Sumanta K. Pal, Hyung L. Kim, and Robert A. Figlin
RENAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Renal cell carcinoma (RCC) constitutes 3% of adult malignancies. The worldwide incidence is increasing at an annual rate of about 2%, with approximately 58,000 new cases per year in the United States and 13,000 associated deaths. Men are affected twice as often as women. RCC is a tumor of adults, occurring primarily in those in their fourth and sixth decades. The incidence and mortality rates for blacks appear to be increasing in excess to those for whites in the United States.
B. Etiology. Approximately 70% of sporadic cases of clear cell RCC (the most common histologic variant) are associated with inactivating mutations of both copies of the Von Hippel-Lindau (VHL) tumor suppressor gene. This results in overexpression of hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF), leading to defective regulation of angiogenesis, which is of major importance in the pathophysiology of RCC.
1. Factors that increase the risk for RCC include the following:
a. Smoking
b. Urban living
c. Family history of renal cancer
d. Thorotrast exposure
e. Obesity
f. Genetic syndromes include
(1) Von Hippel—Lindau disease (associated with germline mutations of the VHL gene; 35% to 45% of these patients have RCC, mostly multiple and bilateral)
(2) Hereditary type 2 papillary RCC: associated with mutations in MET proto-oncogene
(3) Birt-Hogg-Dube (BHD) syndrome
2. Unproven factors that may increase the risk for RCC include polycystic kidney disease, diabetes mellitus, and chronic dialysis.
II. PATHOLOGY AND NATURAL HISTORY
A. Adenocarcinomas (historically named hypernephromas or Grawitz tumors) make up nearly all renal cancers in adults. They are typically round and have a pseudocapsule of condensed parenchyma and connective tissue. Bilateral tumors occur in 2% of sporadic cases, either synchronous or asynchronous.
1. The most common histologic types include clear cell (70%), papillary (10% to 15%), chromophobe (5%), and unclassified RCC (<5%). Sarcomatoid tumors can arise from any cell subtype.
2. These tumors originate from proximal tubular cells, invade local structures, and frequendy extend into the renal vein. Metastasis occurs through the lymphatics and bloodstream. The most common sites of distant metastases are the lungs, liver, bones, and brain. Adenocarcinomas may present with metastases to unusual sites, such as the fingertips, eyelids, and nose. A primary renal cancer may be diagnosed based on the characteristic histology of a metastatic deposit.
3. The natural history of RCC is more unpredictable than that of most solid tumors. The primary tumor has variable growth patterns and may remain localized for many years. Metastatic foci may have long periods of indolent or apparently arrested growth and may be detected many years after removal of the primary tumor.
B. Transitional cell carcinomas are uncommon tumors that arise in the renal pelvis and often affect multiple sites of urothelial mucosa, including the renal pelvis, ureters, and urinary bladder (see “Urinary Bladder Cancer,” Section II). These tumors usually are low grade but are being discovered late in the course of the disease. Transitional cell carcinomas occasionally have a peculiar disposition to spread over the posterior retroperitoneum in a sheet-like fashion, encasing vessels and producing urinary tract obstruction. Hematogenous dissemination occurs, particularly to lung and bone.
C. Rare renal tumors
1. Nephroblastomas (Wilms tumors) appear as large, bulky masses in children but rarely occur in adults (see Chapter 18, “Wilms Tumor”).
2. Lymphomas and sarcomas arising in the kidney have clinical courses similar to their counterparts elsewhere in the abdomen.
3. Juxtaglomerular tumors (reninomas) are rare causes of hypertension and are usually benign.
4. Hemangiopericytomas are renin-secreting tumors associated with severe hypertension and are occasionally malignant (15% of cases).
5. Oncocytomas (7%) are benign tumors originating from a subtype of collecting ducts.
6. Bellini tumors (collecting duct RCC, <1%) are aggressive cancers originating from collecting ducts.
7. Medullary cancer (<1%)
8. Benign renal adenomas. The existence of benign renal adenoma is controversial because it is not possible to determine malignant or benign biologic behavior only by histology on any lesion <3 cm in diameter.
D. Metastatic tumors. The kidney is a frequent metastatic landing site for many malignancies, mainly cancers of the lung, ovary, colon, and breast.
E. Paraneoplastic syndromes commonly occur with renal adenocarcinomas.
1. Erythrocytosis. Renal adenocarcinomas are associated with erythrocytosis in 3% of patients and account for 15% to 20% of cases of inappropriate secretion of erythropoietin. A left flank mass of RCC may be mistaken for an enlarged spleen resulting from polycythemia vera. The differential diagnosis of erythrocytosis is discussed in Chapter 34, “Increased Blood Cell Counts,” Section I. Tumor production of erythropoietin may identify a subset of patients responsive to immunotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α).
2. Hypercalcemia, which occurs in about 5% of patients, associated with parathyroid hormone-like proteins. Hypercalcemia may also be associated with widespread bony metastases.
3. Fever caused by tumor occurs in 10% to 20% of patients.
4. Abnormal liver function (Stauffer syndrome) occurs in 15% of patients. Leukopenia, fever, and areas of hepatic necrosis without liver metastases are noted. The resulting elevated serum levels of alkaline phosphatase and transaminase are reversed after nephrectomy.
5. Hypertension associated with renin production by the tumor occurs in up to 40% of patients and is alleviated by removal of the tumor.
6. Hyperglobulinemia can result in elevated erythrocyte sedimentation rate.
7. Amyloidosis occasionally occurs.
III. DIAGNOSIS
A. Symptoms and signs. Symptoms other than hematuria usually indicate large, advanced tumors. The classic triad of flank pain, a flank mass, and hematuria occurs in <10% of patients with RCC. The combined picture of anemia, hematuria, and fever is rare, but suggestive of renal cancer. The widespread use of ultrasound, CT, and MRI changed significantly the typical presentation of RCC. More than three-fourths of all locally confined tumors are found serendipitously (as an incidental finding), and thus a substantial proportion of patients are symptom free at the time of diagnosis. Therefore, symptoms and signs (as listed below) become rare and currently are more characteristic in cases presenting with advanced disease.
1. Symptoms
a. Gross hematuria is rare.
b. A steady, dull flank pain occurs in a few patients. Colicky pain may develop if blood clots are passed into the ureter.
c. Weight loss may be a presenting feature in <15% of patients.
d. Sudden onset of a left-sided or a right-sided varicocele is rare and usually suggests invasion into the renal vein or inferior vena cava, respectively.
e. Leg edema is the result of locally advanced disease, which causes venous or lymphatic obstruction.
f. Fever, plethora, or symptoms of hypercalcemia or anemia may be presenting features.
g. Symptoms related to metastases, including bone pain or fracture, may occasionally be a presenting symptom.
2. Physical findings
a. A palpable flank mass is rarely present.
b. Fever occurs in about 15% of patients.
c. Pallor from anemia may occur.
B. Diagnostic studies
1. Urinalysis may reveal proteinuria and hematuria. All patients with macroscopic or microscopic hematuria of any degree must have a thorough urologic evaluation.
2. Routine studies
a. Complete blood count, LFT, and renal function studies
b. Hyperglobulinemia may be present in patients with RCC because acute-phase reactant proteins are elevated.
c. Chest radiographs may reveal multiple, large, round (cannonball-like) metastatic deposits that are characteristic of metastatic genitourinary neoplasms.
3. CT scanning of the kidneys is most cost-effective method for evaluating a suspected renal mass and should be the first study for that purpose. Extension through the capsule is usually diagnosed correctly. CT does not detect minimal lymph node involvement.
4. MRI may be as accurate as CT. MRI images demonstrate extension of tumor into the renal vein and vena cava more reliably in preparation for surgery.
5. Ultrasonography with duplex Doppler may assist in imaging tumor thrombus in the inferior vena cava and in defining its extension. It cannot be used for local staging because regional lymph node involvement cannot be imaged.
6. Scans for staging should be performed in the following situations:
a. Bone scan, if there is bone pain or elevated serum alkaline phosphatase levels
b. MRI of the brain, if there are signs of central nervous system abnormalities
7. Percutaneous biopsy of a renal mass has a controversial role and is also believed to be inaccurate in approximately 25% of the cases. This procedure should be restricted to patients with medical conditions that make surgery unduly hazardous and patients with metastatic disease for which a tissue diagnosis is necessary.
C. Renal cysts are usually classified using CT according to the chance of harboring malignancy (Bosniak classification). The following approach is recommended to evaluate potential renal cysts:
1. If a renal cyst is suspected or demonstrated and the findings are not strongly suggestive of cancer, ultrasound is performed to determine whether the mass is cystic. If a simple cyst or a fatty tumor is demonstrated, no further follow-up is usually indicated. If a hyperdense cyst is imaged, the patient should have follow-up studies.
2. Rarely, all imaging modalities are not diagnostic, and surgical exploration is indicated.
3. Bosniak cyst types 3 and 4 are managed in the same fashion as renal cancers.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The current TNM staging system is shown in Table 13.1. A different system is used for cancers of the renal pelvis.
B. Prognostic factors
1. Pathologic stage is the most important prognostic indicator.
a. Tumor size >10 cm is associated with poor prognosis in comparison to smaller lesions.
Table 13.1 TNM Staging System for Cancers of the Kidneya
aAdapted from the AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
A different TNM system is available for the renal pelvis and ureter
b. Venous extension. Renal vein or vena caval involvement is not associated with a hopeless prognosis if managed properly; 25% to 50% of patients survive for 5 years.
2. Histology. Sarcomatoid and unclassified patterns of RCC have a poor prognosis.
a. Nuclear grade correlates with survival across all tumor stages. Fuhrman four-tiered system is most commonly used; it takes into consideration nuclear size, nuclear shape, and nucleolar appearance.
b. Nuclear ploidy was proposed as a potential prognostic marker for survival. Nondiploid tumors are thought to harbor a less favorable prognosis.
3. Disease-free interval. The length of time between nephrectomy and the development of metastases affects the survival of patients with metastatic disease.
a. Nearly all patients who have metastases at the time of surgery or who develop metastases or local recurrence within 1 year of surgery die within 2 years if untreated.
b. Patients who develop metastases >2 years after nephrectomy have a 20% 5-year survival rate from the time metastases are recognized.
4. Integrated prognostic systems. The TNM system can be augmented with more complex systems that take into account various prognostic factors, such as Fuhrman nuclear-grading system and performance status to assess risk and the probability of survival with and without evidence of RCC. Such a system is shown in Figure 13.1.
Figure 13.1. UCLA Integrated staging system: risk group assignment for patients with metastatic renal cell carcinoma. To obtain a patient’s risk group, begin at the top of the decision box and progress downward using the AJCC N and M stages, Fuhrman grade, and ECOG performance status. ECOG PS, Eastern Cooperative Oncology Group performance status (see inside of back cover); Int, intermediate risk; Neph, nephrectomy. Modified from Zisman A, Pantuck A, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002;20:4559, with permission
V. PREVENTION AND EARLY DETECTION
The incidence of renal cancer might be reduced if tobacco-smoking habits could be controlled. Early detection depends on prompt attention to hematuria and other symptoms suggestive of these cancers.
VI. MANAGEMENT
A. Early disease
1. Surgery
a. Radical nephrectomy classically involves removal of all structures contained within Gerota fascia, including kidney, adrenal gland and superior ureter. Radical nephrectomy is generally used for large, locally advanced tumors. The adrenal gland can be safely spared when the tumor is in the lower pole or when a smaller tumor is clearly separate from the adrenal gland. A laparoscopic approach is generally preferred; however, an open approach may be necessary for tumors that involve adjacent structures such as the inferior vena cava.
b. Nephron-sparing surgery (NSS, partial nephrectomy) is the treatment of choice when it is technically feasible. Maximal preservation of renal function is an important goal of surgery since even mild renal insufficiency has been linked to cardiovascular disease and related morbidities such as myocardial infarction and stroke. Most tumors that are <4 cm in diameter are amenable to NSS. A minimally invasive approach using laparoscopy or robotics results in more rapid postoperative recovery when compared to an open approach. Although surgical resection is considered the standard of care, ablative procedures using cryotherapy or radiofrequency ablation can be considered for the smallest and most exophytic tumors.
c. Occlusion of the renal artery using angiographic techniques has been advocated for locally advanced tumors associated with increased vasculature. Occlusion procedures may limit blood loss and make the operation technically easier. It may also provide palliation for symptomatic patients who are not candidates for surgery. However, renal artery occlusion will cause temporary pain, fever, and nausea.
d. Contraindications to surgery include high surgical risk because of unrelated medical diseases. Since the emergence of targeted therapies, the role of surgery (“adjunctive nephrectomy”) in the presence of distant metastases is once again under investigation.
2. Observation is now recognized as an acceptable option for small renal tumors (e.g., tumor <4 cm) in patients who are poor surgical candidates or have a limited life-expectancy. Many of these small tumors are benign; however, even if they are malignant, most small tumors are indolent and progress slowly.
3. RT has no established role in the management of early renal cancers.
4. Chemotherapy has no established role in the management of early renal cancers.
B. Advanced disease
1. Surgery
a. Nephrectomy. For patients treated with immunotherapy, cytoreductive nephrectomy has been shown to extend survival. However, immunotherapy has been largely replaced by a growing number of targeted therapies such as sunitinib and sorafenib. Therefore, ongoing clinical trials are revisiting the role of cytoreductive nephrectomy in patients treated with targeted therapies. Until these trials are completed, cytoreductive nephrectomy remains a well-accepted adjuvant to systemic therapy for patients with good performance status.
b. Resection of metastases. In select patients, metastatic lesions can be surgically resected for curative intent. Metastectomy is most likely to be curative in patients with a single metastatic lesion and in patients with a solitary recurrence identified more than 2 years after the definitive nephrectomy. Prior to performing metastectomy, a thorough metastatic workup is mandatory.
2. RT is used to palliate symptoms from metastases to the central nervous system and bone. Gamma knife radiotherapy is effective for control of brain metastasis.
3. Pharmacotherapy
a. Targeted Agents: Six molecularly targeted therapies are currently approved for the treatment of advanced RCC. These can be broadly divided into two categories: (1) vascular endothelial growth factor (VEGF)-directed therapies and (2) inhibitors of the mammalian target of rapamycin (mTOR). VEGF-directed agents include the monoclonal antibody bevacizumab, and the small molecule tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, and pazopanib. mTOR inhibitors currently approved for RCC therapy include everolimus and temsirolimus.
Each of these agents is supported by phase III data which can guide their clinical utilization. For instance, sunitinib and bevacizumab (with interferon-α, IFN-?α) were evaluated in treatment-naïve patients with advanced clear cell RCC. In contrast, the pivotal trial of pazopanib was performed in patients who were either treatment-naïve or cytokine-refractory. The majority of patients (82%) treated in the phase III evaluation of sorafenib were also cytokine-refractory. Given these reports, the National Comprehensive Cancer Network (NCCN) has rendered a category 1 recommendation to sunitinib, pazopanib, and bevacizumab/IFN-?α, for the first-line therapy of advanced clear cell RCC. Pazopanib also carries a category 1 recommendation for patients with cytokine-refractory disease, as does sorafenib. A category 1 recommendation by NCCN is based on a high level of evidence (e.g., randomized controlled trials) with uniform NCCN consensus.
The pivotal trials for everolimus and temsirolimus assessed distinct populations. Patients in the phase III evaluation of everolimus had advanced clear cell RCC and had been exposed to previous treatment with sunitinib and/or sorafenib. In contrast, the pivotal trial of temsirolimus principally included treatment-naïve patients with poor-risk disease. Uniquely, eligibility was not limited to those patients with clear cell RCC, and patients with treated brain metastases were allowed to enroll. The agent now carries a category 1 recommendation from the NCCN for patients with poor-risk disease.
More extensive experience with VEGF-directed therapies and mTOR inhibitors has suggested class effects associated with these agents. For instance, VEGF-directed therapies appear to cause hypertension, proteinuria, hand–foot syndrome, impaired wound healing, and myelosuppression. In contrast, mTOR inhibitors have been associated with impaired metabolic profiles (i.e., hyperglycemia, hypertriglyceridemia, etc.), mucositis, and rash.
b. Immunotherapy. The role of immunotherapy for kidney cancer has decreased and is being supplanted by rapid progress with antiangiogenic agents. Nonetheless, IL-2 remains the only potentially curative treatment in selected patients with metastatic RCC.
(1) IL-2 administered alone in high-dose regimens produces a response rate of 15% to 20% in good-risk patients and durable remissions lasting for more than a decade in 10% of patients. Significant morbidity and 4% mortality associated with high-dose IL-2 make this therapy very difficult and applicable to only small minority of patients. IL-2 administered in lower dosages or in combination with IFN produces inferior response rates when compared with high-dose IL-2 in randomized trials. Recent data from the Renal SELECT study underscore a dearth of clinical or biologic criteria that identify patients who yield benefit from this modality.
(2) IFN-α as a single agent has modest antitumor activity in the setting of RCC, with a response rate of approximately 15%. With the emergence of effective targeted therapies, IFN-α is used primarily in clinical trials evaluating possible synergistic effects in combination with antiangiogenic agents.
c. Future strategies in the treatment of RCC include redefining the role of nephrectomy in advanced cases in the era of targeted therapies, the development of novel immunotherapeutic strategies (i.e., vaccine based therapy or PD-1 inhibition), and the development of biologic tools to risk stratify patients with both localized and advanced disease.
URINARY BLADDER CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Bladder cancers constitute 4.5% of all cancers in the United States. The disease is 2.5 times more frequent in men than in women and is most frequent in industrial northeastern cities. The average age of onset is the sixth to seventh decade. The incidence doubles in men >75 years of age versus younger men.
B. Risk factors and carcinogens
1. Occupational exposure is associated with 20% of cases. Historically, aniline dye workers were afflicted 30 times more than the general population. Aromatic amines and related compounds are the most abundant bladder carcinogens today. These are chemical intermediates of anilines, rather than the aniline dyes themselves. Leather, paint, and rubber industry workers also appear to have an increased risk for bladder cancer. Proven chemical carcinogens in these industries are 2-naphthylamine, benzidine, 4-aminobiphenyl, and 4-nitrobiphenyl.
2. Schistosomum haematobium infection of the bladder is associated with bladder cancer, particularly with squamous cell histology, in endemic regions of Africa and the Middle East.
3. Smoking increases the risk for bladder cancer fourfold in a dose-dependent fashion. Of men who die of bladder cancer, 85% have a history of smoking.
4. Pelvic irradiation increases the risk for bladder cancer fourfold.
5. Drugs. Cyclophosphamide unequivocally increases the risk for bladder cancer. Other drugs that have been implicated in animal studies but not proved in humans are phenacetin, sodium saccharin, and sodium cyclamate.
II. PATHOLOGY AND NATURAL HISTORY
A. Pathology
1. Histology. Of bladder cancers, 90% are transitional cell carcinoma (TCC), and 8% are squamous cell types. Adenocarcinomas, sarcomas, lymphomas, and carcinoid tumors are rare.
2. Sites of involvement. The majority of TCCs are linked to carcinogen exposures such as smoking. Carcinogens in urine are believed to produce a field-change in the urothelium that predisposes to formation of bladder cancer. Therefore, TCC can develop in any part of the urinary collecting system including the kidney and ureter; however, the bladder is the most common site for TCC because it functions to store urine and has the greatest contact time with urinary carcinogens.
3. Types of bladder cancer
a. Single papillary cancers are the most common type (70%) and the least likely to show infiltration.
b. Diffuse papillary growths with minimal invasion
c. Sessile cancers are often high grade and invasive.
d. Carcinoma in situ (CIS; flat intraepithelial growth) appears either the same as normal mucosa or as a velvety red patch.
4. The panurothelial abnormality or field defect. Bladder cancer appears to be associated with premalignant changes throughout the urothelial mucosa. This concept is suggested by the following observations:
a. Up to 80% of patients treated for superficial tumors develop recurrences at different sites in the bladder.
b. Multiple primary sites are present in 25% of all patients with bladder cancer.
c. Random biopsies of apparently normal areas of mucosa in patients with bladder cancer frequently show CIS.
d. Depending on the reported series, patients with bladder CIS also have ureteral CIS (10% to 60%) and urethral CIS (30%).
e. About 40% of patients presenting with carcinoma of the renal pelvis or ureter develop tumors elsewhere in the urinary tract, usually in the bladder.
B. Natural history
1. CIS of the bladder is multifocal and can affect the entire urothelium. CIS is a high-grade malignancy. Up to 80% of patients with untreated CIS develop invasive bladder cancer within 10 years after diagnosis; the disease is lethal for most of these patients.
2. Low-grade superficial carcinomas have a better prognosis than CIS. Although the recurrence rate is 80%, low-grade, superficial carcinomas do not metastasize. However, 10% of superficial carcinomas may progress to high grade, invasive tumors with potential for metastasis. More than 80% of patients with both superficial cancers and CIS progress to invasive disease.
3. High-grade or invasive tumors are associated with adjacent areas of CIS in 85% of cases. Squamous cell cancers and adenocarcinomas are usually high grade and have an aggressive clinical behavior. Other uncommon and very aggressive histologic variants include sarcomatoid cancer, small cell carcinoma, and micropapillary tumors.
4. Mode of spread. Bladder cancers spread both by lymphatic channels and by the bloodstream. High-grade lesions are more likely to metastasize. Of patients with distant metastases, 30% do not have involvement of the draining lymph nodes. Distant sites of metastases include bone, liver, lung, and, less commonly, skin and other organs. Uremia from ureteral compression by a large pelvic mass, inanition from advancing cancer, and liver failure are the usual causes of death.
5. Iatrogenic tumor implantation. High-grade bladder cancer cells exfoliated by cystoscopy, brushing, transurethral biopsy, or resection were reported to seed other areas of the bladder. Mucosal sites damaged by inflammation or instrumentation appear to be most receptive to such implants.
6. Associated paraneoplastic syndromes
a. Systemic fibrinolysis
b. Hypercalcemia
c. Neuromuscular syndromes
d. Leukemoid reaction
III. DIAGNOSIS
A. Symptoms and signs
1. Symptoms
a. Hematuria occurs as a presenting feature in 90% of patients.
b. Bladder irritability occurs in 25% of patients. Hesitancy, urgency, frequency, dysuria, and postvoiding pelvic discomfort may mimic prostatitis or cystitis. These symptoms occur in patients with CIS as well as in those with tumors that are large, extensive, or near the bladder neck.
c. Pain in the pelvis or flank is associated with locally advanced disease.
d. Edema of the lower extremities and genitalia develops from venous or lymphatic obstruction.
2. Physical findings. The patient is carefully examined for metastatic sites. It is mandatory that a bimanual examination is performed by the urologist through the rectum each time the patient is put under general anesthesia or having a cystoscopy done. The importance of the bimanual examination cannot be overemphasized. It supplies pertinent information concerning local extension of the disease not obtainable by current imaging modalities.
B. Diagnostic studies
1. Routine studies
a. CBC, LFT, and renal function tests
b. Urinalysis
c. Chest radiograph
2. Cystoscopy is the cornerstone procedure for diagnosing bladder cancer. Biopsy is performed of abnormal areas. Biopsies of normal areas at random are performed to search for CIS. Cystoscopy is followed by bimanual pelvic examination under anesthesia in both men and women. Cystoscopy is indicated for patients with the following clinical features:
a. Any gross or microscopic hematuria and a normal upper urinary tract imaging (except female patients with a single episode of acute bacterial cystitis who are <40 years of age and do not smoke)
b. Unexplained or chronic lower urinary tract symptoms
c. Urine cytology that is suspicious for cancer
d. A history of bladder cancer
3. Urography. An intravenous pyelogram (IVP) is useful for imaging the upper urinary tract in patients with unexplained hematuria, or cystoscopic or cytologic evidence of tumor in an attempt to search for primary sites in the ureters or renal pelvis. It is advisable to perform an IVP before cystoscopy, because if a poorly visualized upper system or nonconclusive filling defect is imaged, retrograde pyelography may be performed using a ureteral catheter inserted during the same cystoscopy session.
4. CT urography (CTU). CT scanning of the abdomen and pelvis typically includes three phases: a noncontrast phase, an early postcontrast phase, and the pyelographic phase. During the noncontrast phase, abnormal calcifications (i.e., urinary stones) can be identified. The early postcontrast phase obtained minutes after IV administration of contrast serves to discern renal lesions and to differentiate between abnormal lymph nodes and normal anatomic structures. During the pyelographic phase, the contrast material is observed as it is excreted into the collecting system, allowing the identification of abnormal filling defects within the collecting system. Owing to its higher resolution and diagnostic accuracy, CTU has largely supplanted IVP as the imaging modality of choice for the upper urinary tract.
It is important to obtain a CTU in any patient with hematuria, a history of bladder cancer, or positive cytology. CTU is also useful for staging invasive bladder cancer or upper tract TCC. Abnormally enlarged lymph nodes and visceral metastasis can be observed by CTU. Local invasion into pelvic organs or tumor infiltration into the perivesical fat can also be observed. CT is not reliable for the detection of local invasion, however.
5. Urine cytology detects about 70% of bladder cancers that are subsequently diagnosed by cystoscopy. Cytologic evaluation should not be the primary diagnostic method for patients suspected of having bladder cancer. Urine cytology is useful for the following purposes:
a. Following patients with a history of bladder cancer
b. Screening symptom-free patients who are exposed to environmental carcinogens
c. Evaluating patients with chronic irritative bladder symptoms before cystoscopy is done
6. Bladder tumor markers. Bladder tumor antigen (BTA), nuclear matrix protein 22 (NMP-22), telomerase activity, fibrin degradation products assay, and others are being tested to replace or decrease the frequency of cystoscopy, to serve in follow-up of TCC patients, and to assist in screening and evaluation of hematuria. Some of these tests are promising, but the current standard care for a patient with hematuria or history of TCC remains cystoscopy.
7. Fluorescent in situ hybridization (FISH). Because bladder cancers are associated with typical chromosomal aberrations, their detection in the urine is an accurate and noninvasive modality of TCC detection. The current commercially available FISH test (UroVysion) uses four chromosomal probes to detect an abnormal number of chromosomal copies (CEP17, CEP3, and CEP7) and a single locus-specific indicator probe (9p21). FISH has a sensitivity of 81% and a specificity of 96%, far better than those of cytology.
8. Scans. Bone scans should be performed in patients with bone pain or elevated serum alkaline phosphatase or transaminase levels.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The current TNM staging system is shown in Table 13.2.
Table 13.2 TNM Staging System for Cancers of the Urinary Bladder
Adapted from the AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
B. Prognostic factors. The most important clinical prognostic factors are tumor stage, tumor grade, and the presence of CIS. Untreated patients have a 2-year survival rate <15% and a median survival of 16 months.
1. Histology. Squamous cancers and adenocarcinomas have poorer prognoses than TCC. Likewise, the other aggressive histologic subvariants confer a poor prognosis.
2. Invasion of muscle, lymphatics, or perivesical fat is associated with a poor prognosis. Invasive cancer is associated with a 50% mortality rate in the first 18 months after diagnosis. Delaying cystectomy >12 weeks following the diagnosis of muscle invasive disease (stage T2) may hamper patient survival.
3. CIS progresses to invasive carcinoma in 80% of patients within 10 years of diagnosis.
4. Tumor grade
a. A close relationship exists between tumor grade and stage. Tumor grade alone affects survival in patients with superficial tumors. The 5-year survival rate is 85% with low-grade lesions and 30% with high-grade lesions. Virtually all high-grade superficial tumors become invasive if left untreated.
b. Chromosome number correlates with tumor grade. Tetraploid and aneuploid cells, as opposed to diploid cells, are associated with invasive tumors.
c. Several phenotypic properties that have been offered as markers for biologically more aggressive disease include enhanced expression of the Lewis x antigen; expression of defective p53, together with overexpression of the Rb gene and abnormal epidermal growth factor receptor; reduced expression of transforming growth factors β1, p27, and p15.
5. Size of the primary tumor does not correlate with the risk for dissemination. Large superficial lesions, however, are more likely to recur after therapy than are small lesions.
6. Multifocality is associated with an increased recurrence risk as compared with cases that have a solitary tumor.
V. PREVENTION AND EARLY DETECTION
A. Prevention. Protecting factory workers in certain industries from continuous exposure to bladder carcinogens (e.g., with protective clothing) may be beneficial. The benefit gained by reducing the intake of coffee or artificial sweetener has not been determined. All people should be discouraged from smoking. Folate-enriched diet has been associated with a decreased risk for bladder cancer.
B. Early detection depends on prompt evaluation of all patients with hematuria or chronic irritative bladder symptoms.
VI. MANAGEMENT
A. Early disease: overview
1. Superficial low-grade tumors not associated with CIS are managed by transurethral resection and, when indicated, intravesical chemotherapy. Although the recurrence rate is 80% with this management, the prognosis is good. Fulguration is effective treatment for small lesions.
2. CIS is usually multifocal, persistent, and recurrent. By definition, CIS is a high-grade malignancy and may evolve into invasive carcinoma. CIS is a superficial malignancy and cystoscopic resection or fulguration is effective treatment; however, CIS is usually flat and may not be visible by cystoscopy. Therefore, patients diagnosed with CIS should undergo additional treatment with intravesical bacillus Calmette-Guerin (BCG). Given the high risk of recurrence and progression, patients with CIS need to be followed closely with repeat cystoscopy every 3 months. CIS that recurs rapidly after BCG treatment should be managed with a cystectomy.
3. Invasive tumors that grow into the muscularis propria (>T2) are best treated by anterior pelvic exenteration in women and radical cystoprostatectomy in vmen. Pelvic lymph node dissection is performed to stage the nodes, and some advocate an extended node dissection to enhance the likelihood of a curative resection. Segmental resections of the bladder may be used in highly selected cases (see Section VI.B.2). Radiotherapy and chemotherapy may be appropriate in some cases (see Sections VI.C and D).
B. Early disease: surgery
1. Transurethral resection of bladder tumor (TURBT) is the cornerstone for diagnosing and staging bladder cancer. Differentiating between superficial and muscle-invasive bladder is critical. One or more TURBT procedures and follow-up cystoscopy constitute sufficient treatment for most superficial tumors. Muscle invasive disease requires radical cystectomy; however, small solitary tumors that involve the bladder muscle may be treated with TURBT alone in patients who are poor candidates for radical surgery.
2. Segmental resection (partial cystectomy) is associated with a high risk for recurrence. Segmental resection can be considered for tumors with the following characteristics:
a. Solitary
b. Localized to the bladder dome
c. CIS ruled out with multiple random biopsies
d. Able to be removed with a 2-cm margin of healthy tissue
e. Patients with adenocarcinomas are best suited for partial cystectomy since they are less likely to be due to a field change defect and therefore the tumors are less likely to be multifocal or recur.
3. Intravesical instillations. Because the bladder is a storage organ with no absorptive capacity, cytotoxic agents can be safely instilled into the bladder with virtually no systemic effects. Chemotherapy or immunotherapy has been used for the treatment and prevention of recurrence of superficial TCC. These agents have no role in the treatment of invasive bladder cancer.
Chemotherapeutic agents include thiotepa, mitomycin C, valrubicin, and doxorubicin. Immunotherapy has consisted of BCG with or without IFN-α. Intravesical therapy should be administered for T1 disease, CIS, and for Ta disease that is multifocal or rapidly recurring.
a. BCG is administered weekly for 6 weeks followed by maintenance administration of shorter courses. Maintenance BCG has been shown to augment the effects of a single 6-weekly course.
b. Mitomycin C is also given weekly at a dose of 40 mg each time. A single instillation of mitomycin C immediately following TURBT has been shown to dramatically decrease the risk of tumor recurrence, most likely owing to the prevention of cancer cell seeding. No proof exists that maintenance intravesical chemotherapy has any benefit.
c. BCG instillations are considered more effective in reducing the risks for recurrence and progression, as compared with chemotherapy. Therefore BCG is the treatment of choice for patients who have never received intravesical therapy. BCG is also curative for most patients with CIS. However, there is no proof that any intravesical therapy can alter long-term disease-specific survival.
d. Both chemotherapy and BCG are frequently associated with local side effects, such as bladder irritability, and both can rarely induce systemic adverse reactions. Of particular importance, systemic infection with BCG affects 5% of the cases and may lead to significant morbidity.
4. Radical cystectomy, the standard treatment for invasive bladder cancer, includes excision of the bladder, perivesical fat, and attached peritoneum. Men undergo removal of the entire prostate and seminal vesicles; women undergo en bloc removal of the uterus, adnexa, and cuff of the vagina. Lymphadenectomy is controversial; it may improve survival and therefore, some surgeons advocate an extended node dissection that extends from the pelvis up to the inferior mesenteric artery. There is little doubt that lymphadenectomy provides useful staging information and a classic pelvic node dissection represents the minimal extent of the lymphadenectomy.
a. Urinary diversion procedures. The ureters are diverted into either a loop of ileum that functions as a conduit to an abdominal stoma (ileal conduit, Bricker procedure) or a reservoir constructed from intestine. Generally, reservoirs are created by detubularizing and oversewing a segment of small or large bowel.
If a continent diversion is performed, the reservoir may be implanted orthotopically as a neobladder draining through the urethra using the native sphincter mechanism or attached to a catheterizable, continent stoma, which patients drain via intermittent self-catheterization. Alternative urinary drainage procedures, such as cutaneous implantation of the ureters and ureterosigmoidostomy, were largely abandoned because of a high rate of severe complications.
b. Indications for radical cystectomy
(1) Muscle invasive tumors
(2) CIS not responsive to intravesical therapy
(3) Superficial low-grade tumors that are diffuse, multiple, and frequently recurring and becoming difficult to control with recurrent TURBT and intravesical therapy
(4) High-grade tumors not responsive to intravesical therapy
c. Complications of cystectomy
(1) Mortality rate of 1% to 3%
(2) Blood loss
(3) Rectal injury, ureterocutaneous fistulas, wound dehiscence or infection; small bowel obstructions or fistulas. Small bowel fistulas are associated with a substantial mortality rate.
(4) Thrombophlebitis, pulmonary embolism, and other cardiocirculatory complications
(5) Impotence in men; potency can be preserved in some men by sparing the corporal nerves.
d. Complications of urinary diversion
(1) Urinary tract infection
(2) Obstruction owing to stenosis (fibrosis or tumor growth)
(3) Urinary calculi occasionally occur. Calcium stones are the most common.
(4) Acid–base imbalance: Hyperchloremic metabolic acidosis is the most common and results from the rapid reabsorption of ammonium followed by chloride from the urine by the intestine used for the urinary diversion. The type of diversion (reservoir vs. conduit) and the specific type of bowel segment used determine the type, extent, and gravity of the accompanied electrolyte impairment. The most severe metabolic derangements occur following diversions using sigmoid colon or jejunum.
C. Early disease: RT does not appear to alter the course of CIS favorably.
1. Indications for RT
a. RT is an alternative to surgery for highly motivated patients who desire to retain their bladder and potency within a bladder preservation protocol. These multiple modality treatment plans include aggressive TURBT, RT, and chemotherapy and are conducted in only a few dedicated institutions because such protocols mandate frequent follow-up visits and may end up in delayed cystectomy in up to 20% of cases.
b. Preoperative RT is seldom used. RT does not appear to improve expected survival beyond that achieved by radical surgery alone, although local recurrence is reduced.
c. Postoperative radiation has no proved role in bladder cancer.
2. Complications of RT are discussed in Chapter 11, “General Aspects,” Section IV.A (radiation cystitis) and Chapter 30, Section VI.D (radiation proctitis).
D. Early disease: chemotherapy
1. Adjuvant therapy with systemic cytotoxic agents for patients undergoing cystectomy has been associated with a delay in time to disease progression (8 to 12 months), but no conclusive evidence indicates improvement of survival. Several definitive clinical trials have been attempted, but all trials have closed due to poor accrual, reflecting the difficulty in administering chemotherapy to patients recovering from a major operation.
2. Neoadjuvant therapy is an attempt to provide the earliest possible treatment of micrometastatic disease and to facilitate definitive local therapy. At present, the preferred neoadjuvant regimen is three cycles of M-VAC (see Section VI.E.3), on the basis of a phase III trial by the Southwest Oncology Group that randomized patients to this regimen followed by surgery, or surgery alone. Neoadjuvant therapy has been shown to improve survival; unfortunately, neoadjuvant therapy is underused. At present, the highest level of evidence supports the use of M-VAC as neoadjuvant therapy.
E. Advanced disease
1. Surgery. An attempt to fulgurate large tumors that are bleeding uncontrollably or causing severe irritative symptoms is worthwhile. Often, these symptoms force the caregiver to perform palliative cystectomy and urinary diversion.
2. RT ameliorates hemorrhage in about half of patients and provides substantial local pain relief in areas of bone involvement. Tumor masses that threaten extension through the skin, particularly in the perineum, should be irradiated early. Bacterial cystitis should be treated effectively before the use of RT, if possible.
3. Chemotherapy. Cisplatin-based combination chemotherapy regimens have produced sustained complete responses in up to 45% of patients and represent the best current therapy for advanced bladder cancer, although toxicity can be substantial. Using gemcitabine plus cisplatin (GC) appeared to have similar efficacy but reduced morbidity as compared to M-VAC in a randomized, phase III study.
a. M-VAC is administered in 28-day cycles in the following dosages:
Methotrexate, 30 mg/m2 IV on days 1, 15, and 22
Vinblastine, 3 mg/m2 IV on days 2, 15, and 22
Doxorubicin (Adriamycin), 30 mg/m2 IV on day 2
Cisplatin, 70 mg/m2 IV on day 2
b. GC is administered in 28-day cycles for up to six cycles in the following dosages:
Gemcitabine, 1,000 mg/m2 IV on days 1, 8, 15, and
Cisplatin, 70 mg/m2 IV on day 2
F. Patient follow-up
1. Patients with severe urothelial dysplasia should have urine cytology repeated every 2 to 3 months and cystoscopy with random biopsies every 3 to 6 months.
2. Patients with superficial low-grade cancer treated with intravesical chemotherapy should have cystoscopy performed at 3-month intervals.
3. Patients who have undergone cystectomy should be evaluated every 3 months for the first 2 years, every 6 months for the next 3 years, and yearly thereafter. Urinalysis and urine cytology should be performed at 6-month intervals to search for the development of new primary cancers in the upper urinary tract. Hematuria or a positive cytology should be evaluated with IV urography.
4. For patients having an ileal conduit or continent diversion, urethral washing for cytology is advisable periodically to diagnose local recurrence in the urethra. For the same purpose, patients having orthotopic diversions should have follow-up cystoscopy.
VII. SPECIAL CLINICAL PROBLEMS
A. Gross hematuria can complicate the course of locally advanced bladder cancer. Transurethral fulguration or RT may help. In some retractable cases, the bladder may be treated with instillation of 4% formaldehyde into the bladder under general anesthesia; the agent is retained for 15 minutes. Prior to instillation of formaldehyde, a cystogram needs to be performed to rule out ureteral reflux since formaldehyde can scar and obstruct the ureter. Another option for severe, intractable hematuria is irrigation of the bladder with dilute alum. Alum should not be used in patients with renal insufficiency since alum that gets systemically absorbed is excreted by the kidney.
B. Obstructive uropathy. Uremia can develop in patients with any type of urinary diversion. Obstruction caused by benign conditions, such as stones or stenosis, must be excluded. The urine should be examined for malignant cells, crystals, and blood. If the ureteral orifice can be located, a retrograde pyelogram is performed. Otherwise, IVP or renal radionuclide scan may show obstruction.
Endoscopy may be used to dilate stenotic lesions with some success. Exploratory surgery should be considered to solve the problem in patients who otherwise are clinically free of cancer. Patients with advanced disease commonly benefit from diverting externally with percutaneous nephrostomies or internally with ureteral stents.
C. Impotence. Despite nerve-sparing technique, impotence complicates radical cystectomy in men. Oral agents, intraurethral preparations, intracavernosal injection, and penile prostheses are the available solutions that usually permit restoration of potency and, often, orgasm in these patients.
D. Management of urinary symptoms is discussed in Chapter 5, Section V.
URETHRAL CANCER
I. EPIDEMIOLOGY AND ETIOLOGY. Urethral cancer is extremely rare. Women are affected three times as often as men. The age of onset is usually >50 years. The etiology is not known, but urethral cancer may be associated with gonorrheal urethritis, strictures, or transitional cell carcinoma in the bladder.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Of cases, 80% are squamous cell carcinomas, usually arising from the stratified squamous epithelium of the posterior (proximal or bulbous) urethra (60%) or the anterior (distal or penile) urethra (30%). Fifteen percent are transitional cell carcinomas arising in the prostatic urethra. Adenocarcinomas possibly arise from Cowper glands.
B. Clinical course. Urethral cancer is usually diagnosed late and involves inguinal nodes early on. It also spreads hematogenously to distant organs. Lesions of the anterior urethra are less likely to be associated with widespread metastases than are posterior lesions.
III. DIAGNOSIS. Patients have urinary hesitancy, hematuria, palpable mass, urethral discharge, perineal pain, or enlarged inguinal nodes. Transurethral biopsy establishes the diagnosis. The biopsy and imaging studies contribute to TNM staging.
IV. MANAGEMENT. In both female and male patients, the extensiveness of therapy is determined by the stage, location of the tumor (anterior vs. posterior urethra), and need for local palliation. In women, treatment varies between total urethrectomy and more extensive surgery, which includes cystectomy (with total or partial resection of the vagina), urethrectomy, and pelvic lymph node dissection. In men who have anterior urethral cancer, transurethral resection of the tumor followed by wide local excision is usually sufficient. If the corpora are infiltrated with tumor, partial or total penectomy is usually required. For posterior urethral disease, the combination of radical cystoprostatectomy, total penectomy, and pelvic lymphadenectomy offers improved results. RT has a limited role in urethral cancer therapy for selected cases. Combination chemotherapy regimens are used for patients with metastases.
PROSTATE CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence of prostate cancer (CAP) rose continuously for >20 years. In 1987, it crossed the line of 100 cases per 100,000 (age adjusted, all male population). The peak incidence was seen in 1992 (191/100,000). The incidence declined from 1992 to 1995, and then leveled off. The rise in incidence is basically explained by improved detection capability, mainly using prostate-specific antigen (PSA) and transrectal ultrasound (TRUS) to aim prostate TrueCut biopsies.
The risk for prostate cancer increases steeply with age. One percent incidence is reached at 67 and 72 years of age for black and white men, respectively. A rise in death rate accompanies the rise in the incidence. An age-adjusted death rate peak of 27/100,000 was reported in 1991 in the United States. Thereafter, death rates declined slowly, perhaps because of treatment efforts.
B. Etiology. The cause of prostate cancer is unknown. Several factors are associated with an increased risk.
1. Demography. The risk for developing prostate cancer is highest in Sweden, intermediate in the United States and Europe (and Japanese men who migrated to the United States), and lowest in Taiwan and Japan. Blacks are afflicted 30% more often than are whites. Corrected for stage, blacks also may have lower survival rates.
2. Positive familial history of prostate cancer in the father or brother of a subject increases his risk sevenfold over the general population if the affected relative was diagnosed by 50 years of age. The relative risk declines to fourfold if the diagnosis of the first-degree relative was made after 70 years of age.
3. Hormones. Altered estrogen and androgen metabolite levels have been suggested as a causative mechanism leading to prostate cancer occurrence.
4. Other suggested risk factors, which are not fully established, are increased intake of vitamin A, decreased intake of vitamin D, and occupational exposure to cadmium.
II. PATHOLOGY AND NATURAL HISTORY
A. Histology. Almost all prostate cancers are adenocarcinomas. Transitional, small, and squamous cell carcinomas and sarcomas are rare. The prostate may be the site of metastases from bladder, colon, or lung cancer or from melanomas, lymphomas, or other malignancies.
B. Location. Prostate cancer tends to be multifocal and frequently (70%) arises from the peripheral zone of the prostate (the surgical capsule). Both of these characteristics make removal by transurethral resection of the prostate (TURP) unfeasible for curative intent.
C. Mode of spread. The biology of adenocarcinomas of the prostate is strongly influenced by tumor grade. Low-grade tumors may remain localized for long periods of time. The disease locally invades along nerve sheaths and metastasizes through lymphatic chains. Distant metastases can occur without evidence of nodal involvement. Distant metastases are nearly always present when lymph nodes are involved.
D. Metastatic sites. Bone is the most common site of prostate cancer metastases, almost always producing dense osteoblastic metastatic lesions. Occasionally, patients demonstrate uncharacteristic osteolytic lesions. Liver involvement also occurs, but metastases to the brain, lung, and other soft tissues are rare.
E. Associated paraneoplastic syndromes
1. Systemic fibrinolysis
2. Neuromuscular abnormalities
III. DIAGNOSIS
A. Symptoms and signs
1. Symptoms. Currently, most patients with CAP are asymptomatic at diagnosis.
a. Early prostatic cancer is usually asymptomatic and can be detected as a result of routine digital rectal examination (DRE). It is mainly discovered by serum PSA measurement or, rarely, during TURP for glandular hyperplasia. The presence of severe symptoms usually indicates advanced disease. Symptoms include hesitancy, urgency, nocturia, poor urine stream, dribbling, and terminal hematuria.
b. The sudden onset and rapid progression of symptoms of urinary tract obstruction in men of the appropriate age are most likely to be caused by prostate cancer.
c. Pain in the back, pelvis, or over multiple bony sites is the most common presenting complaint in patients with distant metastases.
d. The sudden onset of neurologic deficiencies, such as paraplegia and incontinence resulting from extradural spinal metastases, may be a presenting feature or may develop during the course of the disease.
2. Physical examination
a. Check for induration or nodularity of the prostate, which often represents prostatic cancer. Nodules of prostatic cancer are typically stony hard and not tender.
b. Examine lateral sulci and for palpable (abnormal) seminal vesicles.
c. Evaluate inguinal nodes for metastatic disease.
d. Evaluate for distant metastases by palpating the skeleton for tender foci and by performing an oriented neurologic examination looking for spinal cord compression.
B. Differential diagnosis of the enlarged prostate
1. Acute prostatitis. Bacterial infection causes dysuria, pain, and often fever. The prostate is tender and enlarged but not hard. Patients with acute bacterial prostatitis will have a positive urine culture.
2. Chronic and granulomatous prostatitis caused by bacterial, tuberculous (including following intravesical BCG instillation), fungal, or protozoan infection may produce a mass that cannot be clinically distinguished from cancer. Biopsy may be necessary to make the diagnosis.
3. Nodular hyperplasia (benign prostatic hypertrophy) is found in men >30 years of age and in 80% of men by 80 years of age. Urinary obstructive symptoms are common. Palpable nodules that are indistinguishable from cancer necessitate biopsy.
4. Other possibilities. Rarely, calculi, amyloidosis, benign adenomas, or infarction of a hyperplastic nodule can cause obstruction or a mass suggestive of cancer.
C. Diagnostic studies
1. Routine studies. Urinalysis, CBC, renal function tests, LFT, alkaline phosphatase, calcium, and chest radiographs
2. PSA is a serine protease that serves as a marker unique to the prostate. Using PSA increases the number of biopsies performed and thus augments the number of patients diagnosed. It significantly augments the yield of DRE in diagnosing prostate cancer in general and organ-confined disease in particular.
a. False-positive results. About 15% of patients with nodular hyperplasia have elevated PSA levels. PSA values can also be increased with prostatic inflammation, surgery, or endoscopy, but not with rectal examination. After a prostate biopsy, PSA is reported to be elevated for at least 6 to 8 weeks. Increased serum PSA concentration has been reported rarely in patients with cancers of the pancreas, parotid gland, and breast.
b. Free PSA is the fraction of PSA that is not bound to the plasma antiproteases α1-antichymotrypsin and α2-macroglobulin. A decreased ratio of free PSA to total PSA is associated with increased probability of prostate cancer. For patients with elevated PSA and no suspect findings on palpation of the prostate, it is recommended to proceed with watchful waiting after one negative biopsy if the free-to-total PSA ratio is >25%.
c. Age-specific PSA. The normal range of PSA in patients without prostate cancer rises with age, mainly as a result of gland enlargement.
d. PSA density indices are mathematic modifications of PSA. The transitional zone (TZ) is located centrally; it is one of the PSA-producing parts of the prostate and is usually increased in size when benign prostate hyperplasia occurs. The indices adjust serum PSA levels for the prostate gland volume (PSA density = PSA/gland volume) or for the TZ volume (PSA TZ = PSA/TZ volume). These indices were found to improve positive-predictive and negative-predictive values in patients with total PSA levels of 4 to 10 ng/mL. PSA TZ is also reported to assist in staging, screening, and sparing prostate biopsies in some patients.
e. Clinical utility of PSA. PSA can detect primary or recurrent tumors of very low volume and is useful for both diagnosis and follow-up. Although PSA is not sufficiently sensitive to be the sole screening method for prostate cancer, it is useful when combined with DRE. About 25% of patients with biopsy-proven prostate cancer have serum PSA levels <4 ng/mL. When PSA is combined with TRUS-guided prostatic biopsies, cancer is detected in 20% of patients with PSA values between 4 and 10 ng/mL and in 60% of patients with values >10 ng/mL.
PSA values may show a progressive increase several years before metastatic disease becomes evident. Such a rise is an indication to look for local recurrence in previously treated patients using physical examination or TRUS. The search for metastatic disease in asymptomatic patients with PSA <10 ng/mL is not routinely indicated.
3. Acid phosphatase, previously the only marker for prostate cancer, is seldom used today.
4. Biopsy techniques
a. TRUS-guided true-cut biopsy is the standard method to diagnose prostate cancer. A six to twelve-core biopsy is taken by sampling the base, apex, and midgland on each side of the gland along two parallel lateral lines.
Most cancers have a hypoechoic appearance in TRUS, although up to 30% of cancers may be isoechoic. When the indication for TRUS-guided biopsy is a PSA > 4 ng/mL, the expected yield for diagnosing prostate cancer reaches 24%. When PSA is >4 ng/mL, the DRE is suspicious, and a hypoechoic lesion is imaged by TRUS, the yield rises to 45%.
b. TURP. Prostate cancer may be found in approximately 5% of TURP performed for benign hyperplasia.
5. Bone scans. The probability of a positive scan is extremely low when the PSA is <10 ng/mL or symptoms are absent.
6. CT scans and MRI are used to assess tumor spread into lymph nodes or the pelvis. These studies are warranted in high-risk patients who have a tumor that is confluent with the pelvic side wall on DRE, a high Gleason score (see tumor grading in Section IV.B.1), or PSA > 20 ng/mL.
IV. STAGING AND PROGNOSTIC FACTORS
A. Staging system. The TNM classification used to stage prostate cancer is shown in Table 13.3. The anatomic stage/prognostic groups for prostate cancer are shown in Table 13.4.
Table 13.3 TNM Staging System for Prostate Adenocarcinoma
aPathologic substaging by biopsy or radical prostatectomy is designated by the “p” prefix for pT2–pT4 and pNX–pN1.
Adapted from the AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010.
Table 13.4 Anatomic Stage/Prognostic Groups for Prostate Cancera
X: When either PSA or Gleason is not available, grouping should be determined by T stage and either PSA or Gleason as available.
aAdapted from the AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010.
B. Prognostic factors
1. Tumor grade strongly affects prognosis. Higher tumor grades are more frequently associated with lymph node and distant metastases. The Gleason scoring system is most commonly used. This system is founded on the glandular appearance and architecture at relatively low-power magnification. Two scores of 1 to 5 points are given for a primary (predominant) site and a secondary (second most prevalent) site. Therefore, Gleason score can sum from 2 to 10 points. Patients having Gleason score of 7 and above have a worse prognosis than patients with lower scores.
2. Involvement of seminal vesicles is associated with a poor prognosis, even in apparently early disease.
3. Extension of tumor beyond the prostate capsule is associated with worse prognosis.
4. High PSA values and elements of PSA kinetics, including rapid PSA rise (high PSA velocity) and short PSA doubling time, are associated with poor prognosis.
5. Predictive Tools such as the Partin Tables and Kattan Nomograms are clinically useful for prognostication in a variety of clinical settings using known prognostic factors.
V. PREVENTION AND EARLY DETECTION. Screening for prostate cancer remains controversial. Early detection as a result of elevated PSA only (T1c disease) results, however, in the identification of more patients with organ-confined disease and perhaps contributes to a reduction in disease-specific mortality. American cancer society guidelines recommend that PSA screening and DRE begin at the age of 50 years. Screening at the age of 40 should be considered in men with positive familial or racial (blacks) risk factors.
VI. MANAGEMENT
A. Overview and philosophy. The management of all stages of prostate cancer is controversial. This disease often has a long natural history; therefore, substantial numbers of patients survive 15 years or longer after the diagnosis (even without treatment). Furthermore, because the disease occurs in older men (who often have significant comorbid illnesses), many patients die from these conditions before they have symptoms or die from prostate cancer.
1. Investigators and clinicians vary widely in their use of surgery, RT, hormonal manipulation, and other measures for treating each stage of disease. Most clinicians agree, however, that treatment of early stage disease with either surgery or RT results in comparable survival. It is unclear at this time whether similar survival rates could be achieved with systemic therapies.
2. All options should be explored when it comes to treatment selection for a specific patient. No prospective head-to-head data are available to show an overall clear-cut advantage for radical retropubic prostatectomy (RRP) over RT, or vice versa. The long-term survival results of modern cryotherapy and modern brachytherapy are not yet ready for a critical comparison with the gold standard therapies. “Watchful waiting” is another option that should be considered.
A newer approach of active surveillance is replacing the “watchful waiting” approach. With active surveillance, patients are clinically monitored twice a year and tumor histology is re-evaluated with annual prostate biopsy to detect disease progression and allocate patients who deserve a curative effort at that point. Recommended criteria for active surveillance are absence of extraprostatic disease on DRE (≤T2), Gleason score ≤6, small volume tumor (fewer than 3 biopsy cores and <50% of any core involved), PSA density <0.15, and a PSA < 10 ng/mL at diagnosis. It is plausible that a long PSA doubling time (i.e., >12 months) would also indicate an indolent disease.
These options should be carefully explained to the patient, exploring the advantages and disadvantages of each treatment modality. The treatment strategy should be tailored according to both the patient’s clinical data and his expectations and lifestyle.
B. Surgery (stages T1 and T3)
1. Stage T1-T2. T1a and T1b prostate cancers are incidentally discovered by histologic evaluation of specimens taken by TURP for symptomatic hyperplasia. T1c prostate cancers are detected by a prostate biopsy that was prompted by an abnormal PSA in a patient with a normal prostate exam. T2 prostate cancers are associated with a nodule that appears on physical exam to be contained within the prostate. Management options include watchful waiting, active surveillance, radical prostatectomy, and RT.
2. Stage T3. On prostate exam, T3 cancers involve the seminal vesicles or locally extend beyond the prostate. Patients with T3 prostate cancer are at high risk for metastatic disease, and preoperative bone scan and pelvic CT are mandatory. Historically, clinical T3 prostate cancer was considered a contraindication for surgery. However, clinical T3 disease without evidence of distant spread can be cured with surgery. To maximize the potential for cure, adjuvant radiation should be considered for patients with pathologically proven T3 disease, particularly if the surgical margin is positive.
3. Radical prostatectomy. In general, patients undergoing surgery should have a life expectancy greater than 10 years. In the United States, the open radical retropubic prostatectomy (RRP) has been largely replaced by robotically assisted radical prostatectomy (RARP). Anatomically, the same dissection is performed in both procedures, however, in the RARP the Da Vinci robot is used to facilitate a minimally invasive laparoscopic approach. The cancer control associated with RARP appears to be similar to RRP, and the decreased blood loss associated with RARP may translate into a more rapid recovery from surgery. At this time, it is unknown if the RARP is associated with greater likelihood of recovering erectile function and urinary control when compared to RRP. Other surgical options include a variety of ablative treatments such as cryotherapy, radiofrequency ablation, and high intensity focused ultrasound. However, in the United States, these options are considered experimental, particularly when used as primary therapy.
4. Complications of radical prostatectomy and lymphadenectomy
a. Radical prostatectomy causes minor incontinence in 10% to 20% of patients. Severe incontinence is reported to occur in no more than 1% to 3%. Potency can be preserved by a skilled surgeon in up to 60% to 70% of younger patients who undergo nerve-sparing radical prostatectomy.
b. Staging lymphadenectomy is performed during radical prostatectomy by sampling the pelvic nodes. Complications specifically due to the lymphadenectomy are rare and include lymphocele, pulmonary embolus, wound infection, and lymphedema.
c. Persistent or recurrent disease following radical extirpation of the prostate is rare provided that patients were carefully selected for surgery. It may occur in 10% to 40% of patients after radical prostatectomy, depending on tumor stage, Gleason score, and pretreatment PSA. Patients who recur during follow-up can often be cured with salvage radiotherapy. Patients with high risk for disease recurrence may benefit from upfront adjuvant radiotherapy, which is administered to prevent a recurrence.
5. Contraindications to radical prostatectomy and lymphadenectomy. Generally speaking, radical prostatectomy is reserved for men who are likely to be cured and who have a life expectancy of at least 10 years. Thus, the following constitute contraindications for radical prostatectomy:
a. Physiologic age >70 to 75 years
b. Metastases to pelvic nodes
c. Disseminated cancer
C. RT for early disease (stages T1 to T3)
1. Indications. RT is widely used in the treatment of patients with stages T1 and T2 disease. Adjuvant androgen deprivation therapy for 6 months to 3 years has been shown to improve survival in this setting. The use of three-dimensional conformal technique and intensity-modulated RT (IMRT) allows improved results and with fewer side effects than standard RT.
For patients with locally advanced disease (stages T3 and T4), 2 to 3 years of adjuvant androgen deprivation therapy has been shown to prolong survival in comparison with 6 months of androgen deprivation therapy in a randomized clinical trial. Increasing the radiation dose is advisable in this selected group. This may be achieved by using conformal external-beam irradiation, proton therapy, or brachytherapy. Other indications for RT include the following:
a. The patient’s medical condition precludes surgery.
b. Node involvement is found at staging lymphadenectomy (RRP is not performed).
c. Residual malignant pelvic disease is found after prostate surgery (i.e., positive surgical margins and slowly rising PSA).
d. Adjuvant RT should be considered for patients at high risk for recurrence following RRP. Several randomized studies show that patients with positive surgical margins, seminal vesicle invasion, or extracapsular extension benefit from adjuvant RT.
2. Complications after about 7,000 cGy given in 7 to 8 weeks and their approximate incidence rates in treated patients are as follows:
a. Impotence: 50% (may be less with conformal RT or brachytherapy)
b. Radiation proctitis with diarrhea, blood-streaked stools, and rectal urgency: <5% (see Chapter 30, Section VI.D)
c. Dysuria, urinary urgency, and frequency: <5%
d. Perineal fistulas: <1%
e. Fecal and urinary incontinence: 1% to 2%
f. Urethral stricture: 1% to 5%
g. Persistent tumor or recurrent disease: 10% to 40%, depending on tumor stage, Gleason score, and pretreatment PSA
3. Brachytherapy and cryotherapy are other therapies intended for cure. These modalities will be judged in the future when enough patients have been treated sufficiently long for ample follow-up data to become available.
D. Advanced disease
1. Surgery. TURP may be used to relieve bladder outlet obstruction even in the presence of advanced disease; however, orchiectomy alone is usually effective.
2. RT is useful in treating the following problems commonly encountered in prostate cancer patients:
a. Isolated, painful bony metastatic sites, despite endocrine therapy
b. Pelvic pain syndromes, urinary tract obstruction, and gross hematuria
c. Metastases to retroperitoneal lymph nodes that produce back pain or scrotal and lower extremity edema
d. Spinal cord compression from vertebral and extradural metastases is a common and rapidly progressive complication of prostate cancer. Cord compression is an emergency; MRI, administration of corticosteroids, and definitive therapy must be undertaken within a few hours after onset of symptoms (see Chapter 32, Section III).
3. Androgen deprivation therapy is the mainstay of treatment for symptomatic advanced prostate cancer because testosterone is the main growth factor for prostate cancer cells. The timing of androgen deprivation therapy is controversial because no conclusive evidence suggests that treatment of asymptomatic patients provides survival advantage. Prolonged androgen deprivation is associated with multiple side effects, including hot flushes, weight gain, erectile dysfunction, osteoporosis, and increased risk of diabetes and cardiovascular disease. Thus, treatment of patients with asymptomatic, advanced disease is not essential.
Orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, and antiandrogens are the available treatments. Each produces symptomatic relief in 80% of patients. Improvement is often dramatic; many bedridden patients crippled with bone pain return to a more functional status.
a. Orchiectomy produces a rapid decline in testosterone level. It is an effective but irreversible procedure. Orchiectomy is advisable as primary treatment for advanced disease, particularly for patients who are noncompliant with androgen blockade or who require emergency blockade for spinal cord compression.
b. LHRH agonists, such as leuprolide (Lupron) and goserelin (Zoladex), appear to be as effective as orchiectomy. These depot drugs are given every 3 months (22.5 mg for leuprolide and 10.8 mg for goserelin). The cost of ongoing treatment with LHRH agonists is substantially greater than with orchiectomy.
c. Antiandrogens combined with LHRH agonists are believed by some investigators to be superior to LHRH agonists alone and to result in a small but significant survival benefit by “total androgen blockade.” Flutamide (Eulexin, 250 mg PO given t.i.d.), bicalutamide (Casodex, 50 mg PO daily), or other antiandrogens are given along with the LHRH agonist.
d. Other agents that may be helpful include the following:
(1) Progestins, such as megestrol acetate, 40 mg PO q.i.d.
(2) Other drugs that inhibit androgen synthesis, such as ketoconazole (200 to 400 mg t.i.d.), have also been shown to be effective. These agents, however, are expensive and are often difficult to tolerate. The benefits of treatment with them are often difficult to separate from the benefits of corticosteroids, which are often given simultaneously.
(3) Corticosteroids, such as prednisone and dexamethasone, often provide symptomatic improvement and may be associated with reductions in PSA levels.
(4) Zoledronic acid (Zometa) is widely used for reduction in bone pain, in time to first skeletal-related events (SRE), and in the incidence of fractures and other complications of bone metastases.
(5) Denosumab (Xgeva) has been compared to zoledronic acid in a pivotal phase III study in prostate cancer. These studies showed an approximate 18% reduction in SREs with denosumab therapy. Denosumab is administered as a monthly subcutaneous injection.
(6) Strontium 89 infusion. The beta emission of 89Sr is used in selected hormone refractory patients to relieve skeletal pain. Responses last about 6 months. Hematologic toxicity is anticipated in the first 2 weeks after administration.
(7) α5-Reductase inhibitors (e.g., finasteride) are used for the treatment of benign prostatic hyperplasia. They are being evaluated in combination with other antiandrogens, for efficacy in treating patients with advanced prostate cancer, but so far no evidence indicates that they provide additional benefits to LHRH agonists and antiandrogens.
4. Chemotherapy. The first chemotherapy drug approved for the treatment of androgen-independent prostate cancer was mitoxantrone based on its palliative effects. Two large randomized clinical trials showed that chemotherapy with docetaxel (Taxotere) given every 3 weeks improves survival and provides superior palliation as compared with mitoxantrone.
For those patients refractory to docetaxel, several therapeutic options are emerging. In a phase III study, the novel taxane cabazitaxel (Jevtana) was compared to mitoxantrone in patients who had previously failed docetaxel-based therapy. Both agents were administered with prednisone. Treatment with cabazitaxel yielded a survival advantage, albeit with an increased rate of neutropenic fevers (and associated deaths).
5. Vaccine therapy. The autologous dendritic cell vaccine, sipuleucel-T (Provenge), was compared to placebo in a phase III study in patients with asymptomatic or minimally symptomatic castration-resistant prostate cancer. Although no difference in time to progression was observed, the treated with sipuleucel-T did yield a survival advantage. The mechanism of action remains somewhat elusive, and the appropriate clinical utilization of the agent is unclear in the face of the cost burden and other agents (i.e., cytotoxic chemotherapy) that could be utilized within the same therapeutic space.
6. Novel endocrine therapies. The CYP17 lyase inhibitor abiraterone has been compared to placebo in a phase III study of patients with castration-resistant disease refractory to docetaxel. A preliminary report from this study suggests a survival advantage with abiraterone, with relatively minimal accompanying toxicity (hyperkalemia, fluid retention, etc.). Abiraterone is also being examined in a phase III trial in patients who are docetaxel-naïve.
Recently, agents have been identified that not only block the interaction between testosterone and the androgen receptor (i.e., in a manner akin to bicalutamide) but also inhibit nuclear translocation of the androgen receptor. MDV3100 is one such agent that is currently in phase III testing. Like abiraterone, MDV3100 is being separately assessed in docetaxel-naïve and docetaxel-refractory patients with castration-resistant disease.
VII. SPECIAL CLINICAL PROBLEMS
A. Cytopenias in prostate cancer are usually part of the end-stage process caused by extensive tumor involvement of the bone marrow or by RT to major marrow-bearing sites. The anemia is typically normochromic and normocytic and sometimes a part of a leukoerythroblastic peripheral blood smear. Other causes must be considered.
B. Obstructive uropathy and uremia may be the fatal complication of prostate cancer. For newly diagnosed disease, systemic androgen deprivation therapy may relieve the urinary obstruction. Ureteral obstruction can be palliated by placing a double-J ureteral stent or a percutaneous nephrostomy. Bladder outlet obstruction due to local extension of the prostate tumor into the urethra can be relieved with by TURP.
C. Dense-bone sclerosis on radiograph in an adult man of the appropriate age who has bone pain usually is diagnostic of prostate cancer. Bone-containing prostate cancer is so densely sclerotic that attempts at marrow biopsy often result in “dry taps” and damaged biopsy needles. The radiologic appearance of Paget disease is distinguished by the fluffy, cotton-like appearance of lesions, by thickening of the bone cortex, and by the dense sclerosis of the pelvic brim (brim sign).
D. Extraosseous extension of prostate cancer is common. Extension of skull or vertebral lesions can produce neurologic deficits. Extension of rib lesions can produce subcutaneous or pleuropulmonary masses. Retro-orbital and cavernous sinus masses can result in proptosis and visual loss. Extraosseous extension of bony lesions necessitates RT.
E. Systemic fibrinolysis. Activators of the fibrinolytic enzyme, plasmin, abound in prostatic tissue. Prostatic disease, especially carcinoma of the prostate, is among the few medical conditions that can produce both significant systemic fibrinolysis and disseminated intravascular coagulation (see Chapter 34, “Coagulopathy,” Section III, for diagnosis and management).
PENILE CANCER
I. EPIDEMIOLOGY AND ETIOLOGY
A. Incidence. Penile cancer constitutes about 0.5% of all cancers in men in the United States and Europe. The incidence is greatly increased in populations that do not uniformly practice circumcision. The average age of onset is about 60 years, peaking at about 80 years of age.
B. Etiology. The etiology of penile cancer is not known. Venereal disease is not a causative factor. The following data suggest that circumcision is preventative:
1. The disease is almost nonexistent in Jewish men, who are all circumcised shortly after birth.
2. In Africa and other countries where circumcision is not performed, penile cancer constitutes 20% of all cancers.
3. Muslims have an intermediate risk for penile cancer. Muslim boys are circumcised at puberty.
II. PATHOLOGY AND NATURAL HISTORY
A. Premalignant lesions
1. Carcinoma in situ
a. Erythroplasia of Queyrat occurs on the glans and prepuce of uncircumcised men. The lesions are flat and reddened or are velvety plaques and may progress to invasive cancer in 10% of patients.
b. Bowen disease appears as a small eczematoid plaque anywhere on the penis. Squamous carcinoma in situ is demonstrated by histology. Bowen disease of the penis, as with squamous carcinoma in situ in other areas of the skin not exposed to sun, is associated with a high incidence of carcinoma of the gastrointestinal tract and lungs.
2. Leukoplakia. Nonspecific plaques of leukoplakia on the glans are almost always associated with squamous carcinoma. Unlike leukoplakia lesions elsewhere, penile lesions are not white.
3. Giant penile condyloma (Buschke-Löwenstein tumor) grossly resembles a cauliflower-like squamous cell cancer and may have foci of cancer. Surgical excision is mandatory.
B. Histology. Squamous cell carcinoma, usually well differentiated, constitutes nearly all penile cancers. Rare penile cancers include melanoma, sarcoma, and metastatic tumor. Squamous carcinoma of the penis may demonstrate variable degrees of keratin formation.
C. Clinical course. If left untreated, penile cancers usually cause death within 2 years.
1. Squamous penile cancer usually starts on the glans or coronal sulcus. As the disease progresses, the corpora cavernosa are invaded. The urethra is usually spared until late in the disease course.
2. The rich lymphatic drainage of this region results in metastases to the inguinal nodes (only one-third of palpable nodes are involved with tumor by histology). Lymphatic metastases are not common if the tumor is confined to the glans or prepuce.
3. The tumor disseminates through the lymphatic system and the bloodstream to distant organs in up to 10% of patients, most often to the lungs and, less frequently, to bone and other sites.
D. Paraneoplastic syndromes. Hypercalcemia may develop with no evidence of bony metastasis (20% of patients).
III. DIAGNOSIS is usually delayed substantially because of denial, personal neglect, shame, guilt, or lack of knowledge.
A. Symptoms and signs
1. The earliest lesion of penile carcinoma is described by patients as a nonhealing sore, often with an associated foul-smelling discharge. Phimosis may mask penile cancer until erosion through the prepuce occurs. Many patients have a long history of a mass. Urinary tract symptoms, such as pain and hematuria, are signs of locally advanced disease.
2. Physical examination usually reveals an exophytic mass. Infection of the tumor is usually present when the patient is examined for symptoms. In about 92% of patients, the tumor arises in the glans penis, prepuce, or both.
B. Laboratory studies
1. Routine blood tests, urinalysis, and chest radiographs are obtained.
2. Biopsy or imprint slides should be done for all patients with a penile mass or with any finding compatible with a precancerous lesion.
3. Liver and bone scans should be obtained only if abnormalities seen on physical examination or blood studies suggest liver or bone involvement.
4. MRI and ultrasound of the penis and pelvis are effective in the staging.
IV. STAGING SYSTEM AND PROGNOSTIC FACTORS
A. Staging system. The TNM classification is used for squamous cell carcinoma. The reader is referred to a current AJCC manual for details of the TNM system.
B. Prognostic factors. Poor prognostic features include endophytic and high-grade lesions, invasion of the shaft, and involvement of draining lymph nodes, especially at the iliac level or higher. Of patients with clinical stage Tis, Ta, or T1 (Jackson stage I or II) tumors, 10% have inguinal node involvement proved by surgery.
V. PREVENTION AND EARLY DETECTION. Prevention of penile cancer can be accomplished by routine early circumcision of male babies. Circumcision should be performed in patients with phimosis and penile discharge, inflammation, or induration. Early detection of penile cancer requires regular inspection of the prepuce and glans at physical examination and biopsy of suspected lesions.
VI. MANAGEMENT
A. Surgery is the principal modality of therapy for penile cancer in the United States. Partial penectomy is sufficient therapy if there is a 2-cm tumor-free margin.
1. Total penectomy is necessary for lesions that invade the body of the penis or are very large.
2. In younger patients with tumor confined to the prepuce, circumcision may be used if close follow-up can be assured; however, the recurrence rate is high.
3. Dissection or routine sampling of the superficial inguinal nodes for patients with low-stage (up to T2), but high-grade, lesions is recommended by some authorities; if the nodes contain tumor, a radical ilioinguinal lymphadenectomy is necessary. Radical lymphadenectomy is routinely performed in patients with stage T3 tumors. The extensiveness of the lymph node dissection (deep vs. superficial inguinal vs. pelvic node dissection; unilateral vs. bilateral; full vs.limited) varies according to local and regional disease extension.
B. RT. The primary role of RT is to avoid penectomy, especially in younger patients. This modality has been used for treating small primary stage I lesions (<3 cm in diameter); the results for RT alone (along with salvage surgery for failures) appear to be the same as those obtained when partial amputation is used as primary therapy.
C. Chemotherapy
1. Premalignant lesions may respond to topical therapy with fluorouracil or to laser therapy in selected cases.
2. Penile cancer appears to be responsive to combination chemotherapy: vincristine, bleomycin, and methotrexate (VBM regimen) or cisplatin and 5-fluoro-uracil. Some authorities use these drugs as an adjunct to surgery or RT for stage T3 and T4 tumors. Response rates of advanced cancer to these drugs may be as high as 50%.
Suggested Reading
Renal Cancer
Belldegrun A, et al. Renal and Adrenal Tumors: Biology and Management. Oxford, UK: Oxford University Press; 2003.
Escudier B, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010;28(13):2144.
Escudier B, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:25.
Hudes G, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356(22):2271.
Motzer R, et al. Sunitinib versus interferon alfa in metastatic renal cell carcinoma. N Engl J Med 2007;356:115.
Rassweiler J, et al. Oncological safety of laparoscopic surgery for urological malignancy: experience with more than 1,000 operations. J Urol 2003;169:2072.
Rini BI, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol 2010;28(13):2137.
Sternberg CN, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase iii trial. J Clin Oncol 2010;28(6):1061.
Zisman A, et al. Reevaluation of the 1997 TNM classification for RCC: T1 and T2 cutoff point at 4.5 cm rather then 7 cm better correlates with clinical outcome. J Urol 2001;166:54.
Zisman A, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002;20:4559.
Urothelial Cancers
Borden LS, et al. Bladder cancer. Curr Opin Oncol 2003;15:227.
Grossman HB, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349(9):859.
Raghavan D. Molecular targeting and pharmacogenomics in the management of advanced bladder cancer. Cancer 2003;97:2083.
Sternberg CN, et al. Chemotherapy for bladder cancer: treatment guidelines for neoadjuvant chemotherapy, bladder preservation, adjuvant chemotherapy, and metastatic cancer. Urology 2007;69 (1 suppl):62.
Von der Maase H, et al. Gemcitabine and cisplatin versus methotrexate, vinblastin, doxorubicin and cisplatin in advanced or metastatic bladder cancer: results of a large randomized, multinational, multicenter, phase III study. J Clin Oncol 2000;17:3068.
Prostate Cancer
Axelson Bill, et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352(19):1977.
de Bono JS, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376(9747):1147.
Graefen M, et al. International validation of a preoperative nomogram for prostate cancer recurrence after radical prostatectomy. J Clin Oncol 2002;20:3206.
Kantoff PW, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med 2010;363(5):411.
Messing EM, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999;341:1781.
Petrylak DP, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351(15):1513.
Pisansky TM. External-beam radiotherapy for localized prostate cancer. N Engl J Med 2006;355(15):1583.
Tannock IF, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502.