Renal Cell Carcinoma

Synonyms and related keywords: renal cell adenocarcinoma, hypernephroma, hypernephroid tumor, Grawitz tumor, von Hippel-Lindau syndrome, VHL syndrome, VHL disease, hereditary papillary renal carcinoma, HPRC, familial renal oncocytoma, FRO, Birt-Hogg-Dube syndrome, BHDS, hereditary renal carcinoma, HRC, Stauffer syndrome, renal cancer, pheochromocytoma, pancreatic cysts, epididymal cystadenomas, endolymphatic sac tumors, central nervous system hemangioblastomas, retinal angiomas, islet cell tumors, fibrofolliculomas, colonic polyps, colonic tumors, pulmonary cysts, paraneoplastic syndromes, hypercalcemia, nonmetastatic hepatic dysfunction, polyneuromyopathy, amyloidosis, anemia, dermatomyositis, hypertension, varicocele, cigarette smoking, obesity, unopposed estrogen therapy, asbestos exposure, cystic kidney disease, renal dialysis, tuberous sclerosis, renal cell carcinoma


INTRODUCTION

Background: Renal cell carcinoma accounts for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. It is characterized by a lack of early warning signs, diverse clinical manifestations, resistance to radiation and chemotherapy, and infrequent but reproducible responses to immunotherapy agents such as interferon alpha and interleukin (IL)-2. New agents, such as sorafenib and sunitinib, having anti-angiogenic effects through targeting multiple receptor kinases, have activity in patients failing immunotherapy. In the past, these tumors were believed to derive from the adrenal gland; therefore, the term hypernephroma was used often.

Pathophysiology: The tissue of origin for renal cell carcinoma is the proximal renal tubular epithelium. Renal cancer occurs in both a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors (VHL, TSC) or oncogenes (MET).

At least 4 hereditary syndromes associated with renal cell carcinoma are recognized: (1) von Hippel-Lindau (VHL) syndrome, (2) hereditary papillary renal carcinoma (HPRC), (3) familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and (4) hereditary renal carcinoma (HRC).

VHL disease is transmitted in an autosomal dominant familial multiple-cancer syndrome, which confers predisposition to a variety of neoplasms, including the following:

• Renal cell carcinoma with clear cell histologic features
• Pheochromocytoma
• Pancreatic cysts and islet cell tumors
• Retinal angiomas
• Central nervous system hemangioblastomas
• Endolymphatic sac tumors
• Epididymal cystadenomas

Renal cell carcinoma develops in nearly 40% of patients with VHL disease and is a major cause of death among these patients. Deletions of 3p occur commonly in renal cell carcinoma associated with VHL disease. The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8. Mutations of the VHL gene result in the accumulation of hypoxia inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor and its receptor (VEGF and VEGFR, respectively). VEGF and VEGFR are important new therapeutic targets.

HPRC is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma. Germline mutations in the tyrosine kinase domain of the MET gene have been identified.

Individuals affected with FRO can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. BHDS is a hereditary cutaneous syndrome. Patients with BHDS have a dominantly inherited predisposition to develop benign tumors of the hair follicle (ie, fibrofolliculomas), predominantly on the face, neck, and upper trunk, and are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.

Frequency:

• In the US: The age-adjusted incidence of renal cell carcinoma has been rising by 3% per year. Approximately 36,160 new cases of renal cell carcinoma were diagnosed in 2005, and more than 12,660 affected individuals died. The greatest increase in incidence currently is observed in African Americans.

• Internationally: Number of deaths worldwide from kidney cancer was expected to exceed 100,000 in 2001.

Mortality/Morbidity: Renal cell carcinoma is the sixth leading cause of cancer death. The 5-year survival rates initially reported by Robson in 1969 were 66% for stage I renal carcinoma, 64% for stage II, 42% for stage III, and only 11% for stage IV. Except for stage I, these survival statistics have remained essentially unchanged for several decades.

Race: Renal cell carcinoma is more common in people of Northern European ancestry (Scandinavians) and North Americans than in those of Asian or African descent. In the United States, its incidence has been equivalent among whites and African Americans, but incidence among African Americans is increasing rapidly.

Sex: Renal cell carcinoma is twice as common in men as in women. The male-to-female ratio is 2:1.

Age: This condition occurs most commonly in the fourth to sixth decades of life, but the disease has been reported in younger people who belong to family clusters.

CLINICAL

History: Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease. Twenty-five to thirty percent of patients are asymptomatic, and their renal cell carcinomas are found on incidental radiologic study.

• Most common presentations

• Hematuria (40%)

• Flank pain (40%)

• Palpable mass in the flank or abdomen (25%)

• Other signs and symptoms

• Weight loss (33%)

• Fever (20%)

• Hypertension (20%)

• Hypercalcemia (5%)

• Night sweats

• Malaise

• Varicocele, usually left sided, due to obstruction of the testicular vein (2% of males)

• Renal cell carcinoma is a unique and challenging tumor because of the frequent occurrence of paraneoplastic syndromes, including hypercalcemia, erythrocytosis, and nonmetastatic hepatic dysfunction (ie, Stauffer syndrome). Polyneuromyopathy, amyloidosis, anemia, fever, cachexia, weight loss, dermatomyositis, increased erythrocyte sedimentation rate, and hypertension also are associated with renal cell carcinoma. (For more information, see Paraneoplastic Syndromes.)

• Cytokine release by tumor (eg, IL-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions.

• Resolution of symptoms or biochemical abnormalities frequently follows successful treatment of the primary tumor or metastatic foci.

Physical:

• Gross hematuria with vermiform clots suggests upper urinary tract bleeding.

• Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with bruit.

• Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease. Organs involved include:

• Lung (75%)

• Soft tissues (36%)

• Bone (20%)

• Liver (18%)

• Cutaneous sites (8%)

• Central nervous system (8%)

• Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.

Causes: A number of cellular, environmental, genetic, and hormonal factors have been studied as possible causal factors for renal cell carcinoma.

• Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-dependent fashion.

• Obesity is another risk factor, particularly in women; increasing body weight has a linear relationship with increasing risk.

• Additional factors associated with development of the disease include the following:

• Hypertension

• Treatment for hypertension

• Unopposed estrogen therapy

• Occupational exposure to petroleum products, heavy metals, solvents, coke-oven emissions, or asbestos

• The risk of renal cell carcinoma is increased with the following:

• Abuse of phenacetin-containing analgesics

• Acquired cystic kidney disease associated with chronic renal insufficiency

• Renal dialysis

• Tuberous sclerosis

• Renal transplantation: With its associated immunosuppression, renal transplantation confers an 80-fold increase in the risk of renal cell cancer.

• VHL disease: This inherited disease is associated with renal cell carcinoma.

DIFFERENTIALS

Lymphoma, Non-Hodgkin
Pyelonephritis, Acute
Pyelonephritis, Chronic
Wilms Tumor

Other Problems to be Considered:

Abscess
Angiomyolipoma (benign neoplasm)
Oncocytoma (benign neoplasm)
Metastasis from distant primary
Metastatic melanoma
Renal adenoma (benign neoplasm)
Renal cyst
Renal infarct
Sarcoma
Transitional cell carcinoma of renal pelvis

WORKUP

Lab Studies:

• Laboratory studies in the evaluation of renal cell carcinoma should include a workup for paraneoplastic syndromes. Initial studies are as follows:

• Urine analysis

• CBC count with differential

• Electrolytes

• Renal profile

• Liver function tests (AST and ALT)

• Calcium

• Erythrocyte sedimentation rate

• Prothrombin time

• Activated partial thromboplastin time

• Other tests indicated by presenting symptoms

Imaging Studies:

• A large proportion of patients diagnosed with renal cancer have small tumors discovered incidentally on imaging studies. A number of diagnostic modalities are used to evaluate and stage renal masses, including the following:

• Excretory urography

• CT scan

• Ultrasonography

• Arteriography

• Venography

• MRI
• PET

• Determining whether a space-occupying renal mass is benign or malignant can be difficult. Radiologic studies should be tailored to enable further characterization of renal masses, so that nonmalignant tumors can be differentiated from malignant ones.

• Excretory urography is not used frequently in the initial evaluation of renal masses because of its low sensitivity and specificity. A small- to medium-sized tumor may be missed by excretory urography.

• Contrast-enhanced CT scanning has become the imaging procedure of choice for diagnosis and staging of renal cell cancer and has virtually replaced excretory urography and renal ultrasound. In most cases, CT imaging can differentiate cystic masses from solid masses and supplies information about lymph node, renal vein, and inferior vena cava involvement.

• Ultrasound examination can be useful in evaluating questionable cystic renal lesions if CT imaging is inconclusive. Large papillary renal tumors are frequently undetectable by renal ultrasound.

• Renal arteriography is not used in the evaluation of a suspected renal mass as frequently now as it was in the past. When inferior vena cava involvement is suspected, either inferior venacavography or MRI angiography is used. MRI is currently the preferred imaging technique. Knowledge of inferior vena cava involvement is important in planning the vascular aspect of the operative procedure.

• A bone scan is recommended for bony symptoms with elevated alkaline phosphatase level.

• PET imaging remains controversial in kidney cancer. Its sensitivity for detecting metastatic lesions is better than for determining the presence of cancer in the renal primary site.

Procedures:

• Percutaneous cyst puncture and fluid analysis is used in the evaluation of potentially malignant cystic renal lesions detected by ultrasonography or CT imaging.

Histologic Findings: Renal cell carcinoma has 5 histologic subtypes, as follows: clear cell (75%), chromophilic (15%), chromophobic (5%), oncocytoma (3%), and collecting duct (2%).

• Unusually clear cells with a cytoplasm rich in lipids and glycogen characterize clear cell carcinoma, which is most likely to show 3p deletion.
• Chromophilic tumors tend to be bilateral and multifocal and may have trisomy 7 and/or trisomy 17.
• Large polygonal cells with pale reticular cytoplasm characterize chromophobic carcinoma, which does not exhibit 3p deletion.
• Renal oncocytoma consists predominantly of eosinophilic cells, in a characteristic nested or organoid pattern, that rarely metastasize and do not exhibit 3p deletion or trisomy 7 or 17.
• Collecting duct carcinoma is an unusual variant characterized by a very aggressive clinical course. This tends to affect younger patients and may present with local or widespread advanced disease. These cells can have 3 different types of growth patterns, (1) acinar, (2) sarcomatoid, and (3) tubulopapillary. The sarcomatoid variant, which can occur with any histologic cell type, is associated with a significantly poorer prognosis.

Table 1. Pathologic Classification of Renal Cell Carcinoma

Cell Type	Features	Growth Pattern	Cell of Origin	Cytogenetics
Clear cell	Most common	Acinar or sarcomatoid	Proximal tubule	3p-
Chromophilic	Bilateral and multifocal	Papillary or sarcomatoid	Proximal tubule	+7, +17, -Y
Chromophobic	Indolent course	Solid, tubular, or sarcomatoid	Cortical collecting duct	Hypodiploid
Oncocytic	Rarely metastasize	Tumor nests	Cortical collecting duct	Undetermined
Collecting duct	Very aggressive	Papillary or sarcomatoid	Medullary collecting duct	Undetermined

Staging:

• The Robson modification of the Flocks and Kadesky system is uncomplicated and is used commonly in clinical practice. This system was employed to correlate stage at presentation with prognosis. The Robson staging system is as follows:

• Stage I - Tumor confined within capsule of kidney

• Stage II - Tumor invading perinephric fat but still contained within the Gerota fascia

• Stage III - Tumor invading the renal vein or inferior vena cava (A), or regional lymph-node involvement (B), or both (C)

• Stage IV - Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant metastases

• The tumor, nodes, and metastases (TNM) classification is endorsed by the American Joint Committee on Cancer (AJCC). The major advantage of the TNM system is that it clearly differentiates individuals with tumor thrombi from those with local nodal disease. In the Robson system, stage III inferior vena caval involvement (IIIA) is the same stage as local lymph node metastases (IIIB). Although patients with Robson stage IIIB renal carcinoma have greatly decreased survival rates, the prognosis for patients with stage Robson IIIA renal carcinoma is not markedly different from that for patients with Robson stage I or II renal carcinoma. The TNM classification system is as follows:

• Primary tumor (T)
  • TX - Primary tumor cannot be assessed
  • T0 - No evidence of primary tumor
  • T1 - Tumor 7 cm or smaller in greatest dimension, limited to the kidney
  • T2 - Tumor larger than 7 cm in greatest dimension, limited to the kidney
  • T3 - Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
  • T3a - Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
  • T3b - Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
  • T3c - Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
  • T4 - Tumor invading beyond the Gerota fascia

• Regional lymph nodes (N) - Laterality does not affect the N classification
  • NX - Regional lymph nodes cannot be assessed
  • N0 - No regional lymph node metastasis
  • N1 - Metastasis in a single regional lymph node
  • N2 - Metastasis in more than 1 regional lymph node

• Distant metastasis (M)
  • MX - Distant metastasis cannot be assessed
  • M0 - No distant metastasis
  • M1 - Distant metastasis

• AJCC stages
  • AJCC stage I - T1, N0, M0
  • AJCC stage II - T2, N0, M0
  • AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0
  • AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1

TREATMENT

Medical Care: More than 50% of patients with renal cell carcinoma are cured in early stages, but outcome for stage IV disease is poor. The probability of cure is related directly to the stage or degree of tumor dissemination, so the approach is curative for early stage disease. Selected patients with metastatic disease respond to immunotherapy, but many patients can be offered only palliative therapy for advanced disease.

• The treatment options for renal cell cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or combinations of these.

• Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates, either for single or combination chemotherapy, usually are lower than 15%. Therefore, various biologic therapies have been evaluated.
• Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators, such as interferon, IL-2 (aldesleukin [Proleukin]), bacillus Calmette-Guérin (BCG) vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation, have been tried.

• Multi-kinase inhibitors
  • Sorafenib
    • On December 20, 2005, the US Food and Drug Administration granted approval for sorafenib (Nexavar), a small molecule Raf kinase and VEGF multi-receptor kinase inhibitor, for the treatment of patients with advanced renal cell carcinoma. This indication is based on the demonstration of improved progression-free survival in a large, multinational, randomized double-blind, placebo-controlled phase 3 study and a supportive phase 2 study. Overall survival results from the phase 3 study are preliminary at this time.
    • The sorafenib phase 3 study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Study endpoints included overall survival, progression-free survival, and response rate. Among 769 patients randomized, the median age was 59 years and 70% were male. Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93% had prior nephrectomies; 99% had received prior systemic therapies, including interleukin 2 (44%) and an interferon (68%). The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55), logrank p less than 0.000001). Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partialresponses.
    • Sorafenib toxicities (based on an updated phase 3 study database of 902 patients) included reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%, treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral mucositis, and hemorrhage also were reported more commonly on the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%).
    • Grade 3 and 4 AEs were unusual; only hand-foot skin reaction occurred at 5% or greater frequency in the sorafenib arm. Laboratory findings included asymptomatic hypophosphatemia in 45% versus 12% and serum lipase elevations in 41% versus 30% of sorafenib versus placebo patients, respectively. Grade 4 pancreatitis was reported in 2 sorafenib patients, although both patients subsequently resumed sorafenib, one at full dose.
    • Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib, and the unusual laboratory alterations on sorafenib therapy. The recommended dose is 400 mg (two 200 mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.
    • Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF, VEGFR-2,3, PDGFR-b, KIT, FLT-3, and RET.
    • Further clinical studies evaluating the role of sorafenib in the first-line setting, in combination with other immunomodulators, are underway. Preliminary results appear promising.
  • Sunitinib (Sutent)
    • Sunitinib is another multi-kinase inhibitor approved by the FDA in January 2006 for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months.
    • The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and b.
    • Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients.
    • A recent phase 3 study evaluating sunitinib in the first-line setting, compared against IFN-a, in patients with metastatic RCC demonstrated significant improvement in PFS and response rates compared against the control arm. These results are considered to be preliminary, and longer-term follow-up is necessary for conclusive results.
  • Other multi-kinase inhibitors undergoing investigation for RCC
    • Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor, which appears to have efficacy in the treatment of tumors, including RCC, which overexpress EGFR. This was recently reported in a phase 3 study in advanced RCC evaluating lapatinib against hormonal therapy in patients who had failed prior therapy.
    • RAD001 (Everolimus) is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. A recent phase 2 trial in patients with metastatic RCC demonstrated promising preliminary clinical results.
  • Future treatment strategies for advanced renal cell carcinoma will likely incorporate a combination of molecular approaches, using multidrug regimens consisting of small molecule kinase inhibitors with biologic therapies and/or immunomodulatory therapies.
  • For early stage RCC, current and future treatment strategies would utilize these molecular approaches earlier in the adjuvant setting in order to improve overall survival rates. Indeed, a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected RCC is currently ongoing and open for patient enrollment.

• Chemotherapy
  • A recent phase 2 trial of weekly intravenous gemcitabine (600 mg/m² on days 1, 8, and 15) with continuous infusion fluorouracil (150 mg/m²/d for 21 d in 28-d cycle) in patients with metastatic renal cell cancer produced a partial response rate of 17%. No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls.
  • Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5-fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol), carboplatin, ifosfamide, gemcitabine, and anthracycline (doxorubicin) all have been used. Floxuridine infusion has a mean response rate of 12%, while vinblastine infusion yielded an overall response rate of 7%. 5-FU alone has a response rate of 10%, but when used in combination with interferon, it had a 19% response rate in some studies.
  • Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p-glycoprotein. Normal renal proximal tubules and renal cell carcinoma both express high levels of p-glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p-glycoprotein can diminish resistance to vinblastine and anthracycline in human renal cell carcinoma cell lines.
• Biologic therapies
  • The interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. The interferons have a direct antiproliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. Interferon-alpha, which is derived from leukocytes, has an objective response rate of approximately 15% (range 0-29%).
  • Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. Many different types and preparations of interferons have been used without any difference in efficacy.
  • IL-2 is a T-cell growth factor and activator of T cells and natural killer cells. IL-2 affects tumor growth by activating lymphoid cells in vivo without affecting tumor proliferation directly.
    • In the initial study by the National Cancer Institute, bolus intravenous infusions of high-dose IL-2 combined with LAK cells produced objective response rates of 33%. In subsequent multicenter trials, the response rate was 16%. Subsequent studies also showed that LAK cells add no definite therapeutic benefit and can be eliminated from the treatment. A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months. Eighty percent of patients who responded completely to therapy with IL-2 were alive at 10 years.
    • Most patients responded after the first cycle, and those who did not respond after the second cycle did not respond to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-FU have not been shown to be more effective than high-dose IL-2 alone.
    • Toxic effects associated with high-dose IL-2 are related to increased vascular permeability and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide). The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive care unit. The major toxic effect of high-dose IL-2 is a sepsis-like syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. Other toxic effects are fever, chills, fatigue, infection, and hypotension. High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and should be offered only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions. Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from thecapillary leak. This syndrome is normally reversible.
• Other experimental approaches for treatment include immunomodulatory drugs, vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.

• The immunomodulator, lenalidomide (Revlimid), a derivative of thalidomide, inhibits VEGF, stimulates T and NK cells, and inhibits inflammatory cytokines. It has been evaluated extensively in hematologic malignancies and recently was reported to demonstrate efficacy in RCC regression and delayed time to progression in a phase 2 study of metastatic RCC.
• Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from renal cell carcinoma. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients then are immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells. Autologous vaccine therapy is now being tried in combination with cytokine therapy.
• Nonmyeloablative allogeneic stem-cell transplantation is another research approach. This can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one recent trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA)-identical sibling or a sibling with a mismatch of a single HLA antigen. Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes, and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed; 3 patients had a complete response, and 7 had a partial response. The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits.

• Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol currently is not recommended. Antiestrogens such as tamoxifen (100 mg/m²/d or more) and toremifene (300 mg/d) also have been tried, with a response rate as low as that of most chemotherapeutic agents.

Surgical Care: Surgical resection remains the only known effective treatment for localized renal cell carcinoma, and it also is used for palliation in metastatic disease.

• Radical nephrectomy, which remains the most commonly performed standard surgical procedure today for treatment of localized renal carcinoma, involves complete removal of the Gerota fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland, with or without ipsilateral lymph node dissection. Radical nephrectomy provides a better surgical margin than simple removal of the kidney, since perinephric fat may be involved in some patients. Twenty to thirty percent of patients with clinically localized disease develop metastatic disease after nephrectomy. Some surgeons believe that the adrenal gland should not be removed because of the low probability of ipsilateral adrenal metastasis and the morbidity associated with adrenalectomy. In the absence of distant metastatic disease with locally extensive and invasive tumors, adjacent structures such as bowel, spleen, or psoas muscle may be excised en bloc during radical nephrectomy.

• Lymph nodes may be involved in 10-25% of patients. The 5-year survival rate in patients with regional node involvement is substantially lower than in patients with stage I or II disease. Regional lymphadenectomy adds little in terms of operative time or risk and should be included in conjunction with radical nephrectomy.

• Approximately 5% of patients with renal cell carcinoma have inferior vena caval involvement. Tumor invasion of the renal vein and inferior vena cava usually occurs as a well-vascularized thrombus covered with its own intimal surface. In patients with renal vein involvement without metastases, radical nephrectomy is performed with early ligation of the renal artery but no manipulation of the renal vein. If the inferior vena cava is involved, then vascular control of the inferior vena cava is obtained both above and below the tumor thrombus, and the thrombus is resected intact, with subsequent closure of the vena cava. Patients with actual invasion of the inferior vena caval wall have poor prognoses, despite aggressive surgical approaches.

• At least 3 common approaches exist for removal of kidney cancer, as follows: (1) the transperitoneal approach, (2) the flank approach, and (3) the thoracoabdominal approach. Approach depends on tumor location and size and the body habitus of the patient. The thoracoabdominal approach offers the advantage of palpation of the ipsilateral lung cavity and mediastinum, as well as the ability to resect solitary pulmonary metastases.

• Laparoscopic nephrectomy is a less invasive procedure, incurs less morbidity, and is associated with shorter recovery time and less blood loss. The need for pain medications is reduced, but operating room time and costs are higher. Disadvantages include concerns about spillage and technical difficulties in defining surgical margins. Laparoscopic partial nephrectomy can be considered at centers with experience in this procedure for early stage renal cell cancer.

• Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise, hypercalcemia, erythrocytosis, or hypertension. Several randomized studies are now showing improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy followed by either interferon or IL-2. If the patient has good physiological status, then nephrectomy should be performed prior to immunotherapy. Reports have documented regression of metastatic renal cell carcinoma after removal of the primary tumor. Adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments.

• About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some long-term survivors. The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision.

• Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, either because of extensive disease or poor overall condition.

• A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy.
• Preoperative radiation therapy yields no survival advantage.
• Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with perinephric fat extension, adrenal invasion, or involved margins. A dose of 4500 cGy is delivered, with consideration of a boost.
• Palliative radiation therapy often is used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurological progression. Surgery also should be considered for solitary brain or spine lesions, followed by postoperative radiotherapy.

• About 11% of patients develop brain metastasis during the course of illness. Renal cell carcinoma is a radioresistant tumor, but radiation treatment of brain metastasis improves quality of life, local control, and overall survival duration. Patients with untreated brain metastasis have a median survival time of 1 month, which can be improved with glucocorticoid therapy and brain irradiation. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.

Consultations:

• Urology

• Oncology

• Radiation oncology

MEDICATION

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Drug Category: Antineoplastic agents -- Few options are available for the systemic therapy of renal cell carcinoma, and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat renal cell carcinoma. Objective response rates, either for single or combination chemotherapy, usually are lower than 15%. The recently approved multi-kinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease.

Drug Name	Aldesleukin (Proleukin) -- IL-2; T-cell growth factor and activator of T cells and natural killer cells. Affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly.
Adult Dose	600,000-720,000 IU/kg q8h for as many as 5 d or per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment
Interactions	Corticosteroids may decrease antitumor effect; NSAIDs increase capillary leak syndrome; potentiates effects of antihypertensive medications
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment May cause sepsis-like syndrome due to "capillary leak"; other toxic effects are flu-like syndrome, fever, chills, fatigue, infection, myelosuppression, hepatic toxicity, neurological and neuropsychiatric findings, hypotension, erythema, rash, urticaria, and alteration in thyroid function (including hyperthyroidism and hypothyroidism); high-dose IL-2 has been associated with treatment-related deaths

Drug Name	Vinblastine (Velban, Alkaban-AQ) -- Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation.
Adult Dose	Per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; IT use may result in death; severe bone marrow suppression; uncontrolled bacterial infection
Interactions	May reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly
Pregnancy	D - Unsafe in pregnancy
Precautions	IT use may result in death Dose-limiting toxicity is myelosuppression; other toxic effects include nausea, vomiting, alopecia, neurologic effects, local skin damage (if extravasated)

Drug Name	Gemcitabine (Gemzar) -- Cytidine analog. After intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA.
Adult Dose	Per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause myelosuppression (particularly thrombocytopenia); toxic effects include flu-like syndrome, LFT abnormalities, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic-uremic syndrome

Drug Name	5-fluorouracil (Adrucil) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. Has cell-cycle specificity with activity in S phase. Inhibits thymidylate synthase by 5-FU metabolite F-dUMP. Metabolite FUTMP incorporates into RNA and F-dUTP incorporates into DNA, resulting in alteration of RNA processing and inhibition of DNA synthesis.
Adult Dose	Per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; poor nutritional status; myelosuppression
Interactions	Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; other immunosuppressants exacerbate bone marrow toxicity; leucovorin enhances toxicity and antitumor activity when given before 5-FU; antifolate analogs (methotrexate and trimetrexate) increase formation of 5-FU metabolite; thymidine and uridine rescue host toxic effect
Pregnancy	D - Unsafe in pregnancy
Precautions	Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (eg, bone marrow suppression) may occur; main toxic effects include myelosuppression, mucositis, diarrhea, metallic taste in mouth, hand-foot syndrome, alopecia, dermatitis, increased pigmentation, cerebellar ataxia, somnolence, confusion, seizure, rarely acute encephalopathy, chest pain syndrome, ECG changes, cardiac enzyme elevation, blepharitis, tear duct stenosis, and cholestatic jaundice with biliary stenosis

Drug Name	Sorafenib (Nexavar) -- First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced renal cell carcinoma.
Adult Dose	400 mg PO bid 1 h ac or 2 h pc
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	CYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding
Pregnancy	D - Unsafe in pregnancy
Precautions	Common adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C)

Drug Name	Sunitinib (Sutent) -- Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET). Indicated for advanced renal cell carcinoma. Reduces tumor size in patients with metastatic kidney cancer whose tumors have progressed following cytokine-based therapy.
Adult Dose	Standard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; concurrent administration with St John's wort
Interactions	Potent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently)
Pregnancy	D - Unsafe in pregnancy
Precautions	Common adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding

Drug Name	Interferon alfa 2a (Roferon A) and 2b (Intron A) -- Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. They have direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules.
Adult Dose	6 million IU/m2 SC in combination with low-dose IL-2 or per protocol
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; vaccination with live vaccine during and for 3 mo after completion of therapy
Interactions	Inhibits antitumor effects of cyclophosphamide; increases effects of phenytoin and phenobarbital; theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or compromised CNS; main toxic effects include flu-like syndrome, fatigue, anorexia, somnolence, confusion, depression, myelosuppression, mild and transient elevation in serum transaminases, mild proteinuria, hypocalcemia, acute renal failure, nephrotic syndrome, alopecia rashes, pruritus, irritation at injection site, chest pain, arrhythmias, congestive heart failure, impotence, decreased libido, menstrual irregularities, and increased incidence of spontaneous abortion

FOLLOW-UP

Further Outpatient Care:

• For stage I and II disease, complete history, physical examination, chest radiographs, liver function tests, BUN and creatinine, and calcium are recommended every 6 months for 2 years, then annually for 5 years. Abdominal CT scan is recommended once at 4-6 months and then as indicated.

• For stage III renal cell carcinoma, physical examination, chest radiographs, liver function tests, BUN and creatinine, and calcium are recommended every 4 months for 2 years, every 6 months for 3 years, and then annually for 5 years. Abdominal CT scan should be performed at 4-6 months, then annually or as indicated.

• Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as 10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response, so close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated.

• Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scan is recommended.

Deterrence/Prevention:

• Avoidance of causative factors such as smoking, obesity, and other factors as described in Causes is recommended.

• Careful surveillance of patients with end-stage renal disease or VHL disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and CT scan is recommended.

Complications:

• Excruciating, sharp, bandlike back pain may be an early warning for cord compression due to metastatic renal cell carcinoma and should not be ignored. Urgent MRI should be performed to rule out cord compression, and high-dose dexamethasone therapy should be started.

Prognosis:

• Metastatic disease has increased survival with (1) a long disease-free interval between initial nephrectomy and the appearance of metastases, (2) the presence of only pulmonary metastases, (3) good performance status, and (4) removal of the primary tumor. Five-year survival rates are as follows:

• After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%, and patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis.

• The 5-year disease-specific survival rate associated with T1 renal carcinoma is 95% and with stage T2 disease, 88%. Patients with T3 renal carcinoma had a 5-year survival rate of 59%, and those with T4 disease had a 5-year disease-specific survival rate of 20%.

• Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12-25%. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB renal cell carcinoma is 18%. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25-50%.

• Five-year survival rates for patients with stage IV disease are low (0-20%).

• A recent trial identified 5 prognostic factors for predicting survival in patients with metastatic renal-cell carcinoma. These factors are used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months. Patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, while patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors were as follows:

• Low Karnofsky performance status (less than 80%)

• High serum lactate dehydrogenase level (>1.5 times upper limit of normal)

• Low hemoglobin (below lower limit of normal)

• High "corrected" serum calcium (>10 mg/dL)
• No prior nephrectomy

Patient Education:

• Patients in the high-risk group should be made aware of the early signs and symptoms, and the need for early intervention for possible cure should be stressed.

• Patients in early stages who have undergone treatment should be educated about possible relapse.

• For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Blood in the Urine and Renal Cell Cancer.

MISCELLANEOUS

Medical/Legal Pitfalls:

• In 25-30% of patients, renal cell carcinoma is asymptomatic and found incidentally on a radiologic study.

• A renal mass of indeterminate etiology should be monitored periodically by imaging study; intravenous pyelography (IVP), ultrasound, or CT scan. A cystic mass can be simply observed. Patients with a solid mass should have a complete workup, including evaluation for metastatic disease and vascular extension of the primary tumor.

• As many as one third of patients with clinically localized disease may develop metastatic disease after nephrectomy, so they should be monitored carefully.

• The major medical pitfall is ignoring a solid renal mass and failing to provide appropriate follow-up care.

Special Concerns:

• Renal cell carcinoma develops in nearly 40% of patients with VHL disease and is a major cause of death in patients with VHL disease. VHL disease and other hereditary forms are transmitted in an autosomal dominant manner. Family members of patients with these syndromes should be educated about familial multiple-cancer syndrome, and genetic counseling should be offered to the patients and family members.