Oncourology

Document Sample
Oncourology Powered By Docstoc
					  MINISTRY OF PUBLIC HEALTH OF UKRAINE
  KHARKOV NATINAL MEDICAL UNIVERSITY


 МИНИСТЕРСТВО ЗДРАВООХРАНЕНИЯ УКРАИНЫ
ХАРЬКОВСКИЙ НАЦИОНАЛЬНЫЙ МЕДИЦИНСКИЙ
             УНИВЕРСИТЕТ




         Oncourology
          Онкоурология
                  Утверждено
                  ученым советом ХНМУ
                  Протокол № 8 от 19.04.2010 г.




            Kharov KNMU- 2010

           Харьков ХНМУ – 2010
Онкоурология: Метод. указ. к практ. занятиям для студентов V-VI
курсов медицинских вузов, обучающихся на английском языке / Сост.
В.И. Стариков, А.Н. Белый.– Харьков: ХНМУ, 2010.– 24 с.

Oncourology is approved by the Scientific Committee of the Kharkov state
medical university and is recommended for V-th, VI-th year students of
medical faculty / Authors: V.I. Starikov, A.N. Bely.– Kharkov: KNMU.2010.
– 24 p.




Authors: Starikov V.I.
         Bely A.N.




                                    2
                                        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:
          Renal cell carcinoma with clear cell histologic features
          Pheochromocytoma
          Pancreatic cysts and islet cell tumors
          Retinal angiomas
          Central nervous system hemangioblastomas
          Endolymphatic sac tumors
          Epididymal cystadenomas
         Renal cell carcinoma develops in nearly 40% of patients with 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


                                                  3
the face, neck, and upper trunk, and are at risk of developing renal tumors, colonic polyps or tumors,
and pulmonary cysts.
        Frequency
         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. 3
        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.1
        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 age1 ; however, the disease
has been reported in younger people who belong to family clusters. 1
        Clinical
        History
        Renal cell carcinoma may remain clinically occult for most of its course. The classic triad of
flank pain, hematuria, and flank mass is uncommon (10%) and is indicative of advanced disease.
Twenty-five to thirty percent of patients are asymptomatic, and their renal cell carcinomas are found
on incidental radiologic study.
         Most common presentations
        o Hematuria (40%)
        o Flank pain (40%)
        o Palpable mass in the flank or abdomen (25%)
         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)
         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,

                                                  4
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
         Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
         Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with
bruit.
         Approximately 30% of patients with renal carcinoma present with metastatic disease.
Physical examination should include thorough evaluation for metastatic disease. Organs involved
include:
        o Lung (75%)
        o Soft tissues (36%)
        o Bone (20%)
        o Liver (18%)
        o Cutaneous sites (8%)
        o Central nervous system (8%)
         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.
         Cigarette smoking doubles the risk of renal cell carcinoma and contributes to as many as
one third of all cases. The risk appears to increase with the amount of cigarette smoking in a dose-
dependent fashion.
         Obesity is another risk factor, particularly in women; increasing body weight has a linear
relationship with increasing risk.
         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.
         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.
         Tuberous sclerosis
         Renal transplantation: Acquired renal cystic disease of the native kidney also predisposes
to renal cell cancer in renal transplant recipients.
         VHL disease: This inherited disease is associated with renal cell carcinoma.
        Workup
        Laboratory Studies
         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
         Liver function tests (AST and ALT)
                                                 5
         Calcium
         Erythrocyte sedimentation rate
         Prothrombin time
         Activated partial thromboplastin time
         Other tests indicated by presenting symptoms
         Imaging Studies
          A large proportion of patients diagnosed with renal cancer have small tumors discovered
incidentally on imaging studies. A number of diagnostic modalities are used to evaluate and stage
renal masses, including the following:
         o Excretory urography
         o CT scan
         o Ultrasonography
         o Arteriography
         o Venography
         o MRI
         o PET
          Determining whether a space-occupying renal mass is benign or malignant can be difficult.
Radiologic studies should be tailored to enable further characterization of renal masses, so that
nonmalignant tumors can be differentiated from malignant ones.
          Excretory urography is not used frequently in the initial evaluation of renal masses because
of its low sensitivity and specificity. A small- to medium-sized tumor may be missed by excretory
urography.
          Contrast-enhanced CT scanning has become the imaging procedure of choice for diagnosis
and staging of renal cell cancer and has virtually replaced excretory urography and renal ultrasound.
In most cases, CT imaging can differentiate cystic masses from solid masses and supplies
information about lymph node, renal vein, and inferior vena cava involvement.
          Ultrasound examination can be useful in evaluating questionable cystic renal lesions if CT
imaging is inconclusive. Large papillary renal tumors are frequently undetectable by renal
ultrasound.
          Renal arteriography is not used in the evaluation of a suspected renal mass as frequently
now as it was in the past. When inferior vena cava involvement is suspected, either inferior
venacavography or MRI angiography is used. MRI is currently the preferred imaging technique.
Knowledge of inferior vena cava involvement is important in planning the vascular aspect of the
operative procedure.
          A bone scan is recommended for patients with bony symptoms and an elevated alkaline
phosphatase level.
          PET imaging remains controversial in kidney cancer. It has better sensitivity for detecting
metastatic lesions than for determining the presence of cancer in the renal primary site.
         Procedures
         Percutaneous cyst puncture and fluid analysis is used in the evaluation of potentially
malignant cystic renal lesions detected by ultrasonography or CT imaging.
         Histologic Findings
         Renal cell carcinoma has 5 histologic subtypes, as follows: clear cell (75%), chromophilic
(15%), chromophobic (5%), oncocytoma (3%), and collecting duct (2%).
          Unusually clear cells with a cytoplasm rich in lipids and glycogen characterize clear cell
carcinoma, which is most likely to show 3p deletion.


                                                  6
         Chromophilic tumors tend to be bilateral and multifocal and may have trisomy 7 and/or
trisomy 17.
         Large polygonal cells with pale reticular cytoplasm characterize chromophobic carcinoma,
which does not exhibit 3p deletion.
         Renal oncocytoma consists predominantly of eosinophilic cells, in a characteristic nested
or organoid pattern, that rarely metastasize and do not exhibit 3p deletion or trisomy 7 or 17.
         Collecting duct carcinoma is an unusual variant characterized by a very aggressive clinical
course. This tends to affect younger patients and may present as local or widespread advanced
disease. These cells can have 3 different types of growth patterns, (1) acinar, (2) sarcomatoid, and
(3) tubulopapillary. The sarcomatoid variant, which can occur with any histologic cell type, is
associated with a significantly poorer prognosis.
        Staging
         The Robson modification of the Flocks and Kadesky system is uncomplicated and is used
commonly in clinical practice. This system was designed to correlate stage at presentation with
prognosis. The Robson staging system is as follows:
        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 lymph-
node involvement (B), or both (C)
        o Stage IV - Tumor invading adjacent viscera (excluding ipsilateral adrenal) or distant
metastases
         The tumor, nodes, and metastases (TNM) classification is endorsed by the American Joint
Committee on Cancer (AJCC). The major advantage of the TNM system is that it clearly
differentiates individuals with tumor thrombi from those with local nodal disease. In the Robson
system, stage III disease includes both inferior vena caval involvement (stage IIIA) and local lymph
node metastases (stage IIIB). Although patients with Robson stage IIIB renal carcinoma have greatly
decreased survival rates, the prognosis for patients with stage Robson IIIA renal carcinoma is not
markedly different from that for patients with Robson stage I or II renal carcinoma.
        The TNM classification system is as follows:
        o Primary tumor (T)
         TX - Primary tumor cannot be assessed
         T0 - No evidence of primary tumor
         T1 - Tumor 7 cm or smaller in greatest dimension, limited to the kidney
         T2 - Tumor larger than 7 cm in greatest dimension, limited to the kidney
         T3 - Tumor extends into major veins or invades adrenal gland or perinephric tissues but
not beyond the Gerota fascia
         T3a - Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
         T3b - Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
         T3c - Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
         T4 - Tumor invading beyond the Gerota fascia
        o Regional lymph nodes (N) - Laterality does not affect the N classification
         NX - Regional lymph nodes cannot be assessed
         N0 - No regional lymph node metastasis
         N1 - Metastasis in a single regional lymph node
         N2 - Metastasis in more than 1 regional lymph node
        o Distant metastasis (M)
         MX - Distant metastasis cannot be assessed
         M0 - No distant metastasis
                                                 7
         M1 - Distant metastasis
        o AJCC stages
         AJCC stage I - T1, N0, M0
         AJCC stage II - T2, N0, M0
         AJCC stage III - T1-2, N1, M0 or T3a-c, N0-1, M0
         AJCC stage IV - T4; or any T, N2, M0; or any T, any N, M1
        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.
          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 stem-
cell transplantation.
          Multikinase inhibitors
         o Sorafenib
          Sorafenib (Nexavar), a small-molecule Raf kinase and vascular endothelial growth factor
(VEGF) multireceptor kinase inhibitor, is approved by the U.S. Food and Drug Administration for
the treatment of patients with advanced renal cell carcinoma. This indication was based on the
demonstration of improved progression-free survival in a large, multinational, randomized double-
blind, placebo-controlled phase 3 study and a supportive phase 2 study.
          The sorafenib phase 3 study was conducted in patients with advanced (unresectable or
metastatic) renal cell carcinoma who had received one prior systemic treatment. Study endpoints
included overall survival, progression-free survival, and response rate.
          Among 769 patients randomized, the median age was 59 years and 70% were male.
          Baseline patient and disease characteristics were well balanced. Regarding prior therapies,
93% had prior nephrectomies; 99% had received prior systemic therapies, including interleukin 2
(44%) and an interferon (68%).
          The median progression-free survival was 167 days in the sorafenib group versus 84 days
in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55, logrank p <0.000001). Time-to-
progression was similarly improved. Tumor response was determined by independent radiologic
review according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Overall, of
672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%)
placebo patients had confirmed partial responses.7
          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
                                                   8
crossed over to sorafenib showed no overall survival benefit with sorafenib, a secondary analysis
that did not include these patients showed significantly improved overall benefit (17.8 v 14.3
months, P = .029).
         Sorafenib toxicities (based on an updated phase 3 study database of 902 patients) included
reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%,
treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral
mucositis, and hemorrhage also were reported more commonly on the sorafenib arm. The incidence
of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%)
compared with the placebo group (0.4%).
         Grade 3 and 4 adverse events were unusual; only hand-foot skin reaction occurred at 5% or
greater frequency in the sorafenib arm. Laboratory findings included asymptomatic
hypophosphatemia in 45% versus 12% and serum lipase elevations in 41% versus 30% of sorafenib
versus placebo patients, respectively. Grade 4 pancreatitis was reported in 2 sorafenib patients,
although both patients subsequently resumed sorafenib, one at full dose.
         Hypertension is a common side effect of sorafenib treatment, and may be high grade.9
Physicians should be aware of the importance of frequent blood pressure monitoring and
management, especially during the first 6 weeks after starting sorafenib.
         The recommended dose is 400 mg (two 200-mg tab) twice daily taken either 1 hour before
or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or
reductions to 400 mg once daily or 400 mg every other day.
         Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF;
VEGFR-2,3; PDGFR-b; KIT; FLT-3; and RET.
         The safety and efficacy of sorafenib were also demonstrated in a nonrandomized, open-
label expanded access program in which 2,504 patients from the United States and Canada were
treated with oral sorafenib 400 mg twice daily. Patients included those with no prior therapy,
nonclear cell renal cell carcinoma, brain metastases, and prior bevacizumab treatment; and elderly
patients. Median overall survival was 50 weeks.
        o Sunitinib (Sutent)
         Sunitinib is another multikinase inhibitor approved by the FDA for the treatment of
metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based
on the high response rate (40% partial responses) and a median time to progression of 8.7 months
and an overall survival of 16.4 months.
         The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and
b.
         Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%),
dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis
occurred in 8%, and hypertension occurred in 5% of patients.
         In a phase 3 study in 750 patients with previously untreated metastatic renal-cell
carcinoma, PFS was longer and response rates were higher in patients who received sunitinib than in
those receiving interferon alfa.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).
         An expanded-access trial provided sunitinib on a compassionate-use basis to 4,564 trial-
ineligible patients with renal cell carcinoma from countries where regulatory approval had not been
granted. Median progression-free survival was 10.9 months (95% CI 10.3-11.2) and overall survival
was 18.4 months (17.4-19.2). These researchers concluded that the safety of sunitinib in these
patients was manageable and its efficacy was encouraging, particularly in subgroups associated with
poor prognosis (eg, those with brain metastases, low performance status, non–clear cell disease, and
elderly patients).
                                                   9
       o Temsirolimus (Torisel)
        Temsirolimus inhibits mTOR (mammalian target of rapamycin), which is a
serine/threonine kinase important in the regulation of cell growth and division. Genes involved with
the response to hypoxia (HIF pathway described above) are also upregulated by mTOR and are
believed to be central to the pathogenesis of kidney cancers.
          Temsirolimus has been tested alone and in conjunction with interferon in patients with
poor prognosis advanced renal cell carcinoma. Temsirolimus monotherapy at a dose of 25 mg IV
weekly resulted in longer overall and progression-free survival compared to interferon (median
survival 10.9 months versus 7.3 months, P= 0.008). 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.
          Common toxicities of temsirolimus include asthenia, rash, anemia, hypophosphatemia, and
hyperlipidemia.
          Temsirolimus has FDA approval for the treatment of advanced renal cell carcinoma at a
dose of 25 mg weekly IV until progression.
         o Everolimus (Afinitor)
          Everolimus (Afinitor) is a serine-threonine kinase inhibitor of mTOR, an important
regulatory protein in cell signaling. Everolimus was approved by the US Food and Drug
Administration in March 2009 for advanced renal cell carcinoma after failure of treatment with
sunitinib or sorafenib.
          In a randomized, double-blind, placebo-controlled, multicenter, phase 3 trial in patients
with metastatic renal cell carcinoma that had progressed during sunitinib and/or sorafenib treatment,
interim analysis showed significantly longer median progression-free survival with everolimus than
with placebo (4.0 vs 1.9 months). Stomatitis, rash, and fatigue were the most commonly reported
adverse events, but were mostly mild or moderate in severity; pneumonitis was uncommon, but
sometimes severe.
         o Other multikinase inhibitors undergoing investigation for renal cell carcinoma
          Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor that appears to have
efficacy in the treatment of tumors, including renal cell carcinoma, which overexpress EGFR. A
phase 3 study in patients with advanced renal cell carcinoma who had failed prior therapy found that
lapatinib was well tolerated and had overall efficacy equivalent to that of hormonal therapy.
          The novel combination of bevacizumab (a neutralizing monoclonal antibody to VEGF)
and interferon has been shown to have activity against metastatic RCC. Completion of this phase 3
trial by Escudier et al found bevacizumab plus interferon alfa-2a effective as first-line treatment in
patients with metastatic RCC.
          Chemotherapy
         o A phase 2 trial of weekly intravenous gemcitabine (600 mg/m2 on days 1, 8, and 15) with
continuous infusion fluorouracil (150 mg/m2/d for 21 d in 28-d cycle) in patients with metastatic
renal cell cancer produced a partial response rate of 17%. No complete responses were noted. Eighty
percent of patients had multiple metastases, and 83% had received previous treatment. The mean
progression-free survival duration of 28.7 weeks was significantly longer than that of historic
controls.
         o 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.
                                                 10
         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.
          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 single-
agent 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.
          In the initial study by the National Cancer Institute, bolus intravenous infusions of high-
dose 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.
          Most patients responded after the first cycle, and those who did not respond after the
second cycle did not respond to any further treatment. Therefore, the current recommendation is to
continue treatment with high-dose IL-2 to best response (up to 6 cycles) or until toxic effects
become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no
regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-FU have
not been shown to be more effective than high-dose IL-2 alone.
          Toxic effects associated with high-dose IL-2 are related to increased vascular permeability
and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide).
The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive
care unit.
          The major toxic effect of high-dose IL-2 is a sepsislike syndrome, which includes a
progressive decrease in systemic vascular resistance and an associated decrease in intravascular
volume due to capillary leak.
          Other toxic effects are fever, chills, fatigue, infection, and hypotension.
          High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and
should be offered only to patients with no cardiac ischemia or significant impairment of renal or
pulmonary functions. Management includes judicious use of fluids and vasopressor support to
maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity
due to noncardiogenic pulmonary edema from the capillary leak. This syndrome is normally
reversible.
          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.

                                                   11
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.
          For previously untreated patients with clear cell renal cell cancer of low or intermediate
risk, sunitinib or the combination of bevacizumab and interferon alpha
          For patients with previously untreated clear cell renal cell cancer with poor prognostic
(high-risk) characteristics, temsirolimus
          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.
          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.
          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.
         o 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.25
         o 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
                                                   12
(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/m2/d or more) and toremifene (300
mg/d) also have been tried, with a response rate as low as that of most chemotherapeutic agents.
         Surgical Care
         Surgical resection remains the only known effective treatment for localized renal cell
carcinoma, and it also is used for palliation in metastatic disease.
          Radical nephrectomy, which remains the most commonly performed standard surgical
procedure today for treatment of localized renal carcinoma, involves complete removal of the Gerota
fascia and its contents, including a resection of kidney, perirenal fat, and ipsilateral adrenal gland,
with or without ipsilateral lymph node dissection. Radical nephrectomy provides a better surgical
margin than simple removal of the kidney, since perinephric fat may be involved in some patients.
Twenty to thirty percent of patients with clinically localized disease develop metastatic disease after
nephrectomy. Some surgeons believe that the adrenal gland should not be removed because of the
low probability of ipsilateral adrenal metastasis and the morbidity associated with adrenalectomy. In
the absence of distant metastatic disease with locally extensive and invasive tumors, adjacent
structures such as bowel, spleen, or psoas muscle may be excised en bloc during radical
nephrectomy.
         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 well-
vascularized thrombus covered with its own intimal surface. In patients with renal vein involvement
without metastases, radical nephrectomy is performed with early ligation of the renal artery but no
manipulation of the renal vein. If the inferior vena cava is involved, then vascular control of the
inferior vena cava is obtained both above and below the tumor thrombus, and the thrombus is
resected intact, with subsequent closure of the vena cava. Patients with actual invasion of the inferior
vena caval wall have poor prognoses, despite aggressive surgical approaches.
         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, high-
grade 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, 2-
naphthylamine, 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, c-myc, and c-jun.
         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 false-
negative 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, small-
volume, 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 false-
positive 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, follicle-
stimulating 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-alpha-
reductase 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, organ-
confined 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 10-
year 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 follow-
up 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 organ-
confined 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 organ-
confined 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 intensity-
modulated 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 FDA-
approved 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
                                                 43
       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.

                                                 44
         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 disease-
specific 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.
                                                  45
        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.14




                                                 46

				
DOCUMENT INFO