course tubular, or collecting oid
5. Ultrasound examination can be useful in evaluating sarcomatoid duct
questionable cystic renal lesions if CT imaging is Oncocyti Rarely Tumor nests Cortical Undeter
inconclusive. Large papillary renal tumors are frequently c metastasiz collecting mined
undetectable by renal ultrasound. Collectin Very Papillary or Medullary Undeter
6. Renal arteriography is not used in the evaluation of a g duct aggressive sarcomatoid collecting mined
suspected renal mass as frequently now as it was in the duct
past. When inferior vena cava involvement is suspected, Staging
either inferior venacavography or MRI angiography is 1. The Robson modification of the Flocks and Kadesky
used. MRI is currently the preferred imaging technique. system is uncomplicated and is used commonly in clinical
Knowledge of inferior vena cava involvement is practice. This system was designed to correlate stage at
important in planning the vascular aspect of the presentation with prognosis. The Robson staging system
operative procedure. is as follows:
7. A bone scan is recommended for patients with bony Stage I - Tumor confined within capsule of kidney
symptoms and an elevated alkaline phosphatase level. Stage II - Tumor invading perinephric fat but still contained
8. PET imaging remains controversial in kidney cancer. It within the Gerota fascia
has better sensitivity for detecting metastatic lesions Stage III - Tumor invading the renal vein or inferior vena cava
than for determining the presence of cancer in the renal (A), or regional lymph-node involvement (B), or both (C)
primary site. Stage IV - Tumor invading adjacent viscera (excluding
Procedures ipsilateral adrenal) or distant metastases
Percutaneous cyst puncture and fluid analysis is used in the 2. The tumor, nodes, and metastases (TNM) classification is
evaluation of potentially malignant cystic renal lesions endorsed by the American Joint Committee on Cancer
detected by ultrasonography or CT imaging. (AJCC). The major advantage of the TNM system is that it
Histologic Findings clearly differentiates individuals with tumor thrombi
Renal cell carcinoma has 5 histologic subtypes, as follows: from those with local nodal disease. In the Robson
clear cell (75%), chromophilic (15%), chromophobic (5%), system, stage III disease includes both inferior vena caval
oncocytoma (3%), and collecting duct (2%). involvement (stage IIIA) and local lymph node
1. Unusually clear cells with a cytoplasm rich in lipids and metastases (stage IIIB). Although patients with Robson
glycogen characterize clear cell carcinoma, which is most stage IIIB renal carcinoma have greatly decreased
likely to show 3p deletion. survival rates, the prognosis for patients with stage
2. Chromophilic tumors tend to be bilateral and multifocal Robson IIIA renal carcinoma is not markedly different
and may have trisomy 7 and/or trisomy 17. from that for patients with Robson stage I or II renal
3. Large polygonal cells with pale reticular cytoplasm carcinoma. The TNM classification system is as follows:
characterize chromophobic carcinoma, which does not Primary tumor (T)
exhibit 3p deletion. TX - Primary tumor cannot be assessed
4. Renal oncocytoma consists predominantly of T0 - No evidence of primary tumor
eosinophilic cells, in a characteristic nested or organoid T1 - Tumor 7 cm or smaller in greatest dimension, limited
pattern, that rarely metastasize and do not exhibit 3p to the kidney
deletion or trisomy 7 or 17. T2 - Tumor larger than 7 cm in greatest dimension,
5. Collecting duct carcinoma is an unusual variant limited to the kidney
characterized by a very aggressive clinical course. This
T3 - Tumor extends into major veins or invades adrenal activated killer (LAK) cells plus IL-2, tumor-infiltrating
gland or perinephric tissues but not beyond the Gerota lymphocytes, and nonmyeloablative allogeneic
fascia peripheral blood stem-cell transplantation.
T3a - Tumor invades adrenal gland or perinephric tissues 2. Multikinase inhibitors
but not beyond the Gerota fascia Sorafenib
T3b - Tumor grossly extends into the renal vein(s) or Sorafenib (Nexavar), a small-molecule Raf kinase and
vena cava below the diaphragm vascular endothelial growth factor (VEGF) multireceptor
T3c - Tumor grossly extends into the renal vein(s) or vena kinase inhibitor, is approved by the U.S. Food and Drug
cava above the diaphragm Administration for the treatment of patients with
T4 - Tumor invading beyond the Gerota fascia advanced renal cell carcinoma. This indication was based
Regional lymph nodes (N) - Laterality does not affect the N on the demonstration of improved progression-free
NX - Regional lymph nodes cannot be assessed survival in a large, multinational, randomized double-
N0 - No regional lymph node metastasis blind, placebo-controlled phase 3 study and a supportive
N1 - Metastasis in a single regional lymph node phase 2 study.
N2 - Metastasis in more than 1 regional lymph node The sorafenib phase 3 study was conducted in patients
Distant metastasis (M) with advanced (unresectable or metastatic) renal cell
MX - Distant metastasis cannot be assessed carcinoma who had received one prior systemic
M0 - No distant metastasis treatment. Study endpoints included overall survival,
M1 - Distant metastasis progression-free survival, and response rate.
AJCC stages Among 769 patients randomized, the median age was 59
AJCC stage I - T1, N0, M0 years and 70% were male.
AJCC stage II - T2, N0, M0 Baseline patient and disease characteristics were well
AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0 balanced. Regarding prior therapies, 93% had prior
AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1 nephrectomies; 99% had received prior systemic
The division of patients with renal cell carcinoma into therapies, including interleukin 2 (44%) and an interferon
low-, intermediate-, and high-risk groups with or without (68%).
metastases may be useful in choosing appropriate The median progression-free survival was 167 days in
therapy for them the sorafenib group versus 84 days in the placebo
Treatment control group (HR 0.44; 95% CI for HR: 0.35-0.55, logrank
Medical Care p <0.000001). Time-to-progression was similarly
The therapeutic approach to renal cell carcinoma is guided by improved. Tumor response was determined by
the probability of cure, which is related directly to the stage independent radiologic review according to Response
or degree of tumor dissemination. More than 50% of patients Evaluation Criteria in Solid Tumors (RECIST) criteria.
with early-stage renal cell carcinoma are cured, but the Overall, of 672 patients who were able to be evaluated
outcome for stage IV disease is poor. Thus, the approach is for response, 7 (2%) sorafenib patients and 0 (0%)
curative for early-stage disease. Selected patients with placebo patients had confirmed partial responses.
metastatic disease respond to immunotherapy, but many Final results of this trial established the efficacy and
patients with advanced disease can be offered only palliative safety of sorafenib in advanced renal cell carcinoma.
therapy. Once improved progression-free survival with sorafenib
1. The treatment options for renal cell cancer are surgery, had been demonstrated, patients assigned to placebo
radiation therapy, chemotherapy, hormonal therapy, were offered sorafenib. Although an analysis that
immunotherapy, or combinations of these. included patients who crossed over to sorafenib showed
Options for chemotherapy and endocrine-based no overall survival benefit with sorafenib, a secondary
approaches are limited, and no hormonal or analysis that did not include these patients showed
chemotherapeutic regimen is accepted as a standard of significantly improved overall benefit (17.8 v 14.3
care. Objective response rates with chemotherapy, months, P = .029).
either single-agent or combination, are usually lower Sorafenib toxicities (based on an updated phase 3 study
than 15%. Therefore, various biologic therapies have database of 902 patients) included reversible skin rashes
been evaluated. in 40% and hand-foot skin reaction in 30%. Diarrhea was
Renal cell carcinoma is an immunogenic tumor, and reported in 43%, treatment-emergent hypertension in
spontaneous regressions have been documented. Many 17%, and sensory neuropathic changes in 13%. Alopecia,
immune modulators have been tried, including oral mucositis, and hemorrhage also were reported more
interferon, IL-2 (aldesleukin [Proleukin]), bacillus commonly on the sorafenib arm. The incidence of
Calmette-Guérin (BCG) vaccination, lymphokine- treatment-emergent cardiac ischemia/infarction events
was higher in the sorafenib group (2.9%) compared with An expanded-access trial provided sunitinib on a
the placebo group (0.4%). compassionate-use basis to 4,564 trial-ineligible patients
Grade 3 and 4 adverse events were unusual; only hand- with renal cell carcinoma from countries where
foot skin reaction occurred at 5% or greater frequency in regulatory approval had not been granted. Median
the sorafenib arm. Laboratory findings included progression-free survival was 10.9 months (95% CI 10.3-
asymptomatic hypophosphatemia in 45% versus 12% 11.2) and overall survival was 18.4 months (17.4-19.2).
and serum lipase elevations in 41% versus 30% of These researchers concluded that the safety of sunitinib
sorafenib versus placebo patients, respectively. Grade 4 in these patients was manageable and its efficacy was
pancreatitis was reported in 2 sorafenib patients, encouraging, particularly in subgroups associated with
although both patients subsequently resumed sorafenib, poor prognosis (eg, those with brain metastases, low
one at full dose. performance status, non–clear cell disease, and elderly
Hypertension is a common side effect of sorafenib patients).
treatment, and may be high grade. Physicians should be Temsirolimus (Torisel)
aware of the importance of frequent blood pressure Temsirolimus inhibits mTOR (mammalian target of
monitoring and management, especially during the first rapamycin), which is a serine/threonine kinase important
6 weeks after starting sorafenib. in the regulation of cell growth and division. Genes
The recommended dose is 400 mg (two 200-mg tab) involved with the response to hypoxia (HIF pathway
twice daily taken either 1 hour before or 2 hours after described above) are also upregulated by mTOR and are
meals. Adverse events were accommodated by believed to be central to the pathogenesis of kidney
temporary dose interruptions or reductions to 400 mg cancers.
once daily or 400 mg every other day. Temsirolimus has been tested alone and in conjunction
Sorafenib targets serine/threonine and receptor tyrosine with interferon in patients with poor prognosis advanced
kinases, including those of RAF; VEGFR-2,3; PDGFR-b; renal cell carcinoma. Temsirolimus monotherapy at a
KIT; FLT-3; and RET. dose of 25 mg IV weekly resulted in longer overall and
The safety and efficacy of sorafenib were also progression-free survival compared to interferon
demonstrated in a nonrandomized, open-label expanded (median survival 10.9 months versus 7.3 months, P=
access program in which 2,504 patients from the United 0.008). There was no significant additive effect of
States and Canada were treated with oral sorafenib 400 interferon combined with temsirolimus. A second study
mg twice daily. Patients included those with no prior combining temsirolimus and interferon over a range of
therapy, nonclear cell renal cell carcinoma, brain dose levels showed overall survival of 18.8 months and
metastases, and prior bevacizumab treatment; and progression-free survival of 9.1 months for the
elderly patients. Median overall survival was 50 weeks. combination. Partial response was observed in 8% and
Sunitinib (Sutent) stable disease in 36% of patients.
Sunitinib is another multikinase inhibitor approved by Common toxicities of temsirolimus include asthenia,
the FDA for the treatment of metastatic kidney cancer rash, anemia, hypophosphatemia, and hyperlipidemia.
that has progressed after a trial of immunotherapy. The Temsirolimus has FDA approval for the treatment of
approval was based on the high response rate (40% advanced renal cell carcinoma at a dose of 25 mg weekly
partial responses) and a median time to progression of IV until progression.
8.7 months and an overall survival of 16.4 months. Everolimus (Afinitor)
The receptor tyrosine kinases inhibited by sunitinib Everolimus (Afinitor) is a serine-threonine kinase
include VEGFR 1-3 and PDGFR a and b. inhibitor of mTOR, an important regulatory protein in
Major toxicities (grade II or higher) include fatigue (38%), cell signaling. Everolimus was approved by the US Food
diarrhea (24%), nausea (19%), dyspepsia (16%), and Drug Administration in March 2009 for advanced
stomatitis (19%), and decline in cardiac ejection fraction renal cell carcinoma after failure of treatment with
(11%). Dermatitis occurred in 8%, and hypertension sunitinib or sorafenib.
occurred in 5% of patients. In a randomized, double-blind, placebo-controlled,
In a phase 3 study in 750 patients with previously multicenter, phase 3 trial in patients with metastatic
untreated metastatic renal-cell carcinoma, PFS was renal cell carcinoma that had progressed during sunitinib
longer and response rates were higher in patients who and/or sorafenib treatment, analysis showed
received sunitinib than in those receiving interferon significantly longer median progression-free survival with
alfa. In final survival analyses, median overall survival everolimus than with placebo. For everolimus, the
was greater in the sunitinib group than in the interferon- median overall survival was 14.8 months compared with
alpha group (26.4 vs. 21.8 months; P=0.051), as was the 14.4 months for placebo (hazard ratio, 0.87; P = .162);
objective response rate (47% vs. 12%; P <0.001).
80% of patients in the placebo arm crossed over to Preclinical studies have shown synergy between
everolimus. interferons and cytotoxic drugs. In several prospective
Other multikinase inhibitors undergoing investigation for randomized trials, combinations do not appear to
renal cell carcinoma provide major advantages over single-agent therapy.
Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase Many different types and preparations of interferons
inhibitor that appears to have efficacy in the treatment have been used without any difference in efficacy.
of tumors, including renal cell carcinoma, which IL-2 is a T-cell growth factor and activator of T cells and
overexpress EGFR. A phase 3 study in patients with natural killer cells. IL-2 affects tumor growth by
advanced renal cell carcinoma who had failed prior activating lymphoid cells in vivo without affecting tumor
therapy found that lapatinib was well tolerated and had proliferation directly.
overall efficacy equivalent to that of hormonal therapy. In the initial study by the National Cancer Institute, bolus
The novel combination of bevacizumab (a neutralizing intravenous infusions of high-dose IL-2 combined with
monoclonal antibody to VEGF) and interferon has been lymphokine-activated killer (LAK) cells produced
shown to have activity against metastatic objective response rates of 33%. In subsequent
RCC. Completion of this phase 3 trial by Escudier et al multicenter trials, the response rate was 16%.
found bevacizumab plus interferon alfa-2a effective as Subsequent studies also showed that LAK cells add no
first-line treatment in patients with metastatic RCC. definite therapeutic benefit and can be eliminated from
3. Chemotherapy the treatment. A high-dose regimen (600,000-720,000
A phase 2 trial of weekly intravenous gemcitabine (600 IU/kg q8h for a maximum of 14 doses) resulted in a 19%
mg/m on days 1, 8, and 15) with continuous infusion response rate with 5% complete responses. The majority
fluorouracil (150 mg/m /d for 21 d in 28-d cycle) in of responses to IL-2 were durable, with median response
patients with metastatic renal cell cancer produced a duration of 20 months. 80% of patients who responded
partial response rate of 17%. No complete responses completely to therapy with IL-2 were alive at 10 years.
were noted. Eighty percent of patients had multiple Most patients responded after the first cycle, and those
metastases, and 83% had received previous treatment. who did not respond after the second cycle did not
The mean progression-free survival duration of 28.7 respond to any further treatment. Therefore, the current
weeks was significantly longer than that of historic recommendation is to continue treatment with high-
controls. dose IL-2 to best response (up to 6 cycles) or until toxic
Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5- effects become intolerable. Treatment should be
fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol), discontinued after 2 cycles if the patient has had no
carboplatin, ifosfamide, gemcitabine, and anthracycline regression. Combinations of IL-2 and interferon or other
(doxorubicin) all have been used. Floxuridine infusion chemotherapeutic agents such as 5-FU have not been
has a mean response rate of 12%, while vinblastine shown to be more effective than high-dose IL-2 alone.
infusion yielded an overall response rate of 7%. 5-FU Toxic effects associated with high-dose IL-2 are related
alone has a response rate of 10%, but when used in to increased vascular permeability and secondary
combination with interferon, it had a 19% response rate cytokine secretion (eg, IL-1, interferon gamma, tumor
in some studies. necrosis factor, nitric oxide). The management of high-
Renal cell carcinoma is refractory to most dose IL-2 toxicities requires inpatient monitoring, often
chemotherapeutic agents because of multidrug in an intensive care unit.
resistance mediated by p -glycoprotein. Normal renal The major toxic effect of high-dose IL-2 is a sepsislike
proximal tubules and renal cell carcinoma both express syndrome, which includes a progressive decrease in
high levels of p -glycoprotein. Calcium channel blockers systemic vascular resistance and an associated decrease
or other drugs that interfere with the function of p - in intravascular volume due to capillary leak.
glycoprotein can diminish resistance to vinblastine and Other toxic effects are fever, chills, fatigue, infection,
anthracycline in human renal cell carcinoma cell lines. and hypotension.
4. Biologic therapies High-dose IL-2 has been associated with a 1-4%
The interferons are natural glycoproteins with antiviral, incidence of treatment-related death and should be
antiproliferative, and immunomodulatory properties. offered only to patients with no cardiac ischemia or
The interferons have a direct antiproliferative effect on significant impairment of renal or pulmonary functions.
renal tumor cells in vitro, stimulate host mononuclear Management includes judicious use of fluids and
cells, and enhance expression of major vasopressor support to maintain blood pressure and
histocompatibility complex molecules. Interferon-alpha, intravascular volume and at the same time to avoid
which is derived from leukocytes, has an objective pulmonary toxicity due to noncardiogenic pulmonary
response rate of approximately 15% (range 0-29%).
edema from the capillary leak. This syndrome is normally nonmyeloablative allogeneic peripheral blood stem-cell
5. Treatment strategies The immunomodulator lenalidomide (Revlimid), a
For early stage renal cell carcinoma, an emerging derivative of thalidomide, inhibits VEGF, stimulates T and
treatment strategy is to utilize these molecular NK cells, and inhibits inflammatory cytokines. It has been
approaches earlier in the adjuvant setting in order to evaluated extensively in hematologic malignancies. In
improve overall survival rates. Indeed, a randomized phase 2 studies of metastatic renal cell carcinoma, it
phase 3 trial of sunitinib versus sorafenib versus placebo demonstrated an antitumor effect in some cases, with
as adjuvant therapy in patients with resected renal cell disease stabilization or durable partial response.
carcinoma is currently ongoing and open for patient Vaccine trials are in early stages of development. Few
enrollment. antigens have been identified that induce T-cell
The optimal sequence or combination of active agents in responses from renal cell carcinoma. One example of
advanced renal cell carcinoma is not yet defined. Based vaccine strategy is to induce the gene for granulocyte-
on decisions derived from level 1 evidence, the following macrophage colony-stimulating factor (GM-CSF) into
may be considered as reasonable targeted therapy autologous cultured renal cell cancer lines by retroviral
choices in patients with metastatic renal cell carcinoma transduction. Patients then are immunized with
who are not eligible for high-dose IL-2 therapy. irradiated tumor cells secreting large amounts of GM-
For previously untreated patients with clear cell renal CSF and are evaluated for immune responses and clinical
cell cancer of low or intermediate risk, sunitinib or the tumor regression. Other approaches to vaccination
combination of bevacizumab and interferon alpha include tumor lysates and dendritic cells. Autologous
For patients with previously untreated clear cell renal vaccine therapy is now being tried in combination with
cell cancer with poor prognostic (high-risk) cytokine therapy. A pilot study of vaccinating with the
characteristics, temsirolimus corresponding mutant von Hippel-Lindau peptides
For patients with previously treated clear cell renal cell demonstrated safety and proved efficacy in generating a
cancer, sorafenib; if standard doses fail, an increase in specific immune response in patients with advanced
dose may produce responses; patients in whom renal cell carcinoma.
sorafenib is failing may be treated with sunitinib if that Nonmyeloablative allogeneic stem cell transplantation is
drug had not been previously used. another research approach. This can induce sustained
The treatment of metastatic renal cell carcinoma is regression of metastatic renal cell carcinoma in patients
problematic, and, wherever possible, patients should be who have had no response to conventional
directed to approved and controlled clinical trials. This immunotherapy. In one trial, 19 patients with refractory
applies as well in the adjuvant treatment of surgically metastatic renal cell carcinoma who had suitable donors
resected renal cell carcinoma, for which no therapy has received a preparative regimen of cyclophosphamide
yet been found to offer survival benefit. and fludarabine, followed by an infusion of peripheral
High-dose interleukin-2 must be considered for robust blood stem cells from a human leukocyte antigen (HLA)-
patients with excellent cardiopulmonary reserve, as it identical sibling or a sibling with a mismatch of a single
remains the only treatment known to induce complete HLA antigen. Patients with no response received as many
and durable remissions, albeit in a minority of patients. as 3 infusions of donor lymphocytes. Two patients died
Prospective studies are underway to identify patients of transplantation-related causes, and 8 died from
more likely to respond to interleukin-2 immunotherapy progressive disease. In 10 patients (53%), metastatic
based on carbonic anhydrase IX expression in the disease regressed; 3 patients had a complete response,
primary tumor and other assessments of immune and 7 had a partial response. The durations of these
function and regulation. This study may help to resolve responses continue to be assessed. Further trials are
the sequence and selection of available agents for needed to confirm these findings and to evaluate long-
individual patients with metastatic disease. term benefits.
Future treatment strategies for advanced renal cell 7. Multiple studies have been conducted using megestrol
carcinoma will likely incorporate a combination of (Megace) in the treatment of renal cell carcinoma. No
molecular approaches, using multidrug regimens benefit has been shown except for appetite stimulation,
consisting of small-molecule kinase inhibitors with so megestrol is currently not recommended.
biologic therapies, immunomodulatory therapies, or Antiestrogens such as tamoxifen (100 mg/m /d or more)
both. and toremifene (300 mg/d) also have been tried, with a
6. Other experimental approaches for treatment include response rate as low as that of most chemotherapeutic
immunomodulatory drugs, vaccines, and agents.
Surgical Care recovery time and less blood loss. The need for pain
Surgical resection remains the only known effective medications is reduced, but operating room time and
treatment for localized renal cell carcinoma, and it also is costs are higher. Disadvantages include concerns about
used for palliation in metastatic disease. spillage and technical difficulties in defining surgical
1. Radical nephrectomy, which remains the most margins. Laparoscopic partial nephrectomy can be
commonly performed standard surgical procedure today considered at centers with experience in this procedure
for treatment of localized renal carcinoma, involves for early stage renal cell cancer.
complete removal of the Gerota fascia and its contents, 3. Palliative nephrectomy should be considered in patients
including a resection of kidney, perirenal fat, and with metastatic disease for alleviation of symptoms such
ipsilateral adrenal gland, with or without ipsilateral as pain, hemorrhage, malaise, hypercalcemia,
lymph node dissection. Radical nephrectomy provides a erythrocytosis, or hypertension. Several randomized
better surgical margin than simple removal of the studies are now showing improved overall survival in
kidney, since perinephric fat may be involved in some patients presenting with metastatic kidney cancer who
patients. Twenty to thirty percent of patients with have nephrectomy followed by either interferon or IL-2.
clinically localized disease develop metastatic disease If the patient has good physiological status, then
after nephrectomy. Some surgeons believe that the nephrectomy should be performed prior to
adrenal gland should not be removed because of the low immunotherapy. Reports have documented regression
probability of ipsilateral adrenal metastasis and the of metastatic renal cell carcinoma after removal of the
morbidity associated with adrenalectomy. In the absence primary tumor. Adjuvant nephrectomy is not
of distant metastatic disease with locally extensive and recommended for inducing spontaneous regression;
invasive tumors, adjacent structures such as bowel, rather, it is performed to decrease symptoms or to
spleen, or psoas muscle may be excised en bloc during decrease tumor burden for subsequent therapy in
radical nephrectomy. carefully controlled environments.
Lymph nodes may be involved in 10-25% of patients. The 4. Renal artery embolization with ethanol and gelatin
5-year survival rate in patients with regional node sponge pledgets has been found effective for palliative
involvement is substantially lower than in patients with treatment in patients who are not candidates for
stage I or II disease. Regional lymphadenectomy adds surgery, or who refuse surgery. A retrospective study in
little in terms of operative time or risk and should be 8 patients with stage IV disease found that ethanol
included in conjunction with radical nephrectomy. ablation controlled hematuria and flank pain.
Approximately 5% of patients with renal cell carcinoma 5. About 25-30% of patients have metastatic disease at
have inferior vena caval involvement. Tumor invasion of diagnosis, and fewer than 5% have solitary metastasis.
the renal vein and inferior vena cava usually occurs as a Surgical resection is recommended in selected patients
well-vascularized thrombus covered with its own intimal with metastatic renal carcinoma. This procedure may not
surface. In patients with renal vein involvement without be curative in all patients but may produce some long-
metastases, radical nephrectomy is performed with early term survivors. The possibility of disease-free survival
ligation of the renal artery but no manipulation of the increases after resection of primary tumor and isolated
renal vein. If the inferior vena cava is involved, then metastasis excision.
vascular control of the inferior vena cava is obtained 6. Radiation therapy may be considered as the primary
both above and below the tumor thrombus, and the therapy for palliation in patients whose clinical condition
thrombus is resected intact, with subsequent closure of precludes surgery, either because of extensive disease or
the vena cava. Patients with actual invasion of the poor overall condition.
inferior vena caval wall have poor prognoses, despite A dose of 4500 centigray (cGy) is delivered, with
aggressive surgical approaches. consideration of a boost up to 5500 cGy.
At least 3 common approaches exist for removal of Preoperative radiation therapy yields no survival
kidney cancer, as follows: (1) the transperitoneal advantage.
approach, (2) the flank approach, and (3) the Controversies exist concerning postoperative radiation
thoracoabdominal approach. Approach depends on therapy, but it may be considered in patients with
tumor location and size and the body habitus of the perinephric fat extension, adrenal invasion, or involved
patient. The thoracoabdominal approach offers the margins. A dose of 4500 cGy is delivered, with
advantage of palpation of the ipsilateral lung cavity and consideration of a boost.
mediastinum, as well as the ability to resect solitary Palliative radiation therapy is often used for local or
pulmonary metastases. symptomatic metastatic disease, such as painful osseous
2. Laparoscopic nephrectomy is a less invasive procedure, lesions or brain metastasis, to halt potential neurological
incurs less morbidity, and is associated with shorter progression. Surgery also should be considered for
solitary brain or spine lesions, followed by postoperative VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced
radiotherapy. renal cell carcinoma.
7. About 11% of patients develop brain metastasis during Adult: 400 mg PO bid 1 h ac or 2 h pc
the course of illness. Renal cell carcinoma is a Sunitinib (Sutent)
radioresistant tumor, but radiation treatment of brain Mulitkinase inhibitor that targets several tyrosine kinase
metastasis improves quality of life, local control, and inhibitors implicated in tumor growth, pathologic
overall survival duration. Patients with untreated brain angiogenesis, and metastatic progression. Inhibits platelet-
metastasis have a median survival time of 1 month, derived growth factor receptors (ie, PDGFR-alpha, PDGFR-
which can be improved with glucocorticoid therapy and beta), vascular endothelial growth factor receptors (ie,
brain irradiation. Stereotactic radiosurgery is more VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT),
effective than surgical extirpation for local control and Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor
can be performed on multiple lesions. receptor type 1 (CSF-1R), and the glial cell-line–derived
Medication neurotrophic factor receptor (RET). Indicated for advanced
The goals of pharmacotherapy are to induce remission, renal cell carcinoma.
reduce morbidity, and prevent complications. Adult
Antineoplastic agents Standard dose: 50 mg PO qd on a schedule of 4 wk on
Few options are available for the systemic therapy of renal treatment followed by 2 wk off treatment, then repeat cycle
cell carcinoma, and no hormonal or chemotherapeutic Dose modification: Increase or reduce dose in 12.5-mg
regimen is accepted as a standard of care to treat renal cell increments based on individual safety and tolerability
carcinoma. Objective response rates, either for single or Coadministration with potent CYP4503A4 inhibitors:
combination chemotherapy, usually are lower than 15%. Minimum dose of 37.5 mg PO qd during treatment phase of
Multikinase inhibitors induce objective responses in up to cycle
40% of patients, but they are not known to cure patients with Coadministration with CYP4503A4 inducers: Maximum dose
metastatic disease. of 87.5 mg PO qd during treatment phase of cycle
Aldesleukin (Proleukin) Temsirolimus (Torisel)
IL-2; T-cell growth factor and activator of T cells and natural Water soluble ester of sirolimus. Binds with high affinity to
killer cells. Affects tumor growth by activating lymphoid cells immunophilin FKBP (FK506 binding protein). This complex
in vivo, without affecting tumor proliferation directly. inhibits mammalian target of rapamycin (mTOR) kinase, a key
Adult: 600,000-720,000 IU/kg q8h for as many as 5 d or per protein in cells that regulates gene translation responsible for
protocol cell cycle regulation. mTOR also reduces cell growth factors
Vinblastine (Velban, Alkaban-AQ) (eg, vascular endothelial growth factor) involved in new
Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to blood vessel development. Indicated for advanced renal cell
specific site on tubulin, prevents polymerization of tubulin carcinoma.
dimers, and inhibits microtubule formation. Adult: 25 mg IV qwk infused over 30-60 min
Gemcitabine (Gemzar) Everolimus (Afinitor)
Cytidine analog. After intracellular metabolism to active Rapamycin-derivative kinase inhibitor. Indicated for
nucleotide, inhibits ribonucleotide reductase and competes advanced renal cell carcinoma after failure of treatment with
with deoxycytidine triphosphate for incorporation into DNA. sunitinib or sorafenib. Reduces cell proliferation and
angiogenesis by inhibition of mTOR pathway.
Fluorinated pyrimidine antimetabolite that inhibits
10 mg PO qd Hepatic impairment (ie, Child-Pugh class B): 5
thymidylate synthase (TS) and interferes with RNA synthesis
mg PO qd Coadministration with strong CYP3A4 inducers:
and function. Has cell-cycle specificity with activity in S phase.
Increase dose by 5-mg increments, not to exceed 20 mg/d
Inhibits thymidylate synthase by 5-FU metabolite F-dUMP.
Treatment interruption and/or dose reduction to 5 mg/d may
Metabolite FUTMP incorporates into RNA and F-dUTP
be required to manage adverse drug effects
incorporates into DNA, resulting in alteration of RNA
processing and inhibition of DNA synthesis. Interferon alfa 2a (Roferon A) and 2b (Intron A)
Interferons are natural glycoproteins with antiviral,
antiproliferative, and immunomodulatory properties.
First oral multikinase inhibitor that targets serine/threonine
They have direct antiproliferative effect on renal tumor cells,
and tyrosine receptor kinases in both the tumor cell and the
stimulate host mononuclear cells, and enhance expression of
tumor vasculature. Targets kinases involved in tumor cell
major histocompatibility complex molecules.
proliferation and angiogenesis, thereby decreasing tumor cell
proliferation. These kinases included RAF kinase, VEGFR-2,
Adult: 6 million IU/m SC in combination with low-dose IL-2 The 5-year disease-specific survival rate in patients with
or per protocol T1 renal carcinoma is 95% and in those with stage T2
Pazopanib (Votrient) disease, 88%. Patients with T3 renal carcinoma have a 5-
Multityrosine kinase inhibitor. Indicated for advanced renal year survival rate of 59%, and those with T4 disease had
cell carcinoma. a 5-year disease-specific survival rate of 20%.
Adult: 800 mg PO qd on empty stomach (at least 1 h ac or 2 h Patients with regional lymph node involvement or
pc) Baseline moderate hepatic impairment: 200 mg PO qd extracapsular extension have a survival rate of 12-25%.
Do not crush or chew (increases bioavailability and Although renal vein involvement does not have a
absorption rate, with possible increased toxicity) markedly negative effect on prognosis, the 5-year
Food also increases bioavailability, possibly resulting in survival rate for patients with stage IIIB renal cell
increased toxicity carcinoma is 18%. In patients with effective surgical
Follow-up removal of the renal vein or inferior vena caval
thrombus, the 5-year survival rate is 25-50%.
Further Outpatient Care
For stage I and II disease, complete history, physical Five-year survival rates for patients with stage IV disease
examination, chest radiographs, liver function tests, BUN and are low (0-20%).
creatinine, and calcium are recommended every 6 months 2. Motzer et al identified 5 prognostic factors for predicting
for 2 years, then annually for 5 years. Abdominal CT scan is survival in patients with metastatic renal-cell
recommended once at 4-6 months and then as indicated. carcinoma. These factors were used to categorize
For stage III renal cell carcinoma, physical examination, chest patients with metastatic renal cell carcinoma into 3 risk
radiographs, liver function tests, BUN and creatinine, and groups. Patients in the favorable-risk group (zero risk
calcium are recommended every 4 months for 2 years, every factors) had a median survival of 20 months. Patients
6 months for 3 years, and then annually for 5 years. with intermediate risk (1 or 2 risk factors) had a median
Abdominal CT scan should be performed at 4-6 months, then survival of 10 months, while patients in the poor-risk
annually or as indicated. group (3 or more risk factors) had a median survival of
Spontaneous regression has been reported anecdotally in only 4 months. The prognostic factors were as follows:
renal cell carcinoma. As many as 10% of patients with I. Low Karnofsky performance status (<80%)
metastatic disease show no progression for more than 12 II. High serum lactate dehydrogenase level (>1.5 times
months. All systemic therapies are associated with upper limit of normal)
treatment-related toxicity and low response, so close III. Low hemoglobin (below lower limit of normal)
observation is an option for asymptomatic metastatic IV. High "corrected" serum calcium (>10 mg/dL)
disease. Once evidence of progression or symptoms appears, V. No prior nephrectomy
appropriate therapy should be initiated. 3. Factors associated with increased survival in patients
Careful surveillance of patients with end-stage renal disease with metastatic disease are as follows: (1) a long disease-
by ultrasonography and CT scan is recommended. free interval between initial nephrectomy and the
Deterrence/Prevention appearance of metastases, (2) the presence of only
Avoidance of causative factors such as smoking, obesity, and pulmonary metastases, (3) good performance status,
other factors as described in Causes is recommended. and (4) removal of the primary tumor.
Careful surveillance of patients with end-stage renal disease Miscellaneous
or VHL disease, those who have undergone renal Medicolegal Pitfalls
transplantation, and other high-risk groups by 1. In 25-30% of patients, renal cell carcinoma is
ultrasonography and CT scan is recommended. asymptomatic and found incidentally on a radiologic
Excruciating, sharp, bandlike back pain may be an early 2. A renal mass of indeterminate etiology should be
warning for spinal cord compression due to metastatic renal monitored periodically by imaging study; intravenous
cell carcinoma and should not be ignored. Urgent MRI should pyelography (IVP), ultrasound, or CT scan. A cystic mass
be performed to rule out cord compression, and high-dose can be simply observed. Patients with a solid mass
dexamethasone therapy should be started. should have a complete workup, including evaluation for
Prognosis metastatic disease and vascular extension of the primary
1. Five-year survival rates are as follows: tumor.
After radical nephrectomy for stage I renal cell 3. As many as one third of patients with clinically localized
carcinoma, the 5-year survival rate is approximately 94%. disease may develop metastatic disease after
Patients with stage II lesions have a survival rate of 79%. nephrectomy, so they should be monitored carefully.
A tumor confined to the kidney is associated with a 4. The major medical pitfall is ignoring a solid renal mass
better prognosis. and failing to provide appropriate follow-up care.
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