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RENAL CELL CARCINOMA
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, and resistance to radiation and chemotherapy. Increasingly, renal call cancers are diagnosed at an earlier stage, and nephron-sparing surgery and thermal ablation are gaining acceptance as a treatment of choice for smaller tumors. Radical nephrectomy is the standard for larger and central tumors. Recent clinical trials have established the role of targeted therapy as the first line of therapy in patients with metastatic disease. While the optimal treatment strategy continues to evolve, three agents that target angiogenesis (sunitinib, bevacizumab, and pazopanib) and an mTOR-targeted therapy (temsirolimus) have been approved as front-line agents. These have largely replaced cytokines (immunotherapy) in treatment-naive patients. Current clinical trials are testing newer agents, combinations of approved agents, and the optimal sequencing of these agents.
Pathophysiology
The tissue of origin for renal cell carcinoma is the proximal renal tubular epithelium. Renal cancer occurs in both a sporadic (nonhereditary) and a hereditary form, and both forms are associated with structural alterations of the short arm of chromosome 3 (3p). Genetic studies of the families at high risk for developing renal cancer led to the cloning of genes whose alteration results in tumor formation. These genes are either tumor suppressors ( VHL, TSC ) or oncogenes ( MET ).
At least 4 hereditary syndromes associated with renal cell carcinoma are recognized: (1) von
Hippel-Lindau (VHL) syndrome, (2) hereditary papillary renal carcinoma (HPRC), (3) familial renal oncocytoma (FRO) associated with Birt-Hogg-Dube syndrome (BHDS), and (4) hereditary renal carcinoma (HRC). von Hippel-Lindau disease is an autosomal dominant syndrome that confers predisposition to a variety of neoplasms, including the following:
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Renal cell carcinoma with clear cell histologic features
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Pheochromocytoma
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Pancreatic cysts and islet cell tumors
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Retinal angiomas
Central nervous system hemangioblastomas
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Endolymphatic sac tumors
Epididymal cystadenomas
Renal cell carcinoma develops in nearly 40% of patients with von Hippel-Lindau disease and is a major cause of death among these patients. Deletions of 3p occur commonly in renal cell carcinoma associated with VHL disease. The VHL gene is mutated in a high percentage of tumors and cell lines from patients with sporadic (nonhereditary) clear cell renal carcinoma. Several kindreds with familial clear cell carcinoma have a constitutional balanced translocation between 3p and either chromosome 6 or chromosome 8. Mutations of the VHL gene result in the accumulation of hypoxia inducible factors (HIFs) that stimulate angiogenesis through vascular endothelial growth factor and its receptor (VEGF and VEGFR, respectively). VEGF and VEGFR are important new therapeutic targets.
Hereditary papillary renal carcinoma is an inherited disorder with an autosomal dominant inheritance pattern; affected individuals develop bilateral, multifocal papillary renal carcinoma.
Germline mutations in the tyrosine kinase domain of the MET gene have been identified.
Individuals affected with familial renal oncocytoma can develop bilateral, multifocal oncocytoma or oncocytic neoplasms in the kidney. Birt-Hogg-Dube syndrome is a hereditary cutaneous syndrome. Patients with Birt-Hogg-Dube syndrome have a dominantly inherited predisposition to develop benign tumors of the hair follicle (ie, fibrofolliculomas), predominantly on
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the face, neck, and upper trunk, and are at risk of developing renal tumors, colonic polyps or tumors, and pulmonary cysts.
Frequency
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Deaths worldwide from kidney cancer exceeded 100,000 in 2001.
In most of Europe, the incidence of kidney cancer has decreased or stabilized over the past decade, perhaps in part because of reduced tobacco smoking in men. Mortality from kidney cancer has also declined in most of Europe, principally in Scandinavia and other western European countries. In men, the mortality rate per 100,000 population fell from 4.8 in 1990-1994 to 4.1 in
2000-2004; in women, the rate fell from 2.1 to 1.8.
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Mortality/Morbidity
Renal cell carcinoma is the tenth leading cause of cancer deaths in males in the United
States. In men, deaths from kidney cancer decreased 3.9% between 1990 and 2005; in women, deaths decreased by 7.8% during that period. Overall, 5-year relative survival increased from 51% to
67% between 1975-1977 and 1996-2004.
2 The 5-year survival rates initially reported by Robson in
1969 were 66% for stage I renal carcinoma, 64% for stage II, 42% for stage III, and only 11% for stage IV.
4 Except for stage I, these survival statistics have remained essentially unchanged for several decades.
Race
Renal cell carcinoma is more common in people of Northern European ancestry
(Scandinavians) and North Americans than in those of Asian or African descent. In the United
States, its incidence is slightly higher among African Americans than among whites: 21.3 versus
19.2 per 100,000 population in men, and 10.3 versus 9.9 per 100,000 population in women.
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Sex
Renal cell carcinoma has a male-to-female preponderance of 1.6:1.
Age
From 2002 – 2006, the median age at diagnosis was 64 years of age 1 ; however, the disease has been reported in younger people who belong to family clusters.
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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.
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Most common presentations o
Hematuria (40%) o
Flank pain (40%) o
Palpable mass in the flank or abdomen (25%)
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Other signs and symptoms o
Weight loss (33%) o
Fever (20%) o
Hypertension (20%) o
Hypercalcemia (5%) o
Night sweats o
Malaise o
Varicocele, usually left sided, due to obstruction of the testicular vein (2% of males)
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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,
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weight loss, dermatomyositis, increased erythrocyte sedimentation rate, and hypertension also are associated with renal cell carcinoma. (For more information, see Paraneoplastic Syndromes.) o
Cytokine release by tumor (eg, IL-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions. o
Resolution of symptoms or biochemical abnormalities may follow successful treatment of the primary tumor or metastatic foci.
Physical
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Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with bruit.
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Approximately 30% of patients with renal carcinoma present with metastatic disease.
Physical examination should include thorough evaluation for metastatic disease. Organs involved include: o
Lung (75%) o
Soft tissues (36%) o
Bone (20%) o
Liver (18%) o
Cutaneous sites (8%) o
Central nervous system (8%)
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Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.
Causes
A number of environmental and genetic factors have been studied as possible causes for renal cell carcinoma.
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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 dosedependent fashion.
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Obesity is another risk factor, particularly in women; increasing body weight has a linear relationship with increasing risk.
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Hypertension may be associated with an increased incidence of renal cell carcinoma.
Phenacetin-containing analgesia taken in large amounts may be associated with increased incidence of renal cell carcinoma.
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There is an increased incidence of acquired cystic disease of the kidney in patients undergoing long-term renal dialysis; this predisposes to renal cell cancer.
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Tuberous sclerosis
Renal transplantation: Acquired renal cystic disease of the native kidney also predisposes to renal cell cancer in renal transplant recipients.
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VHL disease: This inherited disease is associated with renal cell carcinoma.
Workup
Laboratory Studies
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Laboratory studies in the evaluation of renal cell carcinoma should include a workup for paraneoplastic syndromes. Initial studies are as follows: o
Urine analysis o
CBC with differential o
Electrolytes o
Renal profile
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Liver function tests (AST and ALT)
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Calcium
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Erythrocyte sedimentation rate
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Prothrombin time
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Activated partial thromboplastin time
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Other tests indicated by presenting symptoms
Imaging Studies
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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: o
Excretory urography o
CT scan o
Ultrasonography o
Arteriography o
Venography o
MRI o
PET
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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.
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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.
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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.
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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.
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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.
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A bone scan is recommended for patients with bony symptoms and an elevated alkaline phosphatase level.
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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%).
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Unusually clear cells with a cytoplasm rich in lipids and glycogen characterize clear cell carcinoma, which is most likely to show 3p deletion.
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Chromophilic tumors tend to be bilateral and multifocal and may have trisomy 7 and/or trisomy 17.
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Large polygonal cells with pale reticular cytoplasm characterize chromophobic carcinoma, which does not exhibit 3p deletion.
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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.
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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
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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: o
Stage I - Tumor confined within capsule of kidney o
Stage II - Tumor invading perinephric fat but still contained within the Gerota fascia o
Stage III - Tumor invading the renal vein or inferior vena cava (A), or regional lymphnode involvement (B), or both (C) o
Stage IV - Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant metastases
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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: o
Primary tumor (T)
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TX - Primary tumor cannot be assessed
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T0 - No evidence of primary tumor
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T1 - Tumor 7 cm or smaller in greatest dimension, limited to the kidney
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T2 - Tumor larger than 7 cm in greatest dimension, limited to the kidney
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T3 - Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
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T3a - Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
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T3b - Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
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T3c - Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
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T4 - Tumor invading beyond the Gerota fascia o
Regional lymph nodes (N) - Laterality does not affect the N classification
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NX - Regional lymph nodes cannot be assessed
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N0 - No regional lymph node metastasis
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N1 - Metastasis in a single regional lymph node
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N2 - Metastasis in more than 1 regional lymph node o
Distant metastasis (M)
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MX - Distant metastasis cannot be assessed
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M0 - No distant metastasis
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M1 - Distant metastasis o
AJCC stages
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AJCC stage I - T1, N0, M0
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AJCC stage II - T2, N0, M0
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AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0
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AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1 o
The division of patients with renal cell carcinoma into low-, intermediate-, and high-risk groups with or without metastases may be useful in choosing appropriate therapy for them.
Treatment
Medical Care
The therapeutic approach to renal cell carcinoma is guided by the probability of cure, which is related directly to the stage or degree of tumor dissemination. More than 50% of patients with early-stage renal cell carcinoma are cured, but the outcome for stage IV disease is poor. Thus, the approach is curative for early-stage disease. Selected patients with metastatic disease respond to immunotherapy, but many patients with advanced disease can be offered only palliative therapy.
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The treatment options for renal cell cancer are surgery, radiation therapy, chemotherapy, hormonal therapy, immunotherapy, or combinations of these. o
Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates with chemotherapy, either single-agent or combination, are usually lower than 15%. Therefore, various biologic therapies have been evaluated. o
Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators have been tried, including interferon, IL-2 (aldesleukin
[Proleukin]), bacillus Calmette-Guérin (BCG) vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stemcell transplantation.
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Multikinase inhibitors o
Sorafenib
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Sorafenib (Nexavar), a small-molecule Raf kinase and vascular endothelial growth factor
(VEGF) multireceptor kinase inhibitor, is approved by the U.S. Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma. This indication was based on the demonstration of improved progression-free survival in a large, multinational, randomized doubleblind, placebo-controlled phase 3 study and a supportive phase 2 study.
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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.
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Among 769 patients randomized, the median age was 59 years and 70% were male.
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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%).
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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-toprogression 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.
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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
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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).
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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%).
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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.
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Hypertension is a common side effect of sorafenib treatment, and may be high grade.
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Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib.
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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.
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Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF;
VEGFR-2,3; PDGFR-b; KIT; FLT-3; and RET.
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The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, openlabel 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.
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Sunitinib (Sutent)
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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.
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The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and b.
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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.
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In a phase 3 study in 750 patients with previously untreated metastatic renal-cell carcinoma, PFS was longer and response rates were higher in patients who received sunitinib than in those receiving interferon alfa.
11 In final survival analyses, median overall survival was greater in the sunitinib group than in the interferon-alpha group (26.4 vs. 21.8 months; P=0.051), as was the objective response rate (47% vs. 12%; P <0.001).
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An expanded-access trial provided sunitinib on a compassionate-use basis to 4,564 trialineligible 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).
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Temsirolimus (Torisel)
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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.
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Temsirolimus has been tested alone and in conjunction with interferon in patients with poor prognosis advanced renal cell carcinoma. Temsirolimus monotherapy at a dose of 25 mg IV weekly resulted in longer overall and progression-free survival compared to interferon (median survival 10.9 months versus 7.3 months, P= 0.008).
14 There was no significant additive effect of interferon combined with temsirolimus. A second study combining temsirolimus and interferon over a range of dose levels showed overall survival of 18.8 months and progression-free survival of 9.1 months for the combination. Partial response was observed in 8% and stable disease in 36% of patients.
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Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and hyperlipidemia.
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Temsirolimus has FDA approval for the treatment of advanced renal cell carcinoma at a dose of 25 mg weekly IV until progression. o
Everolimus (Afinitor)
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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.
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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.
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Other multikinase inhibitors undergoing investigation for renal cell carcinoma
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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.
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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.
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Chemotherapy o
A phase 2 trial of weekly intravenous gemcitabine (600 mg/m 2 on days 1, 8, and 15) with continuous infusion fluorouracil (150 mg/m 2 /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.
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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.
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o
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.
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Biologic therapies o
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%). o
Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over singleagent therapy. Many different types and preparations of interferons have been used without any difference in efficacy. o
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.
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In the initial study by the National Cancer Institute, bolus intravenous infusions of highdose IL-2 combined with lymphokine-activated killer (LAK) cells produced objective response rates of 33%. In subsequent multicenter trials, the response rate was 16%. Subsequent studies also showed that LAK cells add no definite therapeutic benefit and can be eliminated from the treatment.
21 A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months. Eighty percent of patients who responded completely to therapy with IL-2 were alive at 10 years.
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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.
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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.
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The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak.
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Other toxic effects are fever, chills, fatigue, infection, and hypotension.
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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 the capillary leak. This syndrome is normally reversible.
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Treatment strategies o
For early stage renal cell carcinoma, an emerging treatment strategy is to utilize these molecular approaches earlier in the adjuvant setting in order to improve overall survival rates.
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Indeed, a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected renal cell carcinoma is currently ongoing and open for patient enrollment.
22 o
The optimal sequence or combination of active agents in advanced renal cell carcinoma is not yet defined. Based on decisions derived from level 1 evidence, the following may be considered as reasonable targeted therapy choices in patients with metastatic renal cell carcinoma who are not eligible for high-dose IL-2 therapy.
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For previously untreated patients with clear cell renal cell cancer of low or intermediate risk, sunitinib or the combination of bevacizumab and interferon alpha
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For patients with previously untreated clear cell renal cell cancer with poor prognostic
(high-risk) characteristics, temsirolimus
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For patients with previously treated clear cell renal cell cancer, sorafenib; if standard doses fail, an increase in dose may produce responses; patients in whom sorafenib is failing may be treated with sunitinib if that drug had not been previously used.
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The treatment of metastatic renal cell carcinoma is problematic, and, wherever possible, patients should be directed to approved and controlled clinical trials. This applies as well in the adjuvant treatment of surgically resected renal cell carcinoma, for which no therapy has yet been found to offer survival benefit. o
High-dose interleukin-2 must be considered for robust patients with excellent cardiopulmonary reserve, as it remains the only treatment known to induce complete and durable remissions, albeit in a minority of patients. Prospective studies are underway to identify patients more likely to respond to interleukin-2 immunotherapy based on carbonic anhydrase IX expression in the primary tumor and other assessments of immune function and regulation. This study may help to resolve the sequence and selection of available agents for individual patients with metastatic disease. o
Future treatment strategies for advanced renal cell carcinoma will likely incorporate a combination of molecular approaches, using multidrug regimens consisting of small-molecule kinase inhibitors with biologic therapies, immunomodulatory therapies, or both.
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Other experimental approaches for treatment include immunomodulatory drugs, vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation. o
The immunomodulator lenalidomide (Revlimid), a derivative of thalidomide, inhibits
VEGF, stimulates T and NK cells, and inhibits inflammatory cytokines. It has been evaluated extensively in hematologic malignancies. In phase 2 studies of metastatic renal cell carcinoma, it demonstrated an antitumor effect in some cases, with disease stabilization or durable partial response.
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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. A pilot study of vaccinating with the corresponding mutant von Hippel-Lindau peptides demonstrated safety and proved efficacy in generating a specific immune response in patients with advanced renal cell carcinoma.
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Nonmyeloablative allogeneic stem cell transplantation is another research approach. This can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen
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(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 is currently not recommended. Antiestrogens such as tamoxifen (100 mg/m 2 /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. o
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. o
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 wellvascularized 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. o
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
13

presenting with metastatic kidney cancer who have nephrectomy followed by either interferon or IL-
2. If the patient has good physiological status, then nephrectomy should be performed prior to immunotherapy. Reports have documented regression of metastatic renal cell carcinoma after removal of the primary tumor. Adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments.

Renal artery embolization with ethanol and gelatin sponge pledgets has been found effective for palliative treatment in patients who are not candidates for surgery, or who refuse surgery. A retrospective study in 8 patients with stage IV disease found that ethanol ablation controlled hematuria and flank pain.

26
About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some 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. o
A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. o
Preoperative radiation therapy yields no survival advantage. o
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. o
Palliative radiation therapy is often used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurological progression. Surgery also should be considered for solitary brain or spine lesions, followed by postoperative radiotherapy.

About 11% of patients develop brain metastasis during the course of illness. Renal cell carcinoma is a radioresistant tumor, but radiation treatment of brain metastasis improves quality of life, local control, and overall survival duration. Patients with untreated brain metastasis have a median survival time of 1 month, which can be improved with glucocorticoid therapy and brain irradiation. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.
Medication
The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.
Antineoplastic agents
Few options are available for the systemic therapy of renal cell carcinoma, and no hormonal or chemotherapeutic regimen is accepted as a standard of care to treat renal cell carcinoma.
Objective response rates, either for single or combination chemotherapy, usually are lower than
15%. Multikinase inhibitors induce objective responses in up to 40% of patients, but they are not known to cure patients with metastatic disease.
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
14

months for 3 years, and then annually for 5 years. Abdominal CT scan should be performed at 4-6 months, then annually or as indicated.

Spontaneous regression has been reported anecdotally in renal cell carcinoma. As many as
10% of patients with metastatic disease show no progression for more than 12 months. All systemic therapies are associated with treatment-related toxicity and low response, so close observation is an option for asymptomatic metastatic disease. Once evidence of progression or symptoms appears, appropriate therapy should be initiated.

Careful surveillance of patients with end-stage renal disease by ultrasonography and CT scan is recommended.
Deterrence/Prevention

Avoidance of causative factors such as smoking, obesity, and other factors as described in
Causes is recommended.

Careful surveillance of patients with end-stage renal disease or VHL disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and CT scan is recommended.
Complications
Excruciating, sharp, bandlike back pain may be an early warning for spinal cord compression due to metastatic renal cell carcinoma and should not be ignored. Urgent MRI should be performed to rule out cord compression, and high-dose dexamethasone therapy should be started.
Prognosis

Five-year survival rates are as follows: o
After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%. Patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis. o
The 5-year disease-specific survival rate in patients with T1 renal carcinoma is 95% and in those with stage T2 disease, 88%. Patients with T3 renal carcinoma have a 5-year survival rate of
59%, and those with T4 disease had a 5-year disease-specific survival rate of 20%. o
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%. o
Five-year survival rates for patients with stage IV disease are low (0-20%).

Motzer et al identified 5 prognostic factors for predicting survival in patients with metastatic renal-cell carcinoma.
27 These factors were used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months. Patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, while patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors were as follows: o
Low Karnofsky performance status (<80%) o
High serum lactate dehydrogenase level (>1.5 times upper limit of normal) o
Low hemoglobin (below lower limit of normal) o
High "corrected" serum calcium (>10 mg/dL) o
No prior nephrectomy

Factors associated with increased survival in patients with metastatic disease are as follows: (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.
15

BLADDER CANCER
Bladder cancer is a common urologic cancer. The urothelium in the entire urinary tract may be involved, including the renal pelvis, ureter, bladder, and urethra.
The clinical course of bladder cancer carries a broad spectrum of aggressiveness and risk.
Low-grade, superficial bladder cancers have minimal risk of progression to death; however, highgrade muscle-invasive cancers are often lethal.
Pathophysiology
Almost all bladder cancers are epithelial in origin. The urothelium consists of a 3- to 7-cell mucosal layer within the muscular bladder. Of these urothelial tumors, more than 90% are transitional cell carcinomas. However, up to 5% of bladder cancers are squamous cell in origin, and
2% are adenocarcinomas. Nonurothelial primary bladder tumors are extremely rare and may include small cell carcinoma, carcinosarcoma, primary lymphoma, and sarcoma.
Bladder cancer is often described as a polyclonal field change defect with frequent recurrences due to a heightened potential for malignant transformation. However, bladder cancer has also been described as a problem with implantation and migration from a previously affected site.
The World Health Organization classifies bladder cancers as low grade (grade 1 and 2) or high grade (grade 3). Tumors are also classified by growth patterns: papillary (70%), sessile or mixed (20%), and nodular (10%). Carcinoma in situ (CIS) is a flat, noninvasive, high-grade urothelial carcinoma. The most significant prognostic factors for bladder cancer are grade, depth of invasion, and the presence of CIS.
Upon presentation, 55-60% of patients have low-grade superficial disease, which is usually treated conservatively with transurethral resection and periodic cystoscopy. Forty to forty-five percent of patients have high-grade disease, of which 50% is muscle invasive and is typically treated with radical cystectomy.
Less than 5% of bladder cancers in the United States are squamous cell carcinomas (SCCs).
However, worldwide, SCC is the most common form, accounting for 75% of bladder cancer in underdeveloped nations. In the United States, SCC is associated with persistent inflammation from long-term indwelling Foley catheters and bladder stones. In underdeveloped nations, SCC is associated with bladder infection by Schistosoma haematobium .
Adenocarcinomas account for less than 2% of primary bladder tumors. These tumors are observed most commonly in exstrophic bladders and respond poorly to radiation and chemotherapy.
Radical cystectomy is the treatment of choice.
Small cell carcinomas are aggressive tumors associated with a poor prognosis and are thought to arise from neuroendocrine stem cells.
Carcinosarcomas are highly malignant tumors that contain both mesenchymal and epithelial elements.
Primary bladder lymphomas arise in the submucosa of the bladder and are treated with radiation therapy.
Leiomyosarcoma is the most common sarcoma of the bladder.
Rhabdomyosarcomas most commonly occur in children and carry a poor prognosis.
Frequency
In developed countries, 90% of bladder cancers are TCC. In developing countries, 75% of bladder cancers are SCCs, and most of these cancers are secondary to S haematobium infection.
Mortality/Morbidity
In 2009, an estimated 70,980 new patients will be diagnosed with bladder cancer in the
United States, and 14,330 of those patients will die of the disease.
1
Race
Bladder cancer is more common in whites than in blacks; however, blacks have a worse prognosis than whites.
16

Sex
The male-to-female ratio is 3:1. Women generally have a worse prognosis than men.
Age
The median age at diagnosis is 68 years, and the incidence increases with age.
Clinical
History

Approximately 80-90% of patients with bladder cancer present with painless gross hematuria, which is the classic presentation. Consider all patients with gross hematuria to have bladder cancer until proven otherwise. Suspect bladder cancer if any patient presents with unexplained microscopic hematuria.

Twenty to thirty percent of patients with bladder cancer experience irritative bladder symptoms such as dysuria, urgency, or frequency of urination that are related to more advanced muscle-invasive disease or CIS.

Patients with advanced disease can present with pelvic or bony pain, lower-extremity edema from iliac vessel compression, or flank pain from ureteral obstruction.
Physical


Superficial bladder cancer is rarely found during a physical examination.

Occasionally, an abdominal or pelvic mass may be palpable.
Examine for lymphadenopathy.
Causes
Up to 80% of bladder cancer cases are associated with environmental exposure, which suggests that bladder cancer is potentially preventable. Smoking is the most commonly associated risk factor and accounts for approximately 50% of all bladder cancers. Nitrosamine, 2naphthylamine, and 4-aminobiphenyl are possible carcinogenic agents found in cigarette smoke.
Bladder cancer is also associated with industrial exposure to aromatic amines in dyes, paints, solvents, leather dust, inks, combustion products, rubber, and textiles. Therefore, higher-risk occupations associated with bladder cancer include painting, driving trucks, and working with metal.
Several medical risk factors are associated with bladder cancer. Patients with prior exposure to radiation treatment of the pelvis have an increased risk of bladder cancer. Chemotherapy with cyclophosphamide increases the risk of bladder cancer via exposure to acrolein, a urinary metabolite of cyclophosphamide. Patients with spinal cord injuries who have long-term indwelling catheters have a 16- to 20-fold increased risk of developing SCC of the bladder.
Coffee consumption does not increase the risk of developing bladder cancer. Early studies of rodents and a minority of human studies suggested a weak connection between artificial sweeteners
(eg, saccharin, cyclamate) and bladder cancer; however, most recent studies show no significant correlation.
Although no convincing evidence exists for a hereditary factor in the development of bladder cancer, familial clusters of bladder cancer have been reported. Several genetic mutations have been identified in bladder cancer. Mutations of the tumor suppressor gene for p53, found on chromosome
17, are associated with high-grade bladder cancer and CIS. Mutations of the tumor suppressor gene for p15 and p16, found on chromosome 9, are associated with low-grade and superficial tumors.
Retinoblastoma (Rb) tumor suppressor gene mutations are also noted. Bladder cancer is associated with increased expression of the epidermal growth factor gene and the erb b2 oncogene, and mutations of the oncogenes p21 ras, cmyc, and cjun.
Workup
Laboratory Studies

Any patient with gross or microscopic hematuria should be urologically evaluated.
Microscopic hematuria from bladder cancer may be intermittent; therefore, a repeat negative result
17

on urinalysis does not exclude the diagnosis. Infection may cause hematuria and is usually associated with irritative voiding symptoms (eg, dysuria, frequency, urgency). Irritative voiding symptoms may also be caused by CIS or muscle-invasive bladder cancer. Further evaluate irritative voiding symptoms caused by a urinary tract infection that do not resolve with treatment.


Urinalysis with microscopy

Urine culture to rule out infection, if suspected
Voided urinary cytology (This may be helpful if results are positive, but a negative cytology result cannot be considered definitive. Urinary cytology for routine screening is controversial.)

Newer molecular and genetic markers may help in the early detection and prediction of urothelial carcinoma. o
Newer, voided urine assays (ie, bladder tumor antigen [BTA-Stat, BTA-TRAK], nuclear matrix protein [NMP-22], fibrin/fibrinogen degradation products [FDP]) are being used for the detection and surveillance of urothelial carcinoma. These tests have high false-positive and falsenegative rates. In the future, other newer assays based on telomerase and microsatellite analysis may prove to be a better detection method than urinary cytology. o
Chromosomal alterations have been associated with urothelial carcinoma. One encouraging test is a multitarget interphase fluorescence in situ hybridization (FISH) assay called
UroVysion that consists of probes to the centromeres of chromosomes 3, 7, 17, and the 9p21 region.
Aneuploidy of chromosomes 3, 7, and 17 and deletion of chromosome 9 has been associated with high sensitivity and specificity to detect bladder cancer. Often, this is an anticipatory positive result with a positive finding preceding visual evidence of bladder tumor. o
However, at this time, no urinary assay has been shown to effectively replace cystoscopy for the detection of bladder tumors.
Imaging Studies

Upper-tract imaging is necessary for the hematuria workup and should be able to visualize both the kidneys and the urothelium.

The American Urologic Association Best Practice Policy recommends CT scanning of the abdomen and pelvis with preinfusion and postinfusion phases. This is ideally performed with a CT urography or followed by radiography of the kidneys, ureters, and bladder (KUB) to obtain images similar to those produced with intravenous pyelography (IVP).

Two commonly used alternative studies are IVP and renal ultrasonography. o
The IVP is the traditional standard for upper-tract urothelium imaging; however, it is poor for evaluating the renal parenchyma. o
Ultrasonography is also commonly used; however, urothelial tumors of the upper tract and small stones are easily missed.

Conduct retrograde pyelography in patients in whom contrast CT scanning cannot be performed because of azotemia or a severe allergy to intravenous contrast.
Procedures

Cystoscopy

Obtain biopsy samples of suspicious lesions during cystoscopy. Attempt to include the bladder muscle in the biopsy specimen. This allows the pathologist to determine whether the tumor is muscle invasive.

Transitional cell tumors are typically papillary or sessile, and CIS may appear as an erythematous, velvety lesion. Unless the lesion is in a bladder diverticulum (pseudodiverticulum), attempt to resect the primary tumor completely.

A bladder diverticulum lacks a surrounding muscle layer, and a deep biopsy of a lesion within a diverticulum risks perforating the bladder and extravesical extravasation of cancer cells.
18


Because no muscle layer surrounds the bladder diverticulum, the next step in the progression of a superficial tumor is extravesical spread, requiring more aggressive surgical therapy
(eg, partial cystectomy, open diverticulectomy) rather than a simple resection followed by surveillance.

Further investigate efflux of blood from either ureteral orifice with retrograde pyelography, ureteroscopy, or both.


Urine cytology
Perform urine cytology at the same time as cystoscopy, although its routine use for screening is controversial.

Urine cytology is associated with a significant false-negative rate, especially for low-grade carcinoma (10-50% accuracy rate).

The false-positive rate is 1-12%, but it has a 95% accuracy rate for diagnosing high-grade carcinoma and CIS.

The sensitivity of urine cytology can be increased by obtaining a bladder barbotage cytology (70%) as opposed to a voided cytology (30%).

With a normal finding on cystoscopic examination, further evaluate a positive cytology result on urine study with an upper-tract study and random biopsies of the bladder. Obtain biopsy samples of the prostatic urethra in men.

Other urine markers for bladder cancer o
The use of additional urine markers such as UroVysion (FISH), BTA, and NMP-22 in the initial diagnosis of bladder cancer is controversial. All of these assays may yield false-positive and false-negative results. o
These other tests should not replace urine cytology and cystoscopy, with or without biopsy, for the diagnosis of bladder cancer. However, they may be useful adjuncts to urine cytology and cystoscopy.
Histologic Findings
More than 90% of bladder cancer cases are TCC, approximately 5% are SCC, and less than
2% are adenocarcinoma. Both the stage and tumor grade correlate independently with prognosis.
Staging
The International Union Against Cancer and the American Joint Committee on Cancer
Staging developed the tumor, node, and metastases (TNM) staging system, which is used to stage bladder cancer (see below). Ta and T1 tumors and CIS were once considered superficial bladder tumors. T2, T3, and T4 tumors were traditionally described as invasive bladder cancer. However, urologic oncologists now recommend avoiding the term superficial bladder cancer to describe Ta,
T1, and CIS tumors because it is a misnomer and tends to group patients who may require different treatments and who may have differing prognoses. Urothelial carcinoma is histologically graded as low grade (formerly graded 1-2) or high grade (formerly graded 3). CIS is characterized by full mucosal thickness and high-grade dysplasia of the bladder epithelium and is associated with a poorer prognosis.
The following is the TNM staging system for bladder cancer:

CIS - Carcinoma in situ, high-grade dysplasia, confined to the epithelium

Ta - Papillary tumor confined to the epithelium

T1 - Tumor invasion into the lamina propria

T2 - Tumor invasion into the muscularis propria

T3 - Tumor involvement of the perivesical fat

T4 - Tumor involvement of adjacent organs such as prostate, rectum, or pelvic sidewall

N+ - Lymph node metastasis
19


M+ - Metastasis
More than 70% of all newly diagnosed bladder cancers are non–muscle invasive, approximately 50-70% are Ta, 20-30% are T1, and 10% are CIS. Approximately 5% of patients present with metastatic disease, which commonly involves the lymph nodes, lung, liver, bone, and central nervous system. Approximately 25% of affected patients have muscle-invasive disease at diagnosis.

Clinically stage a patient who has muscle-invasive disease with CT scanning of the abdomen and pelvis, chest radiography, and serum chemistries.

If the patient is asymptomatic with normal calcium and alkaline phosphatase levels, a bone scan is unnecessary.

As many as 50% of patients with muscle-invasive bladder cancer may have occult metastases that become clinically apparent within 5 years of initial diagnosis.


Most patients with overt metastatic disease die within 2 years despite chemotherapy.
Approximately 25-30% of patients with only limited regional lymph node metastasis discovered during cystectomy and pelvic lymph node dissection may survive beyond 5 years.
Treatment
Medical Care
The treatment of non–muscle-invasive (Ta, T1, CIS) and muscle-invasive bladder cancer should be differentiated. Treatments within each category include both surgical and medical approaches.

Non–muscle-invasive disease (Ta, T1, CIS) o
Intravesical immunotherapy (Bacillus Calmette-Guérin [BCG] immunotherapy)

BCG immunotherapy is used in the treatment of Ta, T1, and CIS urothelial carcinoma of the bladder and may help to decrease the rate of recurrence and progression.

BCG immunotherapy is the most effective intravesical therapy and involves a live attenuated strain of Mycobacterium bovis.
Some early studies purported that an immune response against BCG surface antigens cross-reacted with putative bladder tumor antigens, and this was proposed as the mechanism for the therapeutic effect of BCG; however, multiple subsequent studies refute this claim and demonstrate that BCG induces a nonspecific, cytokine-mediated immune response to foreign protein.

Because BCG is a live attenuated organism, it can cause an acute disseminated tuberculosislike illness if it enters the bloodstream (BCG sepsis), possibly resulting in death.
Therefore, the use of BCG is contraindicated in patients with gross hematuria.

BCG typically causes mild systemic symptoms that resolve within 24-48 hours after intravesical instillation. BCG can also cause granulomatous cystitis or prostatitis with bladder contraction.

BCG is recommended for CIS, T1 tumors, and high-risk Ta tumors (large, high-grade, recurrent, or multifocal tumors). This therapy is less effective in reducing the 5-year recurrence rate for low-grade and low-stage urothelial carcinoma (see Table 1 below).

Typically, BCG is administered weekly for 6 weeks. Another 6-week course may be administered if a repeat cystoscopy reveals tumor persistence or recurrence. Recent evidence indicates that maintenance therapy with a weekly treatment for 3 weeks every 6 months for 1-3 years may provide more lasting results.

Consider patients with recurrent CIS for an early cystectomy. At 5 and 10 years, approximately 70% and 30% of patients with CIS who are treated with BCG are disease free, respectively. Recurrent CIS, despite intravesical BCG, is associated with a 63% risk of progression to muscle-invasive bladder cancer. Recurrence after BCG treatment may also occur in the upper urinary tract or prostatic urethra.
20


Interferon alpha or gamma has been used in the treatment of stages Ta, T1 and CIS urothelial carcinoma, either as a single agent therapy or in combination with BCG. Its role has primarily been in post-BCG failure with early promising results. Although BCG with interferon has shown a 42% response with tolerable side effects after BCG failure, no evidence has indicated that re-treating with BCG with interferon is superior to re-treating with BCG alone. o
Intravesical chemotherapy

Valrubicin has recently been approved as intravesical chemotherapy for CIS that is refractory to BCG. In patients whose conditions do not respond to BCG, the overall response rate to valrubicin is approximately 20%, and some patients can delay time to cystectomy. Valrubicin is presently not commercially available.

Other forms of adjuvant intravesical chemotherapy for bladder cancer include intravesical triethylenethiophosphoramide (thiotepa [Thioplex]), mitomycin-C, doxorubicin, and epirubicin.
Although these agents may increase the time to disease recurrence, no evidence indicates that these therapies prevent disease progression.

No evidence suggests that these adjuvant therapies are as effective as BCG.

Muscle-invasive disease (T2 and greater) o
Adjuvant and neoadjuvant chemotherapy

Neoadjuvant chemotherapy prior to either radical cystectomy or external beam radiotherapy is controversial.

The Southwestern Oncology Group (SWOG) conducted a multicenter randomized prospective study that compared neoadjuvant therapy using a methotrexate, vinblastine, doxorubicin
(Adriamycin), and cisplatin (MVAC) combination with surgery alone. The group concluded that neoadjuvant therapy conferred a treatment benefit compared with surgery alone. However, several criticisms of this study exist. The study was purposely underpowered because of slow recruitment
(317 patients over 11 y), because 20% of the patients who were to undergo cystectomy alone never underwent surgery, and because there was no comparison to neoadjuvant therapy alone. In addition, a recent study re-evaluated the SWOG data and found that surgical factors significantly affected outcomes.

In one small series, the T4 tumors of 45% of affected patients responded to chemotherapy, making potentially curative cystectomy possible.

Although no definite evidence of benefit exists, patients with P3-P4 or N+ urothelial carcinoma in the United States are typically advised to receive adjuvant chemotherapy. o
Chemotherapeutic agents for metastatic disease

MVAC is the standard treatment of metastatic bladder cancer. MVAC has an objective response rate of 57-70%, a complete response rate of 15-20%, and a 2-year survival rate of 15-20%.

Gemcitabine and cisplatin (GC) is a newer regimen and has been shown to be as efficacious as MVAC, but with less toxicity. GC is now considered a first-line treatment agent for bladder cancer.

Several novel compounds have shown activity against transitional cell bladder cancer and are now being tested in combination chemotherapy trials. Some of these promising agents are ifosfamide, paclitaxel, docetaxel, and carboplatin.
Surgical Care

Ta, T1, and CIS o
Endoscopic treatment

Transurethral resection of bladder tumor (TURBT) is the first-line treatment to diagnose, to stage, and to treat visible tumors.
21


Patients with bulky, high-grade, or multifocal tumors should undergo a second procedure to ensure complete resection and accurate staging. Approximately 50% of stage T1 tumors are upgraded to muscle-invasive disease.

Electrocautery or laser fulguration of the bladder tumor is sufficient for low-grade, smallvolume, papillary tumors.

No further metastatic workup is needed for obviously superficial tumors.

Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory. o
Radical cystectomy

Although typically reserved for muscle-invasive disease, radical surgery is more appropriately used to treat some cases of non–muscle-invasive bladder cancer.

Thirty-five to fifty percent of patients who undergo cystectomy for Ta, T1, or CIS are discovered to have muscle-invasive disease, with 10-15% demonstrating microscopic lymph node metastasis.

The CIS in upwards of 80% of affected patients progresses to muscle-invasive disease, with 20% of patients found to have muscle-invasive disease at the time of cystectomy.

High-grade T1 tumors that recur despite BCG have a 50% likelihood of progressing to muscle-invasive disease. Cystectomy performed prior to progression yields a 90% 5-year survival rate. The 5-year survival rate drops to 50-60% in muscle-invasive disease.

Patients with unresectable large superficial tumors, prostatic urethra involvement, and
BCG failure should also undergo radical cystectomy.

Muscle-invasive disease (T2 and greater) o
Radical cystoprostatectomy (men)

In men, this is the criterion standard for organ-confined, muscle-invasive bladder cancer
(eg, T2, T3).

Remove the bladder, prostate, and pelvic lymph nodes.

Perform a total urethrectomy for anterior urethral involvement, involvement of the prostatic stroma, or diffuse CIS that involves the prostate. o
Anterior pelvic exenteration (women)

Perform this procedure in women diagnosed with muscle-invasive bladder cancer.

The procedure involves removal of the bladder, urethra, uterus, ovaries, anterior vaginal wall, and pelvic lymph nodes.

If no tumor involvement of the bladder neck is present, the urethra and anterior vaginal wall may be spared with the construction of an orthotopic neobladder. o
Pelvic lymphadenectomy

Approximately 25% of patients undergoing radical cystectomy have lymph node metastases at the time of surgery.

Bilateral pelvic lymphadenectomy (PLND) should be performed in conjunction with radical cystoprostatectomy and anterior pelvic exenteration.

PLND adds prognostic information by appropriately staging the patient and may confer a therapeutic benefit.

The boundaries of a standard PLND include the bifurcation of the common iliac artery and vein superiorly, the genitofemoral nerve laterally, the obturator fossa posteriorly, and the circumflex iliac vein (or node of Cloquet) inferiorly.

Extended PLND includes the lymph nodes in the presacral region and those surrounding the common iliac vessels to the level of the aortic bifurcation. The additional benefit of an extended
PLND is controversial. Based on several retrospective studies, some experts believe that an extended dissection provides additional staging information and offers a survival benefit. However, no
22

randomized trials to date have proven that an extended PLND is more beneficial than a standard
PLND. o
After performing a cystectomy, a urinary diversion must be created from an intestinal segment. The various types of urinary diversions can be separated into the following continent and incontinent diversions:

Conduit (incontinent diversion; see image below): Conduits can be constructed from either ileum or colon. The ileal conduit is the most common incontinent diversion performed and has been used for more than 40 years with excellent reliability and minimal morbidity. A small segment of ileum (at least 15 cm proximal to the ileocecal valve) is taken out of gastrointestinal continuity but maintained on its mesentery, with care to preserve its blood supply. The gastrointestinal tract is restored with a small-bowel anastomosis. The ureters are anastomosed to an end or side of this intestinal segment and the other end is brought out as a stoma to the abdominal wall. Urine continuously collects in an external collection device worn over the stoma.

Indiana pouch (continent diversion; see image below): This is a continent urinary reservoir created from a detubularized right colon and an efferent limb of terminal ileum. The terminal ileum is plicated and brought to the abdominal wall. The ileocecal valve acts as a continence mechanism.
The Indiana pouch is emptied with a clean intermittent catheterization 4-6 times per day.

Neobladder (continent diversion; see image below): Various segments of intestine including ileum, ileum and colon, and sigmoid colon can be used to construct a reservoir. The ureters are implanted to the reservoir, and the reservoir is anastomosed to the urethra. This operation has been performed successfully in men for more than 20 years and, more recently, in women. The orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder. Patients have volitional control of urination and void by Valsalva. Contraindications to performing continent urinary diversions include multiple comorbid health problems, chronic renal insufficiency, hepatic dysfunction, and advanced disease stage. o
Laparoscopic and robotic surgery

Recently, laparoscopic and robotic-assisted radical cystectomies have been performed in small numbers at select tertiary academic centers.

The urinary diversion is almost universally performed extracorporeally through a miniature laparotomy incision. Initially, some centers attempted to create the urinary diversion laparoscopically, but this was abandoned because of inferior outcomes.
2

Immediate postoperative complication rates and functional outcomes appear to be similar to those of open radical cystectomy and urinary diversion. In addition, a few studies suggest faster recovery of bowel function and less use of postoperative narcotics. However, these findings have not been corroborated by other contemporary studies.

Intermediate and long-term oncologic outcomes for these minimally invasive approaches remain undefined.

At this time, open radical cystectomy and urinary diversion should be considered the standard of care for invasive bladder cancer, and patients should be counseled to this end.

Both laparoscopic and robotic-assisted radical cystectomy remain investigative procedures that should be performed only at major academic medical centers after appropriate informed consent. o
Radiation therapy

External beam radiation therapy has been shown to be inferior to radical cystectomy for the treatment of bladder cancer. The overall 5-year survival rate after treatment with external beam radiation is 20-40% compared to a 90% 5-year survival after cystectomy for organ-confined disease.

Although inferior to radical cystectomy, external beam radiation therapy is used in various countries other than the United States for T2-T3 urothelial carcinoma of the bladder.
23


Neoadjuvant external beam radiation therapy has been attempted for muscle-invasive bladder cancer, with no improvement in survival rate. o
In certain facilities, a bladder-preserving strategy for T2-T3 urothelial carcinoma is applied using a combination of external beam radiation, chemotherapy, and endoscopic resection.

Survival rates associated with this approach are comparable with those of cystectomy in selected patients.

This combination has a widespread application that is limited by the complexity of the protocol, its toxicity, and a high mortality rate.

The mortality rate in the 2 largest US series with the longest follow-up study is 4-5%. In comparison, the mortality rate for most modern cystectomy series is 1-2%.

In addition, a significant number of patients ultimately require salvage cystectomy, which is associated with significantly increased morbidity and decreased options for urinary diversions. In some series, local recurrence of bladder cancer is as high as 50-60% despite the completion of bladder-preserving therapy.
Medication
MVAC is the standard treatment for metastatic bladder cancer. No proven role exists for adjuvant chemotherapy. When selecting therapy, the MVAC combination has substantial toxicity and must be weighed against the expected benefit. The major dose-limiting toxicity is myelosuppression. The new combination regimens (eg, gemcitabine, cisplatin) show response rates and median survival comparable to MVAC but with less toxicity.
Follow-up
Further Outpatient Care
The high rate of disease recurrence and progression in non–muscle invasive bladder cancer underscores the need for careful follow-up studies. Surveillance for these patients includes cystoscopy and bladder wash cytologies every 3 months for 2 years, then every 6 months for 2 years, and then at least yearly.
Cystoscopy
Cystoscopy is the primary diagnostic modality for the diagnosis of bladder carcinoma because it confers low risk and can be performed in the physician's office. Although it is the criterion standard for detecting bladder cancer, cystoscopy is invasive and relatively expensive.
3 Moreover, visibility can be reduced by bleeding, and flat urothelial lesions such as CIS may be difficult to distinguish from normal bladder tissue. Thus, cytologic analysis of voided urine is frequently used as an adjunctive test to aid in identifying occult cancers.
Cytology
Voided urine cytology is the standard noninvasive method for diagnosis in the detection of bladder carcinoma. Cytology is used to assess morphologic changes in intact cells. Unfortunately, however, the sensitivity of cytology is low, with various studies reporting values between 11% and
76%.
4 Sensitivity depends largely on the degree of tumor differentiation. High-grade tumors with marked pleomorphism and distinctly abnormal nuclear features are identified more accurately.
Small and/or well-differentiated tumors are less likely to exfoliate cells because intercellular attachments are better preserved and the degree of morphological departure from normal is smaller, complicating cytologic recognition.
5 This results in poor sensitivity in low-grade and early-stage cancers. Several other factors affect the sensitivity of cytology, including specimen quality, number of exfoliated cells, and pathologist expertise. The overall low sensitivity of cytology is due to its low sensitivity in detecting low-grade bladder tumors.
6
In addition, instrumentation may cause reactive cellular changes, contributing to variability in interpretation. False-positive reports of malignant cells are uncommon, but ambiguous reports of atypical cells are frequent. Bladder wash cytology yields more tumor cells in the sample and is more
24

sensitive in identifying cancer, especially for high-grade tumors, but it also yields a higher falsepositive rate than voided urine cytology.
7
Noninvasive urine markers can offer an alternative to the standard means of detecting bladder cancer or can be used as an adjunct to cystoscopy.
8
Genetic aberrations
The study of genetic aberrations commonly associated with urothelial carcinoma provides a more objective assessment for diagnosing and detecting recurrent disease. Homozygous loss of chromosome band 9p21, the site for the tumor suppressor gene p16, is a known early genetic event in the development of papillary carcinoma and urothelial CIS.
9
Increased chromosomal instability and aneuploidy have been implicated in tumor progression. A study by Sokolova et al of 9 genetic markers for detecting urothelial carcinoma showed that polysomy of chromosomes 3, 7, and 17 and deletion of 9p21 were the most sensitive and specific markers, detecting 95% of recurrent urothelial carcinoma.
10 Halling et al established that a threshold of 5 or more cells with polysomy was 84% sensitive and 92% specific for detecting recurrent urothelial cancer.
9
Fluorescence in situ hybridization
A commercial FISH assay (UroVysion), which includes probes for the centromeres for chromosomes 3, 7, and 17 and has a locus-specific probe for 9p21, was developed to screen for recurrent urothelial carcinoma and was recently approved by the US Food and Drug Administration
(FDA) for diagnostic studies.
Initial comparisons of urine cytology with FISH for detecting bladder cancer recurrence showed that FISH yielded a greater sensitivity.
11 FISH is 42-83% sensitive for detecting pTa and pT1 lesions and 92-100% sensitive for pT2-4 invasive lesions in patients with known bladder cancer, while urine cytology yields sensitivities of 24-50% for pTa and pT1 lesions and 78-85% for pT2-4 invasive lesions.
12 For suspected new cases of urothelial carcinoma, cytology yields a reported diagnostic sensitivity of 48%, while no data are available for FISH evaluation of these cases.
13
Laudadio et al compared the diagnostic sensitivity of FISH with concurrent biopsy and cytological assessments.
14 FISH analysis was found to yield a high sensitivity for detecting new cases of urothelial carcinoma, as well as recurrences. Their study showed FISH detected 95% of cases with high-grade carcinoma, while cytology detected 41% of such cases. FISH yielded an overall specificity of 65%, compared to 93% with cytology. From this data, the authors concluded that FISH is considerably more sensitive and only slightly less specific than cytology in diagnosing urothelial carcinoma. They recommended FISH as a useful initial diagnostic tool in patients suspected of both new and recurrent bladder cancer.
Nuclear matrix protein-22
Nuclear matrix, first described in 1974, is the nonchromatin structure that supports nuclear shape and organizes DNA. It also takes part in DNA replication and transcription, as well as RNA processing.
15,16,17 NMP-22 is involved in the proper distribution of chromatin to daughter cells during cell division and is found in the nuclear matrix of all cell types. NMP-22 is thought to be released from the nuclei of tumor cells after they die and can be detected in the urine. Research has found that persons with bladder cancer may have urinary NMP-22 levels up to 25 times that in healthy persons.
18
The NMP-22 BladderChek test is an in vitro immunoassay intended for the qualitative detection of NMP-22 in urine. It determines whether NMP-22 is present in urine and provides an absolute positive or negative test result, much in the same manner as a pregnancy test. The NMP-22 assay detects elevated amounts of nuclear mitotic apparatus protein, a component of the nuclear matrix essential for cell division that is released into the urine during cell death. Unlike cytologic examinations and FISH-based tests, detection of NMP-22 protein does not depend on the recovery of intact cells. It is a painless and noninvasive assay that provides results within 30 minutes and is the only in-office test approved by the FDA for the diagnosis of bladder cancer.
25

Grossman et al compared the NMP-22 BladderChek test with cystoscopy and voided urine cytology for surveillance of recurrent bladder cancer.
5 Initial cystoscopy alone detected 91% of the cancers. The combination of the NMP-22 test with cystoscopy increased overall sensitivity to 99%
( P =0.005). The NMP-22 test was significantly more sensitive than cytologic analysis of voided urine. The authors concluded that, when combined with cystoscopy, the NMP-22 test improves the detection of recurrence in patients with a history of bladder cancer. Unlike cytologic analysis, this test does not require expert analysis or laboratory time, does not depend on intact cells, and provides unambiguous results. In addition, the NMP-22 test provides results during the patient visit, and its cost is less than half that of cytology.
Of concern with the NMP-22 assay is its variability of performance in detecting bladder cancer. A report by Shariat et al assessed the variability in the diagnostic performance of NMP-22 for detecting recurrence and progression in patients with Ta, T1, and/or CIS TCC of the bladder.
19
NMP-22 voided urine levels were measured in 2,871 patients who underwent office cystoscopy for monitoring previous stage Ta, T1, and/or CIS bladder cancer at 12 institutions. Their results showed that the manufacturer cutoff of 10 U/mL detected 57% of cases with a 19% false-positive rate. For each NMP-22 cutoff assessed, NMP-22 had a higher sensitivity for detecting grade III and stage T2 or greater bladder cancer than for detecting any cancer.
No optimal cutoffs for detecting any or aggressive bladder cancer could be derived based on
NMP-22 values. The authors concluded that there is a substantial degree of heterogeneity in the diagnostic performance of NMP-22 applied to populations from different institutions. There was no clearly defined NMP-22 cutoff, but there was a continuum of risk for recurrence and progression.
Conclusions
Several reviews have been performed to assess the myriad urine markers proposed for bladder cancer surveillance. They note that none of the markers has been proven sensitive and specific enough to replace cystoscopy.
20 While FISH and NMP-22 are promising, the clinical evidence is insufficient to warrant the substitution of the cystoscopic follow-up scheme with any of the currently available urine marker tests.
21
If FISH and NMP-22 are considered to have some utility when used to complement or replace cytology, a dilemma arises when their results conflict with each other. Of particular interest is how to treat a patient with positive cytology and/or FISH findings when cystoscopy findings are negative.
Because cytology is the most reliable urine test for detecting bladder cancer, a positive cytology finding should be treated as cancer until proven otherwise. If cystoscopy findings are negative in the setting of positive cytology findings, further evaluation of the urinary tract is required. The upper urinary tract should be evaluated with contrast imaging. Cystoscopy with bilateral retrograde pyelography and bilateral ureteral washings should be performed. At the time of this procedure, ureteroscopy may also be performed if possible upper tract disease is suspected. The urinary tract distal to the bladder—the shorter urethra in women or the longer urethra in men, with its prostatic, bulbar, and penile portions—must also be assessed during cystoscopy. If the findings of all of these examinations remain negative, one must maintain a heightened suspicion and perform routine surveillance with more regularity.
In the setting of negative cystoscopy findings, negative urine cytology findings, and positive
FISH findings, 2 possible scenarios arise. This result is either falsely positive, or it may be an anticipatory positive result, meaning that such patients have a 30% chance of developing a bladder tumor over 2 years, despite having negative cytology and cystoscopic evaluation findings. Patients in this category should also undergo surveillance with increased frequency (see Table 2).
Patients who have undergone radical cystectomy require routine surveillance to monitor for local recurrence or the development of metastatic disease. Abdominal and pelvic CT scanning and chest radiography should be performed annually. Some patients with more adverse pathology at the
26

time of cystectomy (eg, locally advanced disease, lymph node metastases) may require more frequent imaging.
The retained male urethra is at risk for cancer recurrence after radical cystoprostatectomy.
Urethral recurrence occurs in approximately 7% of patients after cystoprostatectomy.

Cancer involving the prostate (urothelium or stroma) at the time of cystoprostatectomy is the most significant risk factor for urethral recurrence.

Monitoring the retained urethra has historically included periodic urethral cytology with subsequent biopsy, if indicated. However, some small studies have suggested monitoring with urethral washings does not confer a survival benefit.


22
Gross hematuria or bloody urethral discharge requires immediate workup.
A positive urethral cytology or biopsy finding warrants immediate urethrectomy.
Complications

The morbidity of untreated bladder cancer is significant and includes hematuria, dysuria, irritative urinary symptoms, urinary retention, incontinence, ureteral obstruction, and pelvic pain.


The radical cystectomy perioperative mortality rate is 1-2%.

The local recurrence rate is 5-10%; however, it increases to 15-25% for T3-T4 disease.
The 2 most common complications are small-bowel obstruction and ureteroenteric stricture (see Table 3 at the end of this section).

Radical cystectomy o
The reported overall early and late complication rate associated with radical cystectomy is approximately 25%-30%. However, this may be an underestimation of the true complication rate because of a lack of standardized reporting in published studies. o
Many patients undergo a radical cystectomy and have multiple comorbid health risk factors (eg, advanced age, cardiovascular disease, pulmonary disease). o
Despite these difficulties, this procedure may be performed safely in patients older than 80 years. o
Following a radical cystectomy, all men are impotent if the parasympathetic nerves from the pelvic plexus (S2-S4) to the corpora cavernosum are not spared at the time of surgery; however, a nerve-sparing approach may reduce the impotency rate to approximately 40-50%.

Orthotopic neobladder o
With the recent advances in surgical technique, this procedure is becoming the diversion of choice. o
Risk factors include daytime and nighttime urinary incontinence of approximately 10% and 15%, respectively. o
Urinary incontinence may develop from multiple factors, including injury to the external urethral sphincter, increased urine production from solute absorption, and relaxation of the external sphincter, which is greater at night.
Prognosis

Non–muscle invasive bladder cancer has a good prognosis, with 5-year survival rates of
82-100%. o
The 5-year survival rate decreases with increasing stage, as follows:

Ta, T1, CIS – 82-100%

T2 – 63-83%

T3a – 67-71%

T3b – 17-57%

T4 – 0-22%
27


Prognosis for metastatic urothelial cancer is dismal, with only 5% of patients living 2 years after diagnosis.

Early diagnosis and improvements in treatment of bladder cancer may be responsible for the improved survival rate.

Further studies of molecular determinants of bladder cancer development and progression aid in prevention, earlier diagnosis, and treatment. Much progress has been made in the treatment of advanced bladder cancer; however, researchers must further elucidate optimal agents and regimens.

The underlying genetic changes that result in a bladder tumor occur in the entire urothelium, making the whole lining of the urinary system susceptible to tumor recurrence (ie, 70% within 5 y).

Non–muscle invasive bladder cancer o
The risk of progression, defined as an increased tumor grade or stage, depends primarily on the tumor grade. o
The risk of progression increases with tumor grade, as follows:

Grade I – 10-15%

Grade II – 14-37%

Grade III – 33-64% o
CIS alone, or in association with Ta or T1 papillary tumor, carries a poorer prognosis and a recurrence rate of 63-92%. o
Diffuse CIS is an especially ominous finding, with 78% progressing to muscle-invasive disease in one study. o
Other risk factors for recurrence and progression include the tumor size, multifocality, number of tumors, high tumor grade, advanced stage, the presence of CIS, and the time interval to recurrence. Patients with tumor recurrences within 2 years, and especially with recurrences within 3 months, have an aggressive tumor and an increased risk of disease progression.
28

Prostate Cancer
Prostate cancer is the most common noncutaneous cancer among males. Lung and bronchial cancer account for 37% of cancer-related death in males; prostate and colon cancers account for another 10% each. The diagnosis and treatment of prostate cancer continue to evolve. With the development of prostate-specific antigen (PSA) screening, prostate cancer is being diagnosed earlier in the disease course. Although prostate cancer can be a slow-growing cancer, thousands of men die of the disease each year. Education is important to help men understand the risk of progression and the various treatment options. This article provides a current overview of the biology, pathology, diagnostic techniques, natural history, and screening of this disorder.
Incidental Findings
In the modern era, most patients present because of abnormalities in a screening PSA level or findings on digital rectal examination (DRE) rather than because of symptoms. However, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive prostatic symptoms.
Elevated prostate-specific antigen level
PSA is a single-chain glycoprotein that has chymotrypsinlike properties. PSA slowly hydrolyzes peptide bonds, thereby liquifying semen. The upper limit of normal for PSA is 4 ng/mL.
Some advocate age-related cutoffs, such as 2.5 ng/mL for the fifth decade of life, 3.5 ng/mL for the sixth decade of life, and 4.5 ng/mL for the seventh decade of life. Others advocate race-specific reference ranges. Using recent data from screening studies, some have advocated upper limits of normal of 2.5 ng/mL instead of 4 ng/mL.
Prostate-specific antigen velocity
PSA velocity is an important concept. A PSA velocity of lower than 0.75 ng/mL/y has traditionally been used to prompt a prostate biopsy. However, recent data suggest that, among men younger than 50 years, a PSA velocity of 0.6 ng/mL/y may be more appropriate.
Percent of free prostate-specific antigen
The measurement of bound and free PSA is a recent development that can help to differentiate mildly elevated PSA levels due to cancer from elevated levels due to benign prostatic hyperplasia. The lower the ratio of free-to-total PSA, the higher the likelihood of cancer. Free PSA is reported as a percentage. For example, among men with greater than 25% free PSA, only 8% are found to have cancer at prostate biopsy. In contrast, more than half of men with less than 10% free
PSA are found to have cancer at biopsy. While cutoffs may be used, the percentage of free PSA is usually used as an additional factor in making an informed recommendation for or against biopsy.
Generally, these percentages are useful in patients who have a PSA level in the range of 4-10 ng/mL.
This information is most useful in men with very large glands or in men in whom one biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many recommend biopsy without the additional free-PSA test or consider a trial of antibiotic therapy for 4-6 weeks before repeating the PSA test. If antibiotic therapy quickly lowers the PSA level to within the reference range, the cause of the prior elevation is less likely to be prostate cancer, and the PSA test should be repeated within a few months.
Abnormal digital rectal examination findings
Various factors are considered when a DRE is performed. A nodule is important, but findings such as asymmetry, difference in texture, and bogginess are important clues to the patient's condition and should be considered in conjunction with the PSA level. Change in texture over time can offer important clues about the need for intervention. Cysts or stones cannot be accurately differentiated from cancer based on DRE findings alone; therefore, maintain a high index of suspicion if the DRE results are abnormal. In addition, if cancer is detected, the DRE findings form the basis of clinical staging of the primary tumor (ie, tumor [T] stage in the tumor node metastases
[TNM] staging system). In current practice, the DRE results are normal but the PSA readings are abnormal in most patients diagnosed with prostate cancer.
29

Local Symptoms
In the pre-PSA era, patients with prostate cancer commonly presented with local symptoms.
Urinary retention developed in 20-25% of these patients, back or leg pain developed in 20-40%, and hematuria developed in 10-15%. Currently, with PSA screening, patients report urinary frequency
(38%), decreased urine stream (23%), urinary urgency (10%), and hematuria (1.4%). However, none of these symptoms is unique to prostate cancer and each could arise from various other ailments.
Forty-seven percent of patients are asymptomatic.
Metastatic Symptoms
Metastatic symptoms include weight loss and loss of appetite; bone pain, with or without pathologic fracture (because prostate cancer, when metastatic, has a strong predilection for bone); and lower extremity pain and edema due to obstruction of venous and lymphatic tributaries by nodal metastasis. Uremic symptoms can occur from ureteral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.
Frequency
With the advent of PSA screening, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated so they can select the most appropriate treatment.
According to figures from the American Cancer Society, 186,330 new cases will be diagnosed in 2008 and 26,000 men will die from prostate cancer. Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years.
Prevalence rates of prostate cancer remain significantly higher in African American men than in white men, while the prevalence in Hispanic men is similar to that of white men. Hispanic men and African American men present with more advanced disease, most likely related to external
(eg, income, education, insurance status) and cultural factors. In addition, African American men generally have higher levels of testosterone, which may contribute to the higher incidence of carcinoma.
Between 1989 and 1992, incidence rates of prostate cancer increased dramatically, probably because of earlier diagnoses in asymptomatic men as a result of the increased use of serum PSA testing. In fact, the incidence of organ-confined disease at diagnosis has increased because both PSA testing and standard DRE are performed.
Prostate cancer incidence rates are continuing to decline; rates in white men peaked in 1992, and they peaked in African American men in 1993.
During 1992-1996, mortality rates associated with prostate cancer declined significantly, approximately 2.5% per year. Although mortality rates are continuing to decline among white and
African American men, mortality rates in African American men remain twice as high as in white men, based on 2008 American Cancer Society projections.
Prostate cancer is also found during autopsies performed following other causes of death.
The rate of this latent or autopsy cancer is much greater than that of clinical cancer. In fact, it may be as high as 80% by age 80 years.
The prevalence of clinical cancer varies by region, and these differences may be due to some of the genetic, hormonal, and dietary factors discussed in Etiology. High rates are reported in northern Europe and North America, intermediate rates are reported in southern Europe and Central and South America, and low rates are reported in Eastern Europe and Asia.
Interestingly, the prevalence of the latent or autopsy form of the disease is similar worldwide. Together with migration studies, this suggests that environmental factors, such as diet, may play a significant promoting role in the development of a clinical cancer secondary to a latent precursor.
Etiology
Genetics
Gene alterations on chromosome 1, 17, and the X chromosome have been found in some patients with a family history of prostate cancer. The hereditary prostate cancer 1 ( HPC1 ) gene and
30

the predisposing for cancer of the prostate ( PCAP ) gene are on chromosome 1, while the human prostate cancer gene is on the X chromosome. In addition, genetic studies suggest that a strong familial predisposition may be responsible for as many as 5-10% of prostate cancer cases. Recently, several reports have suggested a shared familial risk (inherited or environmental) for prostate and breast cancer. Men with a family history of prostate cancer have a higher risk of developing prostate cancer and are also likely to present 6-7 years earlier.
Race
African American men have a higher prevalence and more aggressive prostate cancer than white men, who, in turn, have a higher prevalence than men of Asian origin. Studies have found that young African American men have testosterone levels that are 15% higher than in young white men.
Furthermore, evidence indicates that 5-alpha reductase may be more active in African Americans than in whites, implying that hormonal differences may play a role. The independent contribution of race alone is difficult to qualify when the effects of health care access, income, education, and insurance status are also considered.
Diet
A high-fat diet may lead to increased risks, while a diet rich in soy may be protective. These observations have been proposed as reasons for the low prevalence of this cancer in Asia. Rates of prostate cancer are much greater in Japanese American men than in native Japanese men, supporting the association of a high-fat diet with cancer. Cell culture studies have shown that omega-6 fatty acids are positive stimulants of prostate cancer cell growth, while omega-3 fatty acids are negative stimuli. These fats may exert their effects by alterations of sex hormones or growth factors or through effects on 5-alpha reductase.
Soy seems to decrease the growth of prostate cancer cells in mouse models; however, apart from epidemiologic factors, no direct evidence supports a beneficial effect in humans. Vitamin E may have some protective effects because it is an antioxidant. Decreased levels of vitamin A may be a risk factor because this can promote cell differentiation and stimulate the immune system. Vitamin
D deficiency was suggested as a risk factor, and studies show an inverse relationship between ultraviolet exposure and mortality rates for prostate cancer. However, a specific correlation between
1,25-dihydroxyvitamin D levels and palpable disease, well-differentiated tumors, or mortality is inconclusive.
Selenium may have a protective effect based on epidemiologic studies and is also believed to extend its effect via its antioxidant properties. The Selenium and Vitamin E Cancer Prevention Trial
(SELECT) is an ongoing intergroup, phase 3, randomized, controlled trial designed to test the efficacy of selenium and vitamin E alone and in combination in the prevention of prostate cancer.
Hormones
Hormonal causes have also been postulated. Androgen ablation causes a regression of prostate cancer. In addition, as indirect evidence of hormonal causes, eunuchs do not develop adenocarcinoma of the prostate.
Hsing and Comstock performed a large study comparing patients with prostate cancer with controls and found no difference in levels of testosterone, dehydrotestosterone, prolactin, folliclestimulating hormone, or estrone.
1
The Prostate Cancer Prevention Trial studied the prevalence of prostate cancer between a control group and a group given a 5-alpha-reductase inhibitor (finasteride). While the 5-alpha reductase inhibitor appeared to decrease the prevalence of tumors, those that did arise appeared histologically more aggressive. Only long-term follow-up of these patients will determine whether this more aggressive histology accurately reflects the underlying biology of these tumors or whether it is an artifact of the treatment.
The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC),
ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines
Committee jointly convened a Panel of experts who used the results from a systematic review of the
31

literature to develop evidence-based recommendations on the use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention.
The Expert Panel concluded that asymptomatic men with a PSA level of less than 3 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-alpha-reductase inhibitors for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer).
Men who are taking 5-alpha-reductase inhibitors for benign conditions, such as lower urinary tract (obstructive) symptoms (LUTS), may benefit from a similar discussion; these patients should understand that the improvement of LUTS relief should be weighed with the potential risks of high-grade prostate cancer from 5-alpha-reductase inhibitors (although most of the Panel members judged the risk of high-grade prostate cancer to be unlikely). A reduction of approximately
50% in PSA level by 12 months is expected in men taking a 5-alpha-reductase inhibitor; however, because these changes in PSA may vary among men, and within individual men over time, the Panel has no recommendations for a specific cut point to trigger a biopsy for men taking a 5-alphareductase inhibitor. No specific cut point or change in PSA level has been prospectively validated in men taking a 5-alpha-reductase inhibitor.
2
Pathophysiology
Prostate cancer develops when the rates of cell division and cell death are no longer equal, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most (95%) prostate cancers are adenocarcinomas.
Approximately 4% of cases of prostate cancer have transitional cell morphology and are thought to arise from the urothelial lining of the prostatic urethra. Few cases have neuroendocrine morphology. When present, they are believed to arise from the neuroendocrine stem cells normally present in the prostate or from aberrant differentiation programs during cell transformation.
Of prostate cancer cases, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.
Natural history
The natural history is still relatively unknown, and many aspects of progression are poorly understood. Symptoms or abnormal DRE findings in the pre-PSA era brought only 40-50% of patients with prostate cancer to medical attention, and these patients usually had locally advanced disease. The advent of PSA testing has helped to identify patients with less-advanced, organconfined disease.
In fact, the pendulum has shifted to the point that certain members of the urologic community feel that active surveillance, also known as expectant management, may have a role. Twenty-year outcome data from Connecticut confirm that mortality rates due to tumors with a
Gleason score of 2-4 was less than 7%.
3 Urologists at Johns Hopkins University advocate active surveillance in patients with a PSA density of less than 0.1 ng/mL, with no adverse pathologic findings on needle biopsy, and with tumors with a Gleason score of 6 that are smaller than 3 mm.
Evidence suggests that most prostate cancers are multifocal and heterogeneous. Cancers can start in the transitional zone or, more commonly, the peripheral zone. When these cancers are locally invasive, the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces occurs relatively late.
The mechanism for distant metastasis is poorly understood. The cancer spreads to bone early, occasionally without significant lymphadenopathy. Currently, 2 predominant theories have been proposed for spread—the mechanical theory and the seed-and-soil theory.
32


The mechanical theory involves direct spread through the lymphatics and venous spaces into the lower lumbar spine.

Advocates of the seed-and-soil theory believe that tissue factors that allow for preferential growth in certain tissues, such as the bone, must be present. Lung, liver, and adrenal metastases have also been documented. Specific tissue growth factors and extracellular matrices are possible examples.
The doubling time in early-stage disease is as slow as 2-4 years, but this changes as the tumor grows and becomes more aggressive. Larger tumors usually have a higher Gleason grade and a faster doubling time.
Natural history by stage


T1a - Progression over 10 years (uncommon)

T1b - Tumor-related death rate of 10% in 10 years
T2 - Ten-year metastasis-free survival rate of 81% with grade 1, 58% with grade 2, and
26% with grade 3

T3 - Lymph node metastasis at presentation in 50% and approximately 25% rate of 10year disease-free survival
The natural history of clinically localized disease varies, with lower-grade tumors having a more indolent course, while some high-grade lesions progress to metastatic disease with relative rapidity. Several studies have examined the cancer-specific and quality-of-life outcomes associated with a watchful-waiting approach to localized disease.

Albertsen et al monitored patients who received no initial treatment for prostate cancer.
3
As disease progression occurred, many received antiandrogens. Men with poorly differentiated tumors lost 6-8 years of life, while those with moderately differentiated tumors lost 4-5 years. Of all men monitored for 10 years, 40% died of causes other than prostate cancer. This study was performed prior to PSA screening.

Graversen et al compared watchful waiting with radical prostatectomy.
4 They found no overall difference in survival, but they did find that a high Gleason score was associated with poor survival in both groups.

Chodak et al confirmed this finding by analyzing 6 studies and finding a 34% survival rate associated with grade 3 tumors versus an 87% disease-specific survival rate associated with grade 1 and 2 tumors.
5 The metastasis-free survival rate also significantly dropped as the grade progressed from 1 to 3.

Johansson et al (2004) reported their recent update on a population-based cohort study with a mean observation period of 21 years.
6 In this study, 223 patients with early-stage, initially untreated prostatic cancer were observed. Symptomatic patients with tumor progression received hormonal treatment (orchiectomy or estrogens). Thirty-nine (17%) developed metastatic disease, with most cancers having an indolent course during the first 10-15 years. However, further followup at 15-20 years revealed a substantial decrease in cumulative progression-free survival (from 45% to 36%), survival without metastases (from 76.9% to 51.2%), and prostate cancer–specific survival
(from 78.7% to 54.4%). Prostate cancer mortality increased from 15 deaths per 1000 person-years during the first 15 years to 44 deaths per 1000 person-years beyond 15 years of follow-up.
Taken together, these data suggest that, although most prostate cancers diagnosed at an early stage have an indolent course, local tumor progression and aggressive metastatic disease may develop in the long term. In addition, these findings would support early radical treatment, notably among patients with an estimated life expectancy exceeding 15 years.
33

Screening
DRE and PSA evaluation are the 2 components necessary for a modern screening program.
Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it is very useful for directing prostatic biopsies.
The indications for screening are controversial. The American Cancer Society recommends that both PSA evaluation and DRE should be offered annually, beginning at age 50 years, to men who have at least a 10-year life expectancy and to high-risk younger men. Information should be provided to patients regarding potential risks and benefits of intervention.
Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.
7
Advocates of screening believe that early detection is crucial to finding organ-confined disease and to reducing the likelihood of mortality. When symptoms develop or when DRE results become positive, most cases have already advanced beyond organ-confined disease. Those who do not advocate screening worry that screening will detect cancers that are not biologically significant
(ie, in patients who will die with prostate cancer rather than from it). Currently, age-specific PSA cutoffs are used to guide screening. The trend is toward lowering the threshold level to 2.5 ng/mL, but this has not yet been widely accepted.
Men who choose to undergo screening should begin at age 50 years. Men in high-risk groups, such as African Americans and those with a strong familial predisposition (2 or more affected first-degree relatives), should begin screening at a younger age (40-45 y). These men are less likely to have the latent form of the disease and benefit from treatment. More data on the precise age to start prostate cancer screening are needed for men at high risk.
Recent data from Canadian and Austrian studies suggest that mortality rates are lower as a result of PSA screening. Canadian data have shown that, from 1989-1996, the mortality rate was lower in the PSA-screened cohort than in the control group. Recent studies from Tyrol, Austria, also show a beneficial result for screening in reducing disease-specific mortality. These beneficial effects are likely due to the fact that treatment rather than observation may enhance disease-specific survival. This was recently shown in a 2002 Scandinavian study, which reported that radical prostatectomy was associated with significantly reduced disease-specific mortality compared with watchful waiting. No difference in overall survival was noted.
Currently, US data have shown a mortality rate decrease of 1% per year since 1990, which coincides with the advent of PSA screening. Other theories have been proposed to account for the decrease, and these include changing treatment practices and artifacts in mortality rates secondary to the changing incidence.
Abnormal rectal examination findings
Findings from the DRE are crucial. An irregular firm prostate or nodule is typical, but many cancers are found in prostates that feel normal. Pay careful attention to the prostate consistency, along with the seminal vesicles and adjacent organs, to detect spread of the disease to these structures.


Overdistended bladder due to outlet obstruction
Neurologic findings secondary to cord compression: Other subtle findings, such as paresthesias or wasting, are uncommon.


Lower extremity lymphedema

Supraclavicular adenopathy

Lower extremity deep venous thrombosis
Cancer cachexia
34

Transrectal ultrasonography
TRUS is used to examine the prostate for hypoechoic areas, which are commonly associated with cancers but are not specific enough for diagnostic purposes. At least 6 or, more recently, 10 or more systematic biopsy specimens of peripheral and, occasionally, transitional zones are taken under ultrasonographic guidance. Samples should include most areas of the gland, irrespective of ultrasonographic abnormalities.
Staging
The 2002 TNM staging system is used to stage prostate cancer, as follows:


T - Primary tumor

TX - Primary tumor cannot be assessed

T0 - No evidence of primary tumor


T1 - Clinically inapparent tumor not palpable or visible by imaging
T1a - Tumor incidental histologic finding in less than or equal to 5% of tissue resected
T1b - Tumor incidental histologic finding in greater than 5% of tissue resected

T1c - Tumor identified by needle biopsy (because of elevated PSA level); tumors found in
1 or both lobes by needle biopsy but not palpable or reliably visible by imaging


T2 - Tumor confined within prostate

T2a - Tumor involving less than half a lobe

T2b - Tumor involving less than or equal to 1 lobe

T2c - Tumor involving both lobes
T3 - Tumor extending through the prostatic capsule; no invasion into the prostatic apex or into, but not beyond, the prostatic capsule

T3a - Extracapsular extension (unilateral or bilateral)

T3b - Tumor invading seminal vesicle(s)

T4 - Tumor fixed or invading adjacent structures other than seminal vesicles (eg, bladder neck, external sphincter, rectum, levator muscles, pelvic wall)


NX - Regional lymph nodes (cannot be assessed)

N0 - No regional lymph node metastasis
N1 - Metastasis in regional lymph node or nodes
Regional lymph nodes are assessed via surgical removal or biopsy of the pelvic lymph nodes, including the obturator chain. The surgical boundaries include the bifurcation of the common iliac, the obturator nerve, and the node of Cloquet.
Distant metastasis


PM1c - More than 1 site of metastasis present

MX - Distant metastasis cannot be assessed

M0 - No distant metastasis


M1 - Distant metastasis
M1a - Nonregional lymph node(s)

M1b - Bone(s)
M1c - Other site(s)
Workup
Determine the PSA level. Age-related PSA levels can be assessed, as can clinical evidence of prostatitis. If the physician believes that an elevated PSA level may be due to infection, 4-6 weeks of antibiotics are provided, and then the PSA level is rechecked.
Perform a DRE. This is examiner-dependent, and serial examinations, over time, are best.
Regard nodules or changes in the texture or the level of asymmetry with a high index of suspicion.
35

Physical examination findings alone cannot reliably differentiate a cyst or calculus from cancer foci; therefore, a biopsy is warranted in these circumstances.
Perform a biopsy to aid in diagnosis and determine the Gleason score. Antibiotics are administered, and an enema is often provided before the procedure, followed by a short course of antibiotics after the biopsy. Coagulation tests are not routinely performed, but patients are instructed to stop aspirin and nonsteroidal anti-inflammatory drugs 10 days prior to the biopsy. Many physicians use lidocaine prior to the biopsy, while others do not. The number of biopsies that should be performed is debated. Sextant versus 12- versus 18-core biopsy protocols are published in the literature. The 12- or 18-core protocols yield more specimens from the lateral regions and usually sample the transition zone. Several studies have demonstrated an increase in the cancer detection rate, while others have not.
In patients with a persistently elevated PSA level in the face of negative biopsy results, the literature supports repeating the biopsy once or twice. Of cancer cases, 31% were detected on repeat biopsy and 39% were detected if the PSA value was greater than 20 ng/mL. If all the biopsy results are negative, a repeat round of biopsies has been suggested when the PSA increases by 25% from the level at which the last biopsies were performed.
Further workup depends on the clinical staging. A higher clinical stage of cancer determined by DRE findings, PSA level, and Gleason score (as determined by biopsy) correlates with an increased risk of extraprostatic spread, and these tests are considered key factors in determining the staging workup and predicting patient prognosis.
The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.
In addition, a series of nomograms has been issued from the Memorial Sloan-Kettering Cancer
Center; these nomograms are used to predict biochemical-free survival after surgery and radiation.
The most commonly used is the Kattan nomogram.
Men with PSA levels less than 10 ng/mL and low- or moderate-grade histology (Gleason score <7) with no findings or minimal findings on physical examination may proceed to surgery or brachytherapy without further studies. Men with PSA levels greater than 10 ng/mL, high-grade histology (Gleason score >7), or physical findings that suggest stage T3 disease should probably undergo a staging CT scanning and bone scan. CT scanning is the one modality with evidence-based guidelines. The CT scanning can be used to evaluate extension into the bladder and lymph nodes to help stage the patient's cancer or to consider lymph node sampling prior to treatment. TRUS is no better than DRE, and positron emission tomography scans have not been proven effective.
MRI is superior to bone scan in evaluating bone metastasis but is impractical for routine total-body surveys. Instead, it is used to determine the etiology of questionable lesions found on bone scans. MRI is promising for local staging but is not readily accessible, and no published guidelines are available.
Neither CT scanning nor MRI can be used to determine if lymph nodes are reactive or contain malignant deposits unless the nodes are significantly enlarged and a percutaneous biopsy can be performed.
There is increasing interest in using metabolic activity to detect cancer foci. Positron emission tomography (PET) uses glucose analogue 18 F-fluorodeoxyglucose (18 F-FDG) to detect cancer, but studies thus far have been disappointing for prostate cancer detection.
C-choline PET scans fused with CT imaging show more promise but are not yet the standard of care. Likewise, there is renewed interest in ProstaScint scans fused with MRI or CT images. This modality involves a murine monoclonal antibody that reacts with prostate-specific membrane antigen to identify cancer both in the prostate and in metastatic deposits.
Finally, conventional endorectal MRI is helpful for localizing cancer within the prostate and seminal vesicles and for local staging. Dynamic contrast-enhanced MRI and MR spectroscopic imaging are also complementary in local staging, but their use is currently limited to a research setting.
36

Histologic findings
The most commonly used system of classifying histologic characteristics of prostate cancer is the Gleason score, which is determined using the glandular architecture within the tumor.
The predominant pattern and the second most common pattern are given grades from 1-5.
The sum of these 2 grades is referred to as the Gleason score. Scoring based on the 2 most common patterns is an attempt to factor in the considerable heterogeneity within cases of prostate cancer. In addition, this scoring method was found to be superior for predicting disease outcomes compared with using the individual grades alone.
Grades are based on the extent to which the epithelium assumes a normal glandular structure. A grade of 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern (less malignant to more malignant). This scheme of grading histological features greatly depends on the skill and experience of the pathologist and is subject to some degree of individual variation.


A score of 2-4 is considered low grade or well differentiated.

A score of 5-7 is considered moderate grade or moderately differentiated.
A score of 8-10 is considered high grade or poorly differentiated.
Although the change in glandular architecture represented by the Gleason score is currently the most widely used and correlative histological parameter, it is not the only histological change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology, neuroendocrine differentiation, and vascularity can be observed and may have great prognostic significance.
Perineural invasion is an indicator of invasiveness and is considered in terms of which side should possibly undergo a nerve-sparing procedure and whether a patient might benefit more from high- or low-risk brachytherapy.
Prostatic intraepithelial neoplasia (PIN) represents the putative precancerous end of the morphologic continuum of cellular proliferations within prostatic ducts, ductules, and acini.
Two grades of PIN are identified. Low-grade PIN is mild dysplasia. High-grade PIN encompasses moderate and severe dysplasia. High-grade PIN is considered by most to be a precursor of invasive carcinoma. Men with high-grade PIN alone can be started on finasteride and monitored closely.
The continuum that culminates in high-grade PIN and early invasive cancer is characterized by basal cell layer or basement membrane disruption, progressive loss of secretory differentiation markers, increasing nuclear and nucleolar abnormalities, increasing proliferative potential, and increasing variation in DNA content (aneuploidy).
Clinical studies suggest that PIN predates a carcinoma by 10 or more years. The clinical importance of recognizing PIN is based on its strong association with carcinoma. Recent studies claim that men with high-grade PIN in a prostate biopsy specimen have a 35-50% chance of being diagnosed with prostate cancer after a subsequent biopsy. Atypical small acinar proliferation
(ASAP) has also been associated with higher cancer detection rates. The identification of PIN in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma. In most men, this means repeat biopsies if the PSA level changes significantly. The same may also be true for ASAP findings after biopsy.
Future and Controversies
Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over another remains controversial. The choice of definitive therapy has been suggested to make a significant difference in long-term survival in less than 10% of patients. This means that most patients are either cured by any definitive therapy or present with incurable disease that cannot be detected, and, ultimately, any treatment modality fails to be curative.
37

A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that no single therapy can be considered the preferred treatment for presumed organconfined prostate cancer. The AHRQ based this conclusion partly on the lack of data regarding efficacy and partly on the concept that differences in adverse effects, convenience, and costs among the available therapies may be important factors in the choice of treatment in an individual patient.
The AHRQ noted that, although all treatment options carry adverse effects, patient satisfaction with therapy is high.
8
Molecular prognostic markers
Over the past few years, several molecular markers have been shown to aid in the prognostication of patients undergoing treatment for localized and metastatic prostate cancers.
Assessment of the molecular alterations or gene products of TP53, RB, BCL2, cathepsin-D, CDH1, and PTEN, among many others, have been reported. Prospective trials are needed to assess these markers more thoroughly before their implementation in current management is recommended.
Reverse transcriptase-polymerase chain reaction
Reverse transcriptase-polymerase chain reaction (RTPCR) testing may be able to find very small amounts of PSA nucleic acid in the blood stream, prostatic fossa, or bone marrow. In the future, this may be helpful in determining which patients have residual tumor following surgery
(RTPCR-positive prostate fossa) or a higher rate of tumor recurrence (RTPCR-positive lymph nodes at surgery or persistently positive bone marrow samples months after treatment).
Grades are based on the extent to which the epithelium assumes a normal glandular structure. Grade 1 indicates a near-normal pattern, and grade 5 indicates the absence of any glandular pattern (less malignant to more malignant). Grades 2-4 are considered low grade; grades 5-
7 are considered moderate grade; and grades 8-10 are considered high grade. This scheme of grading histological features greatly depends on the skill and experience of the pathologist and is thus subject to some degree of individual variation.
Although the change in glandular architecture represented by the Gleason score is the most widely used and correlative histological parameter, it is by no means the only histological change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology,
DNA ploidy, neuroendocrine differentiation, and vascularity can be observed and may have prognostic significance.
High-grade prostatic intraepithelial neoplasia
A prostatic intraepithelial neoplasia (PIN) is the putative precancerous end of the morphologic continuum of cellular proliferations within prostatic ducts, ductules, and acini. Experts identify 2 grades of PIN, low grade and high grade. High-grade PIN is considered a precursor to invasive carcinoma and may also coexist with cancer in the same gland. The continuum, which culminates in high-grade PIN and early invasive cancer, is characterized by basal cell layer disruption, basement membrane disruption, progressive loss of secretory differentiation markers, increasing nuclear and nucleolar abnormalities, increasing proliferative potential, and increasing variation in DNA content (ie, aneuploidy).
Clinical studies suggest that PIN predates carcinoma by 10 years or more. The clinical importance of recognizing PIN is based on its concomitant association with carcinoma; therefore, if it is identified in prostate biopsy specimens, a thorough search for concurrent invasive carcinoma is warranted.
Standard treatments for localized prostate cancer include surgery, radiation therapy (external beam or brachytherapy with and without androgen ablation), or observation, which is also termed watchful waiting. Three significant factors enter into the decision for the selection of therapy.


First, the overall life expectancy of patients as determined by age and comorbidities
Second, the biological characteristics of the tumor, together with its predicted aggressiveness and behavior
38


Third, the preferences of the patient for the various treatment options, with consideration of complications, adverse effects, relative efficacy, and quality-of-life issues
With respect to the tumor characteristics, models have been developed that combine the clinical stage (as determined by digital rectal examination [DRE] findings), Gleason score after biopsy, and serum concentration of PSA in an attempt to better predict which men have organconfined cancer as opposed to those who may have local extension. In addition, these models can be used to predict the time to biochemical failure and the time to the development of clinical metastatic disease in patients with rising PSA levels.
In addition, these models have been adapted to personal-computer and handheld-computer platforms and can be used with ease in clinical practice. One such program can be downloaded free of charge from the Prostate Nomogram section of the Memorial Sloan-Kettering Cancer Center Web site. The Partin tables are another excellent nomogram for predicting prostate cancer spread and prognosis.
Nonsurgical Therapy
Early localized disease (clinical stage T1-2N0M0)

Active surveillance o
Active surveillance is becoming more popular as physicians worry more about overtreatment of prostate disease. The difficulty with prostate cancer is knowing which variants will be aggressive. Active surveillance refers to PSA testing every 3 months and repeat biopsy at 18- to
24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment. A rapid PSA level rise or patient choice can also prompt proceeding to treatment.
2 o
Watchful waiting, a program of regular examinations used to monitor symptoms, is considered in patients of advanced age or those who have significant life-limiting comorbidities and a life expectancy of less than 10 years. In addition, watchful waiting is appropriate in patients who do not harbor well-differentiated tumors. o
Recent evidence supports these recommendations, and further evidence suggests that patients who undergo watchful waiting for more than 15 years sustain significant disease progression. o
A 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that men with clinically localized prostate cancer detected by methods other than PSA testing who were treated with radical prostatectomy experienced fewer deaths due to prostate cancer, marginally fewer deaths from any cause, and fewer distant metastases than men who underwent watchful waiting. The AHRQ notes that the advantage of radical prostatectomy with regard to lower cancer-specific and overall mortality rates appears to be limited to men younger than 65 years but is unrelated to baseline PSA level or histologic grade.
3

Androgen ablation o
Androgen ablation has been used in some patients who are unwilling to undergo potentially curative treatment options yet want some form of treatment beyond watchful waiting. o
Androgen ablation can be performed in multiple ways, such as via luteinizing hormone– releasing hormone agonists, luteinizing hormone–releasing hormone antagonists, or oral antiandrogens (steroidal and nonsteroidal; see Medication). o
In 2002, See et al reported early results from studies using the antiandrogen bicalutamide
(Casodex).
4 o
The AHRQ review noted that, in 3 randomized controlled trials, androgen deprivation with bicalutamide alone or in addition to radical prostatectomy or external beam radiation therapy did not reduce cancer recurrence or mortality.

3
External beam radiation therapy o
This is used with curative intent in patients with clinically localized cancer and is often combined with androgen ablation.
39

o
Techniques include (1) conventional external beam (4-field box); (2) conformal external beam, which delivers higher doses of radiation to the prostate while sparing adjacent tissues better than the conventional approach; and (3) intensity-modulated radiation therapy, which is a highly conformal treatment technique for radiation treatment planning and delivery; the increased control permits higher doses with reduced acute and late toxicities. o
The AHRQ reviewed 5 randomized controlled trials of external beam radiotherapy and concluded that no regimen, whether conventional, high-dose conformal, dose fractionation, or hypofractionation, was superior in reducing overall or disease-specific mortality.
3 o
External beam radiation therapy can be used concomitantly with androgen ablation.

Several Radiation Therapy Oncology Group and European Organization for Research and
Treatment of Cancer trials have determined that androgen ablation, when combined with external radiation, yields improved disease-specific survival and increased time to recurrence in patients with locally advanced or high-grade prostate cancer. The advantage of this approach in patients with early disease remains to be determined, but it could offer significant advantages when used in younger patients with significant expected longevity (>20 y).

Androgen ablation has traditionally been achieved with luteinizing hormone–releasing hormone agents combined with antiandrogens, although variations on this theme have been described. Androgen ablation commonly begins several months before radiation is initiated and continues for several months or years afterward.

In the Radiation Therapy Oncology Group 85-31 study, 945 analyzable subjects (477 in adjuvant arm, 468 in observation arm) had a median follow-up of 4.5 years. Actuarial projections showed that, at 5 years, 84% in the adjuvant goserelin arm and 71% in the observation arm still had no evidence of local recurrence. The corresponding figures for freedom from distant metastases and disease-free survival are 83% versus 70% and 60% versus 44%, respectively. If PSA levels greater than 1.5 ng/mL are included as failures in these rates, the 5-year disease-free survival rate is 53% in the adjuvant goserelin arm and 20% in the observation arm. The 5-year survival rate (for the entire population) is 75% in the adjuvant arm and 71% in the observation arm. However, in patients with tumors with a Gleason score of 8-10, the difference in actuarial 5-year survival (66% in the adjuvant goserelin arm vs 55% in the observation arm) reaches statistical significance.

The AHRQ concluded that, in high-risk patients (as defined by PSA levels and Gleason histologic score [PSA >10 ng/mL or Gleason score >6]), adding androgen ablation to external beam radiotherapy may decrease overall and disease-specific mortality but increases adverse effects. o
Complications of external radiotherapy include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence (7-10%). Patients also exhibit the symptoms of androgen deprivation (eg, decreased libido, impotence, hot flashes) if undergoing this form of therapy in conjunction with radiation therapy.

Brachytherapy o
Types of brachytherapy include low–dose rate brachytherapy and high–dose rate brachytherapy. o
In the low–dose rate type, radioactive palladium or iodine seeds are placed into the prostate. In the high–dose rate type, temporary implants are placed in the prostate. The theoretical advantage is the capacity to optimize the dose after needles are in place. Improved outcomes compared with permanent brachytherapy have not been demonstrated to date. o
Either type may be used alone or in combination with external beam radiotherapy, depending on the PSA level and the cancer grade. Most practitioners do not use brachytherapy in conjunction with external beam therapy in patients with early (well-differentiated) localized disease and low (<10 ng/mL) PSA levels. In more advanced cases, external beam therapy with or without neoadjuvant and adjuvant androgen ablation is used.
40

o
Complications of brachytherapy are generally similar to those of conformal or intensitymodulated external radiotherapy.

Transperineal cryotherapy o
Low temperatures have been used for centuries in the form of ice packs. In the 1960s, liquid nitrogen enabled physicians to achieve temperatures of -190°C (-310°F). Advances in insulated probes have allowed urologists to freeze a specific zone of tissue, causing necrosis in that area. o
The mechanism of cell death due to cryotherapy involves 3 processes—direct mechanical shock, osmotic shock, and cellular hypoxia. The freezing process entails a freeze-thaw cycle that leads to mechanical shearing, which, in turn, disrupts cell membranes and allows them to become permeable and responsive to the osmotic forces in the intracellular space. This leads to hyperosmotic shock and causes shrinkage and protein loss. As the thaw occurs, the hypotonic tumor cell surroundings cause the cells to lyse. o
Interest in cryotherapy has been renewed owing to transrectal ultrasonographic monitoring of the prostate and improved percutaneous probes. Third-generation, gas-driven probes are smaller, allow for better conformal treatment of the gland, and offer the ability of heating, thus accelerating the thaw process and reducing operative time. In addition, by using these argon gas–driven probes, the freezing process can be turned on and off very rapidly, allowing precise extension of the ice ball. o
Currently, cryotherapy is an outpatient procedure performed with the patient in the lithotomy position. The cryoprobes are inserted through the perineum under transrectal ultrasonographic guidance. The bladder is filled with warm saline. A urethral warmer that keeps the urethra protected from the low temperatures in the surrounding gland is placed into the bladder. In essence, the procedure is very similar to high dose rate brachytherapy. o
Complications include tissue sloughing, perineal ecchymosis, stricture or contracture, incontinence, impotence (in >90%), and, rarely (in previously nonirradiated disease), fistula formation between the urinary and gastrointestinal tracts. In multicenter studies, 75% of patients had
PSA levels of greater than 0.4 ng/mL 12 months after primary treatment (no previous prostate radiation). A 2010 review found that the incontinence rate had improved to less than 5%, while the rate of rectal fistula was less than 0.5%.
5 o
As the experience with cryotherapy has increased, there is now 10-year data supporting its use in terms of biochemical control and quality of life. Cohen et al used a nadir plus 2 ng/dL definition of biochemical recurrence (Phoenix) and demonstrated 10-year biochemical disease–free survival rates of 80.56%, 74.16%, and 45.54% for low, moderate, and high-risk groups, respectively.
6 Such data have led to a 2008 American Urological Association (AUA) Best Practice
Policy Statement on cryosurgery that confirms the evidence of therapeutic benefit and the acceptably low treatment-associated morbidity yielded by cryosurgery.
7 o
Based on this and other studies, the US Medicare program has begun reimbursing for both primary and salvage cryotherapy for prostate cancer, but the latter only in selected clinical situations. o
As concern with overtreatment of prostate cancer has emerged, many centers are trying
"focal" cryotherapy. This is analogous to a "male lumpectomy," in which only the cancerous portion of the gland is treated, as opposed to the entire prostate. Onik et al reported on the results of 3-year follow-up in 48 men who underwent focal cryotherapy; 94% had stable PSA levels, and 90% had maintained potency.
8 However, the focal approach is still considered experimental and needs more experience with an oncologic approach. Focal cryoablation may be most appropriate for men who would otherwise be candidates for active surveillance but who are uncomfortable with this approach, as pointed out by the 2007 International Task Force on Prostate Cancer and the Focal Lesion
Paradigm.

9
High-intensity focused ultrasound
41

o
High-intensity focused ultrasound (HIFU) is an acoustic ablation technique that uses ultrasound waves to destroy prostate tissue. Like cryotherapy, this is a transperineal procedure that does not involve ionizing energy (radiation). o
A multicenter national trial is currently comparing the effectiveness of cryotherapy with
HIFU. o
HIFU has been available since 1993 in Canada, Europe, and Mexico but is not yet FDAapproved for use in the United States. Patients who undergo the procedure require a catheter for about 10 days after therapy. While US urologists perform the procedure in Mexico and the
Dominican Republic, patients should be counseled that the cure rates with this technique have not been proven.
10
Locally advanced disease (T3-4N0M0)

Watchful waiting: Because of the aggressive nature of these tumors, watchful waiting is an option only in highly selected patients with life expectancies of less than 5 years.

External beam radiotherapy: Treat patients as described above in External beam radiation therapy.

Brachytherapy: If brachytherapy is used, it is often combined with external beam and hormonal therapy.
Surgical Therapy
The goal is disease-free survival if the cancer is localized. The goal is symptom-free survival if the cancer has spread outside the confines of the prostatic capsule.
Early localized disease (T1-2N0M0)
Radical prostatectomy involves removal of the prostate and seminal vesicles. Pelvic lymphadenectomy includes the medial half of the external iliac and obturator fossa from the bifurcation of the internal and external iliacs to the node of Cloquet. Currently, 3 approaches are used to remove the prostate gland.

Radical retropubic prostatectomy: This can be performed using either an open or laparoscopic technique. The laparoscopic technique can be performed with robotic assistance.

Radical perineal prostatectomy: Advantages include less discomfort, quicker return of bowel function, and shorter hospitalization. Disadvantages include specialized instruments, lack of node sampling or node sampling performed on a separate date, and, in some studies, higher fecal incontinence rates.

Nonrobotic laparoscopic prostatectomy: Early data from Europe show a steep learning curve. However, once this curve is overcome, early data on intraoperative and postoperative complications appear to be similar to those of open prostatectomy. Although the follow-up was short
(<5 y), cancer control appeared equal to that of the open procedure. The long-term rates of continence, anastomotic stricture, and sexual function remain to be determined in larger studies with longer follow-up. Head-to-head outcome studies are currently in progress.

Robotic-assisted laparoscopic prostatectomy has supplanted pure laparoscopic prostatectomy. At high-volume centers, outcomes appear to be similar to those of open prostatectomy. Proponents of the technique suggest that the magnification offered by the laparoscope and the multiple degrees of freedom will eventually improve potency and continence outcomes. Head-to-head outcome studies are currently ongoing.
11
The following criteria are general suggestions for any candidate for radical prostatectomy.
However, regardless of the approach, the many exceptions and treatment choices must be individualized to each patient's specific situation.


Patient younger than 75 years

Few comorbidities, with life expectancy longer than 10 years
Histologically, Gleason score of 7 or less
42


PSA level less than 20 ng/mL
The nomograms mentioned above (see Prostate Nomogram) that combine clinical stage,
Gleason score after biopsy, serum PSA level, and other parameters can be used to predict the probability of lymph node involvement. Generally, because the false-negative rate of frozen section analysis of lymph nodes is approximately 3%, patients with a less than 3% projected chance of harboring metastatic prostate cancer in their lymph nodes can safely avoid pelvic lymphadenectomy.
At the very least, these patients can avoid having samples of their lymph nodes sent for frozen section analysis in the operating room.
Patients with tumors with higher Gleason scores and PSA levels require a lymph node dissection and frozen section analysis in the operating room only if the surgery is aborted in the context of positive findings. However, series from the Mayo Clinic have shown that continuing with the radical prostatectomy and subsequent antigen deprivation even in the face of cancer-positive nodes has resulted in good long-term survival.
Complications from radical prostatectomy vary widely. This variation depends on the surgeon and center, with high-volume centers generally having superior outcomes. Complications may include impotence, urinary incontinence, strictures, and, possibly, fecal incontinence. Potency rates in previously potent patients vary greatly (5-80%) and depend on patient age and whether a nerve-sparing surgery (unilateral or bilateral) is performed or whether a non–nerve-sparing surgery is performed. Incontinence (4-30%) also depends on the patient's age and whether the surgery is nerve sparing or non–nerve sparing. Strictures (10%) and, rarely, fecal incontinence occur; the latter may occur more commonly with perineal prostatectomy.
Locally advanced disease (T3-4N0M0)
Radical prostatectomy is only occasionally indicated for patients who have undergone a high level of selection and long-term neoadjuvant androgen ablation. The benefit of long-term (ie, >6 mo) neoadjuvant androgen ablation prior to surgery is currently being studied in clinical trials.
Follow-up
Follow-up is not standardized; however, practitioners use general guidelines that are mainly derived from publications that report outcomes on various methods of treatment. In addition, the
National Comprehensive Cancer Network, an alliance of 19 cancer centers, publishes follow-up guidelines for the various treatment modalities discussed below.

Watchful waiting and androgen ablation o
A DRE and PSA test are performed every 3-12 months. o
Although not unanimous, many experts believe that treating patients for metastatic disease with androgen ablation before they become symptomatic offers the potential for increased survival.
Hence, bone scans are performed yearly in many patients. An alternative approach has been to perform yearly bone scans once the serum PSA level exceeds 40 ng/mL, which is associated with a significant probability of positive bone scan results. o
Some have recommended biopsy of the prostate at 18-24 months to determine if the grade of the cancer has changed. If such a grade change occurs, some physicians and patients may consider more definitive therapy.

Radical prostatectomy o
DRE has not been shown to offer any added advantage in the detection of local recurrence beyond PSA testing; hence, it is not routinely performed. o
PSA testing is performed every 3-4 months for the first 2 years, every 6 months for the third and fourth years, and yearly thereafter.

External beam radiotherapy o
DRE and PSA are performed every 3-6 months for 5 years, then annually thereafter. o
Some practitioners perform biopsy of the prostate at 18-24 months following treatment.

Brachytherapy
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o
PSA testing is performed every 3-6 months for 1 year, then annually thereafter. o
Some practitioners perform biopsy of the prostate at 18-24 months following treatment.

Biochemical recurrence o
A biochemical recurrence (ie, measurable PSA) is considered to have occurred following radical prostatectomy if the PSA level is greater than 0.2 ng/mL or greater than the minimal detectable level of the assay. For example, using the ultrasensitive PSA assays, a cutoff of 0.01 ng/mL or 0.05 ng/mL can be used. o
The definition of a biochemical recurrence following radiation is more complex, and significant debate still surrounds this topic. Three options for determining biochemical recurrence include (1) 2-3 consecutive rises in the PSA level following a nadir (ASTRO definition); (2) nadir plus 2 rises in the PSA level (Phoenix definition 12 ); and (3) an absolute cutoff of 0.2, 0.5, or 1 ng/mL. o
Biochemical recurrence should prompt closer follow-up and consideration of alternate therapies. When the PSA level begins doubling every 10-12 months or reaches a level of 20 ng/mL, imaging studies may be performed.

Bone scan

Chest radiography

CT scanning of the abdomen and pelvis

Potentially, transrectal ultrasound–guided rebiopsy of the prostate or prostatic fossa in patients treated with radical prostatectomy

ProstaScint scan (Cytogen; Princeton, NJ), ie, capromab pendetide scan: The basis for this nuclear scan is prostate-specific membrane antigen, a glycoprotein restricted to the prostate whose level is elevated in men with prostate cancer. Prostate-specific membrane antigen is conjugated to the CYT-356 antibody and is used in immunoscintigraphy. This antibody is labeled with indium
(In)–111 and is used to detect extraprostatic spread. Most commonly, it is used in patients who have biochemical recurrence but who are candidates for additional external beam radiotherapy. The
ProstaScint scan is especially useful for identifying localized recurrence and lymphatic spread.

Positron emission tomography scan: This is an imaging study that uses cancer metabolism to illuminate cancer spread to other organs.

MRI spectroscopy: This study combines anatomic information with metabolic activity to detect residual cancer in the gland.

Salvage therapy o
Patients who have PSA (biochemical) failure following radical prostatectomy and have no evidence of metastatic disease have the options of watchful waiting, radiotherapy, or hormonal ablation as salvage therapy. The choice of therapy depends on the timing of the recurrence (ie, soon after surgery) and the rate of PSA level elevation. o
Similarly, patients who have PSA failure following radiation therapy have the options of watchful waiting, brachytherapy, prostatectomy, cystoprostatectomy, cryotherapy, and hormonal ablation. o
Newer concepts in treatment include intermittent hormone therapy and sequential blockade. Intermittent hormone therapy refers to cycles on androgen ablation and cycles off androgen ablation to keep the PSA level low and to minimize the adverse physical effects of androgen blockade. o
The use of docetaxel (Taxotere) as a chemotherapeutic agent has been effective in metastatic hormone-refractory prostate cancer. Studies evaluating the role of Taxotere earlier in the disease course are ongoing.
For excellent patient education resources, visit eMedicine's Prostate Health Center and
Cancer and Tumors Center. Also, see eMedicine's patient education article Prostate Cancer.
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Complications
Emergent Care
Urinary retention
This may be secondary to urethral strictures, bladder outlet obstruction, or a blood clot.
Attempt placement of a 20-24F Foley catheter. The catheter should go into the hub before any fluid is placed into the balloon port. If this is at all difficult, do not force insertion of the catheter.
Strictures require dilatation by a urologist.
Long-term urinary retention or malignant urinary obstruction due to untreated prostate cancer can lead to chronic renal failure, which manifests as uremic symptoms and an elevated serum creatinine level. Patients on watchful waiting protocols are at risk for this if they are not closely monitored.
Hematuria
This may manifest as a small element of prostate venous bleeding or it may lead to large clots. Hematuria is more common in patients who have undergone radiation therapy.
Vigorously irrigate the bladder with copious amounts of fluid to remove all evidence of clots. Sterile water is best because it helps to lyse the clot. However, use care because absorption of the fluid may occur in situations in which prostatic venous channels are open.
Incontinence due to bladder spasm or irritation is common immediately after various prostate treatments. While patients have urinary catheters, oxybutynin, tolterodine, belladonna and opium suppositories, and phenazopyridine (Pyridium) may be used to decrease symptoms.
Although uncommon, a urethrorectal fistula may occur after surgery or radiation. Manage the fistula with urinary and fecal diversion using appropriate protocols and services.
Rectal bleeding and tenesmus are observed in patients treated with radiation.
Bone pain due to metastatic disease requires narcotics, awareness of fractures, and, possibly, palliative radiation. These lesions tend to be blastic as well as lytic.
Treatment of complications
Prostatic bleeding may be treated with androgen ablation, ketoconazole, aminocaproic acid
(Amicar), diethylstilbestrol (Stilphostrol), and bisphosphonates.
Bone pain due to metastatic disease requires narcotics, awareness of fractures, and, possibly, palliative radiation or strontium therapy.
Ureteral obstruction due to lymphadenopathy may be treated with a ureteral stent or percutaneous nephrostomy.
Outcome and Prognosis
Disease-specific survival for early localized disease at 10 years
The ranges of the disease-free 10-year survival rates for early localized disease listed below are wide because the outcomes of these treatments vary as a function of tumor aggressiveness (ie, based on Gleason score and PSA level). In addition, series from various institutions show significant differences.

Radical prostatectomy (80-95%)

Brachytherapy and external radiation (80-95%)

Watchful waiting (50-73%)
Disease-specific survival for advanced localized disease at 10 years
The disease-specific 10-year survival rate for advanced localized disease in patients treated with brachytherapy and external radiation is 40-62%. Holmberg et al found improved diseasespecific survival in patients treated with surgery compared with watchful waiting (4.6% vs 8.9%).
13
Future and Controversies
Survival benefits when comparing the different modalities used for treating localized prostate cancer remain controversial. In the future, the measurement of bound and free PSA will help discriminate between more aggressive and less aggressive cancers.
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Molecular prognostic markers
Over the past few years, research has shown that several molecular markers aid in the prognostication of patients undergoing treatment for localized and metastatic prostate cancers.
Researchers report on the assessment of the molecular alterations or gene products of TP53, RB,
BCL2, cathepsin-D, CDH1, and PTEN, among many others. Prospective trials are needed to assess these markers more thoroughly before their implementation in current patient management is recommended.
Reverse transcriptase-polymerase chain reaction
Reverse transcriptase-polymerase chain reaction (RT-PCR) testing may be able to identify very small amounts of PSA nucleic acid in the blood stream, prostatic fossa, or bone marrow. In the future, RT-PCR may be helpful for determining which patients have residual tumor following surgery (eg, RT-PCR–positive prostate fossa) or higher rates of tumor recurrence (eg, RT-PCR– positive lymph nodes at surgery, persistently positive bone marrow samples months after treatment).
Gene therapy
Treatment options may include corrective gene therapy (ie, replacing a normal tumor suppressor gene in tumors with a mutated one) or toxic gene therapy to destroy cancer cells. Clinical trials using prostate-specific adenovirus, which expresses a gene toxic to prostate cancer cells, currently are underway in several centers worldwide. Other options include tumor vaccines or vaccination with tumor- or prostate-specific proteins such as PSA.
Other treatments


Vitamin D analogs

Antiangiogenesis agents

Antimetastatic agents that slow cancer progression
Radiation sensitizers: These may be used to increase the sensitivity of cancer cells to cell death by radiation. These may include photosensitizers or chemotherapeutic agents coupled with radiation.
Prostate cancer screening
Despite the apparent survival advantage of early diagnosis conferred by PSA screening, a recent U.S. Preventive Services Task Force statement recommends against screening for prostate cancer in men aged 75 years or older. The statement also concludes that, currently, the balance of benefits versus drawbacks of prostate cancer screening in men younger than age 75 years cannot be assessed because of insufficient evidence.
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