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.
Pathophysiology                                                    Frequency
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.
Age                                                                 Causes
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
 Fever (20%)
                                                                    7. Renal transplantation: Acquired renal cystic disease of
 Hypertension (20%)
                                                                         the native kidney also predisposes to renal cell cancer in
 Hypercalcemia (5%)
                                                                         renal transplant recipients.
 Night sweats
                                                                    8. VHL disease: This inherited disease is associated with
 Malaise
                                                                         renal cell carcinoma.
 Varicocele, usually left sided, due to obstruction of the
                                                                    Differential Diagnoses
     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
                                                                    Laboratory Studies
     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.)
                                                                             o Electrolytes
 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
                                                                    3. Calcium
     may follow successful treatment of the primary tumor or
                                                                    4. Erythrocyte sedimentation rate
     metastatic foci.
                                                                    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.
                                                                    Imaging Studies
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%)
                                                                          Ultrasonography                      MRI
 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
                                                                               e                           duct
     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
     reversible.                                                       transplantation.
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.
5-fluorouracil (Adrucil)
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,
Sorafenib (Nexavar)
                                                                     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
Complications                                                           study.
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.
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.

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