Drugs Expert

Renal cell carcinoma (RCC, also known as hypernephroma) is a kidney cancer that originates in the lining of the proximal convoluted tubule, the very small tubes in the kidney that filter the blood and remove waste products. RCC is the most common type of kidney cancer in adults, responsible for approximately 80% of cases.  It is also known to be the most lethal of all the genitourinary tumors. Initial treatment is most commonly a radical or partial nephrectomy and remains the mainstay of curative treatment. Where the tumour is confined to the renal parenchyma, the 5-year survival rate is 60-70%, but this is lowered considerably where metastases have spread.

It is resistant to radiation therapy and chemotherapy, although some cases respond to immunotherapy. Targeted cancer therapies such as sunitinib, temsirolimus, bevacizumab, interferon-alpha, and possibly sorafenib have improved the outlook for RCC (progression-free survival), although they have not yet demonstrated improved survival.

What are the Causes and Risk factors of Renal Cell Carcinoma?

The exact cause of renal cell cancer has not been determined. A number of different factors seem to contribute to renal cell cancer. These factors include the following:

• Cigarette smoking doubles the risk of renal cell cancer and contributes to as many as one third of all cases. The more someone smokes, the greater the risk is of that person developing renal cell cancer.
• Obesity is a risk factor. As body weight increases, so does the risk of developing renal cell cancer. This is especially true in women.
• Occupational exposure to petroleum products, heavy metals, solvents, coke-oven emissions, or asbestos
• Cystic kidney disease associated with chronic (long-term) renal insufficiency
• Cystic changes in the kidney and renal dialysis
• Tuberous sclerosis
• Von Hippel-Lindau (VHL) disease, an inherited disease associated with several cancers
• Hereditary renal cancer
• Associated malignancy such as lymphoma

What are the Symptoms of Renal Cell Carcinoma?

A wide range of symptoms can be present with renal carcinoma depending on which areas of the body have been affected. The classic triad is hematuria (blood in the urine), flank pain and an abdominal mass. This triad only occurs in 10-15% of cases, and is generally indicative of more advanced disease. Today, the majority of renal tumors are asymptomatic and are detected incidentally on imaging, usually for an unrelated cause.

Signs may include:

• Abnormal urine color (dark, rusty, or brown) due to blood in the urine (found in 60% of cases)
• Loin pain (found in 40% of cases)
• Abdominal mass (25% of cases)
• Malaise, weight loss or anorexia (30% of cases)
• Polycythemia (5% of cases)
• Anaemia resulting from depression of erythropoietin (30% of cases)
• The presenting symptom may be due to metastatic disease, such as a pathologic fracture of the hip due to a metastasis to the bone
• Varicocele, the enlargement of one testicle, usually on the left (2% of cases). This is due to blockage of the left testicular vein by tumor invasion of the left renal vein; this typically does not occur on the right as the right gonadal vein drains directly into the inferior vena cava.
• Vision abnormalities
• Pallor or plethora
• Hirsutism – Excessive hair growth (females)
• Constipation
• Hypertension (high blood pressure) resulting from secretion of renin by the tumour (30% of cases)
• Elevated calcium levels (Hypercalcemia)
• Stauffer syndrome – paraneoplastic, non-metastatic liver disease
• Night Sweats
• Severe Weight Loss

Patients may also experience the following symptoms:

• Recurrent fevers which occur in 9% of the patients
• Cold intolerance
• Back pain
• Chronic fatigue
• Leg and ankle swelling
• Loss of appetite

Classification

Recent genetic studies have altered the approaches used in classifying renal cell carcinoma. The following system can be used to classify these tumors:

• Clear cell renal cell carcinoma (VHL and others on chromosome 3)
• Papillary renal cell carcinoma (MET, PRCC)
• Chromophobe renal cell carcinoma
• Collecting duct carcinoma

Renal epithelial neoplasms have characteristic cytogenetic aberrations that can aid in classification.

• Clear cell carcinoma: loss of 3p
• Papillary carcinoma: trisomy 7, 16, 17
• Chromophobe carcinoma: hypodiploid with loss of chromosomes 1, 2, 6, 10, 13, 17, 21

Array-based karyotyping can be used to identify characteristic chromosomal aberrations in renal tumors with challenging morphology. Array-based karyotyping performs well on paraffin embedded tumors and is amenable to routine clinical use. See also Virtual Karyotype for CLIA certified laboratories offering array-based karyotyping of solid tumors.

Other associated genes include TRC8, OGG1, HNF1A, HNF1B, TFE3, RCCP3, and RCC17.

Diagnosis

Laboratory 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 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 patients with bony symptoms and an elevated alkaline phosphatase level.
• PET imaging remains controversial in kidney cancer. It has better sensitivity for detecting metastatic lesions than for determining the presence of cancer in the renal primary site.

Procedures

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

Histologic Findings

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

• 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 as local or widespread advanced disease. These cells can have 3 different types of growth patterns, (1) acinar, (2) sarcomatoid, and (3) tubulopapillary. The sarcomatoid variant, which can occur with any histologic cell type, is associated with a significantly poorer prognosis.

Staging

• The Robson modification of the Flocks and Kadesky system is uncomplicated and is used commonly in clinical practice. This system was designed to correlate stage at presentation with prognosis. The Robson staging system is as follows:
  • Stage I – Tumor confined within capsule of kidney
  • Stage II – Tumor invading perinephric fat but still contained within the Gerota fascia
  • Stage III – Tumor invading the renal vein or inferior vena cava (A), or regional lymph-node involvement (B), or both (C)
  • Stage IV – Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant metastases
• The tumor, nodes, and metastases (TNM) classification is endorsed by the American Joint Committee on Cancer (AJCC). The major advantage of the TNM system is that it clearly differentiates individuals with tumor thrombi from those with local nodal disease. In the Robson system, stage III disease includes both inferior vena caval involvement (stage IIIA) and local lymph node metastases (stage IIIB). Although patients with Robson stage IIIB renal carcinoma have greatly decreased survival rates, the prognosis for patients with stage Robson IIIA renal carcinoma is not markedly different from that for patients with Robson stage I or II renal carcinoma. The TNM classification system is as follows:
  • Primary tumor (T)
    • TX – Primary tumor cannot be assessed
    • T0 – No evidence of primary tumor
    • T1 – Tumor 7 cm or smaller in greatest dimension, limited to the kidney
    • T2 – Tumor larger than 7 cm in greatest dimension, limited to the kidney
    • T3 – Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
    • T3a – Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
    • T3b – Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
    • T3c – Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
    • T4 – Tumor invading beyond the Gerota fascia
  • Regional lymph nodes (N) – Laterality does not affect the N 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
  • The division of patients with renal cell carcinoma into low-, intermediate-, and high-risk groups with or without metastases may be useful in choosing appropriate therapy for them.

Methods of Treatment

If it is only in the kidneys, which is about 40% of cases, it can be cured roughly 90% of the time with surgery. If it has spread outside of the kidneys, often into the lymph nodes or the main vein of the kidney, then it must be treated with adjunctive therapy, including cytoreductive surgery. RCC is resistant to chemotherapy and radiotherapy in most cases, but does respond well to immunotherapy with interleukin-2 or interferon-alpha, biologic, or targeted therapy. In early stage cases, cryotherapy and surgery are the preferred options.

Watchful waiting

Small renal tumors (< 4 cm) are treated increasingly by way of partial nephrectomy when possible. Most of these small renal masses manifest indolent biological behavior with excellent prognosis. More centers of excellence are incorporating needle biopsy to confirm the presence of malignant histology prior to recommending definitive surgical extirpation. In the elderly, patients with co-morbidities and in poor surgical candidates, small renal tumors may be monitored carefully with serial imaging. Most clinicians conservatively follow tumors up to a size threshold between 3–5 cm, beyond which the risk of distant spread (metastases) is about 5%.

Surgery

Micrograph of embolic material in a kidney removed because of renal cell carcinoma (cancer not shown). H&E stain.

Surgical removal of all or part of the kidney (nephrectomy) is recommended. This may include removal of the adrenal gland, retroperitoneal lymph nodes, and possibly tissues involved by direct extension (invasion) of the tumor into the surrounding tissues. In cases where the tumor has spread into the renal vein, inferior vena cava, and possibly the right atrium, this portion of the tumor can be surgically removed, as well. In cases of known metastases, surgical resection of the kidney (“cytoreductive nephrectomy”) may improve survival, as well as resection of a solitary metastatic lesion. Kidneys are sometimes embolized prior to surgery to minimize blood loss.

Surgery is increasingly performed via laparoscopic techniques. These have the advantage of being less of a burden for the patient and the disease-free survival is comparable to that of open surgery. For small exophytic lesions that do not extensively involve the major vessels or urinary collecting system, a partial nephrectomy (also referred to as “nephron sparing surgery”) can be performed. This may involve temporarily stopping blood flow to the kidney while the mass is removed as well as renal cooling with an ice slush. Mannitol can also be administered to help limit damage to the kidney. This is usually done through an open incision although smaller lesions can be done laparoscopically with or without robotic assistance.

Laparoscopic cryotherapy can also be done on smaller lesions. Typically a biopsy is taken at the time of treatment. Intraoperative ultrasound may be used to help guide placement of the freezing probes. Two freeze/thaw cycles are then performed to kill the tumor cells. As the tumor is not removed followup is more complicated (see below) and overall disease free rates are not as good as those obtained with surgical removal.

Percutaneous therapies

Percutaneous, image-guided therapies, usually managed by radiologists, are being offered to patients with localized tumor, but who are not good candidates for a surgical procedure. This sort of procedure involves placing a probe through the skin and into the tumor using real-time imaging of both the probe tip and the tumor by computed tomography, ultrasound, or even magnetic resonance imaging guidance, and then destroying the tumor with heat (radiofrequency ablation) or cold (cryotherapy). These modalities are at a disadvantage compared to traditional surgery in that pathologic confirmation of complete tumor destruction is not possible. Therefore, long-term follow-up is crucial to assess completeness of tumour ablation.

Medications

RCC “elicits an immune response, which occasionally results in dramatic spontaneous remissions.” This has encouraged a strategy of using immunomodulating therapies, such as cancer vaccines and interleukin-2 (IL-2), to reproduce this response. IL-2 has produced “durable remissions” in a small number of patients, but with substantial toxicity. Another strategy is to restore the function of the VHL gene, which is to destroy proteins that promote inappropriate vascularization. Bevacizumab, an antibody to VEGF, has significantly prolonged time to progression, but phase 3 trials have not been published. Sunitinib (Sutent), sorafenib (Nexavar), and temsirolimus, which are small-molecule inhibitors of proteins, have been approved by the U.S. F.D.A.

Treatment with tyrosine kinase inhibitors including nexavar, pazopanib, and rapamycin have shown promise in improving the prognosis for advanced RCC since 2004.

• Sorafenib
  • Sorafenib (Nexavar), a small-molecule Raf kinase and vascular endothelial growth factor (VEGF) multireceptor kinase inhibitor, is approved by the U.S. Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. This indication was based on the demonstration of improved progression-free survival in a large, multinational, randomized double-blind, placebo-controlled phase 3 study and a supportive phase 2 study.
  • The sorafenib phase 3 study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Study endpoints included overall survival, progression-free survival, and response rate.
    • Among 769 patients randomized, the median age was 59 years and 70% were male.
    • Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93% had prior nephrectomies; 99% had received prior systemic therapies, including interleukin 2 (44%) and an interferon (68%).
    • The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55, logrank p <0.000001). Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partial responses.
    • Final results of this trial established the efficacy and safety of sorafenib in advanced renal cell carcinoma. Once improved progression-free survival with sorafenib had been demonstrated, patients assigned to placebo were offered sorafenib. Although an analysis that included patients who crossed over to sorafenib showed no overall survival benefit with sorafenib, a secondary analysis that did not include these patients showed significantly improved overall benefit (17.8 v 14.3 months, P = .029).
  • 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 adverse events 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.
  • Hypertension is a common side effect of sorafenib treatment, and may be high grade. Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib.
  • The recommended dose is 400 mg (two 200-mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.
  • Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF; VEGFR-2,3; PDGFR-b; KIT; FLT-3; and RET.
  • The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, open-label expanded access program in which 2,504 patients from the United States and Canada were treated with oral sorafenib 400 mg twice daily. Patients included those with no prior therapy, nonclear cell renal cell carcinoma, brain metastases, and prior bevacizumab treatment; and elderly patients. Median overall survival was 50 weeks.
• Sunitinib (Sutent)
  • Sunitinib is another multikinase inhibitor approved by the FDA for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months.
  • The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and b.
  • Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients.
  • In a phase 3 study in 750 patients with previously untreated metastatic renal-cell carcinoma, PFS was longer and response rates were higher in patients who received sunitinib than in those receiving interferon alfa. In final survival analyses, median overall survival was greater in the sunitinib group than in the interferon-alpha group (26.4 vs. 21.8 months; P=0.051), as was the objective response rate (47% vs. 12%; P <0.001).
  • An expanded-access trial provided sunitinib on a compassionate-use basis to 4,564 trial-ineligible patients with renal cell carcinoma from countries where regulatory approval had not been granted. Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival was 18.4 months (17.4-19.2). These researchers concluded that the safety of sunitinib in these patients was manageable and its efficacy was encouraging, particularly in subgroups associated with poor prognosis (eg, those with brain metastases, low performance status, non–clear cell disease, and elderly patients).
• Temsirolimus (Torisel)
  • Temsirolimus inhibits mTOR (mammalian target of rapamycin), which is a serine/threonine kinase important in the regulation of cell growth and division. Genes involved with the response to hypoxia (HIF pathway described above) are also upregulated by mTOR and are believed to be central to the pathogenesis of kidney cancers.
  • Temsirolimus has been tested alone and in conjunction with interferon in patients with poor prognosis advanced renal cell carcinoma. Temsirolimus monotherapy at a dose of 25 mg IV weekly resulted in longer overall and progression-free survival compared to interferon (median survival 10.9 months versus 7.3 months, P= 0.008). There was no significant additive effect of interferon combined with temsirolimus. A second study combining temsirolimus and interferon over a range of dose levels showed overall survival of 18.8 months and progression-free survival of 9.1 months for the combination. Partial response was observed in 8% and stable disease in 36% of patients.
  • Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and hyperlipidemia.
  • Temsirolimus has FDA approval for the treatment of advanced renal cell carcinoma at a dose of 25 mg weekly IV until progression.
• Everolimus (Afinitor)
  • Everolimus (Afinitor) is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. Everolimus was approved by the US Food and Drug Administration in March 2009 for advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.
  • In a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients with metastatic renal cell carcinoma that had progressed during sunitinib and/or sorafenib treatment, interim analysis showed significantly longer median progression-free survival with everolimus than with placebo (4.0 vs 1.9 months). Stomatitis, rash, and fatigue were the most commonly reported adverse events, but were mostly mild or moderate in severity; pneumonitis was uncommon, but sometimes severe.
• Other multikinase inhibitors undergoing investigation for renal cell carcinoma
  • Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor that appears to have efficacy in the treatment of tumors, including renal cell carcinoma, which overexpress EGFR. A phase 3 study in patients with advanced renal cell carcinoma who had failed prior therapy found that lapatinib was well tolerated and had overall efficacy equivalent to that of hormonal therapy.
  • The novel combination of bevacizumab (a neutralizing monoclonal antibody to VEGF) and interferon has been shown to have activity against metastatic RCC. Completion of this phase 3 trial by Escudier et al found bevacizumab plus interferon alfa-2a effective as first-line treatment in patients with metastatic RCC.

Chemotherapy

Most of the currently available cytostatics are ineffective for the treatment of RCC. Their use can not be recommended for the treatment of patients with metastasized RCC,as response rates are very low,often just 5-15%,and most responses are short lived. The use of Tyrosine Kinase (TK) inhibitors, such as Sunitinib and Sorafenib, and Temsirolimus are described in a different section

Vaccine

Cancer vaccines, such as TroVax, have shown promising results in phase 2 trials for treatment of renal cell carcinoma. However, issues of tumor immunosuppression and lack of identified tumor-associated antigens must be addressed before vaccine therapy can be applied successfully in advanced renal cell cancer.

Drugs rating:

	Title	Votes	Rating
1	Sutent (Sunitinib)	29		(8.2/10)
2	Xeloda (Capecitabine)	25		(8.1/10)
3	Tarceva (Erlotinib)	40		(8.0/10)
4	Nexavar (Sorafenib)	11		(8.0/10)
5	Torisel (Temsirolimus)	13		(7.1/10)
6	Provera (Medroxyprogesterone)	122		(6.8/10)
7	Avastin (Bevacizumab)	13		(6.8/10)
8	Depo-Provera (Medroxyprogesterone)	35		(5.7/10)
9	Proleukin (Aldesleukin)	0		(0/10)
10	Votrient (Pazopanib)	0		(0/10)
11	Afinitor (Everolimus)	0		(0/10)
12	PegIntron (Peginterferon Alfa-2b)	0		(0/10)

Prognosis

The five year survival rate is around 90-95% for tumors less than 4 cm.

If it has metastasized to the lymph nodes, the 5-year survival is around 5 % to 15 %.

For those that have tumor recurrence after surgery, the prognosis is generally poor. Renal cell carcinoma does not generally respond to chemotherapy or radiation. Immunotherapy, which attempts to induce the body to attack the remaining cancer cells, has shown promise. Recent trials are testing newer agents, though the current complete remission rate with these approaches are still low, around 12-20% in most series. Most recently, treatment with tyrosine kinase inhibitors including nexavar, pazopanib, and rapamycin have shown promise in improving the prognosis for advanced RCC since 2004.

Follow-up

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.