Andrea B. Apolo and William L. Dahut
EPIDEMIOLOGY
It is estimated that 72,570 patients were diagnosed with bladder cancer in 2013 and that 15,210 died of the disease in the United States and more than 385,000 individuals are diagnosed with incident bladder cancer per year worldwide. There is a male:female ratio of 3:1, with a peak incidence of occurrence in the seventh decade of life, making bladder cancer the fourth and eighth most commonly diagnosed cancer in men and women, respectively.
ETIOLOGY
■Cigarette smoking: Smoking is the most common cause of bladder cancer, with smokers having twice the risk of developing bladder cancer compared to nonsmokers. Smoking explains a similar proportion of bladder cancer in both sexes, with population-attributable risks of 50% in men and 52% in women. There is an association between the duration and amount of cigarette smoking and the development of bladder cancer in both transitional and squamous histology.
■Occupational exposures: Occupational exposures to chemical carcinogens are associated with an increased risk of bladder cancer. Workers exposed to arylamines in the dye, paint, rubber, and leather industries are at increased risk.
■Analgesics: The abuse of analgesics, particularly phenacetin, is associated with an increased risk of urothelial cancers, especially in the renal pelvis.
■Treatment-related risks: Prior treatment with pelvic radiation and cyclophosphamide increases the risk of urothelial cancers.
■Chronic infections or inflammation: In endemic areas, chronic infection with Schistosoma hematobium predisposes patients to develop squamous cell cancer (SCC) of the bladder as a result of squamous metaplasia. Individuals with an ongoing source of inflammation (i.e., a spinal cord injury patient with an indwelling catheter) have a higher incidence of bladder cancer, especially SCC, than the general population. Progressive inflammation of the renal parenchyma also occurs in patients with Balkan nephropathy, predisposing patients to low-grade cancers of the upper urinary tracts.
■Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome, an autosomal dominant germline mutation in mismatch repair genes, predominantly MSH2 rather than in MSH1, increases the lifetime risk of urothelial carcinoma of the ureter and renal pelvis. Individuals with HNPCC develop upper urinary tract tumors at a younger age with an almost equal gender ratio compared to the general population.
■Thiazolidinediones such as pioglitazone and rosiglitazone indicated as second-line treatment of type 2 diabetes mellitus have been associated with an increase risk in bladder cancer. In June 2011, the U.S. Food and Drug Administration (FDA) warned that use of pioglitazone (Actos) for more than 1 year may be associated with an increased risk of bladder cancer.
■Arsenic-contaminated drinking water: Epidemiologic studies provide solid evidence in favor of the carcinogenic risk of ingested arsenic and its association with bladder cancer.
■Aristolochic acid, which may be found in Chinese herbal remedies such as Fangchi, has been associated with urothelial carcinoma particularly upper tract tumors. Individuals who develop aristolochic acid-associated tumors tend to be younger and female.
PATHOLOGY
■The majority of urothelial carcinoma tumors originate in the bladder. Upper tract urothelial carcinoma tumors, including renal pelvis, ureter, and urethra, are less common and account for 5% to10% of all urothelial carcinomas.
■Urothelial carcinoma also known as transitional cell carcinoma (TCC) accounts for 90% to 95% of all bladder tumors in the United States. Other bladder cancer histologies include 5% SCC, 1 to 2% adenocarcinomas, and almost 1% small cell tumors. Urothelial tumors often have a mixture of divergent histologies that include urothelial carcinoma and squamous, sarcomatoid, adenocarcinoma, and/or nested micropapillary subtypes.
■Carcinomas in situ (CIS) are flat tumors that usually present as diffuse urothelial involvement in patients with non–muscle-invasive bladder tumors. CIS increases the risk of subsequent invasive disease and recurrence, whether it occurs alone or in association with non–muscle-invasive bladder tumors.
■Patients with upper-tract urothelial tumors have a 20% to 40% incidence of synchronous or metachronous bladder cancer. Patients with bladder cancer have about a 1% to 4% incidence of synchronous or metachronous upper-tract tumor.
CLINICAL FEATURES
■Painless gross or microscopic hematuria occurs in about 85% of patients, and symptoms of bladder irritability are seen in 20% of patients.
■Patients with invasive disease may present with flank pain due to ureteral obstruction.
■Constitutional symptoms such as weight loss, abdominal pain, or bone pain may be present in patients with advanced disease.
SCREENING
Hematuria is the most commonly presenting symptom of patients with bladder cancer. Studies evaluating the role of screening for bladder cancer have examined the utility of conventional Hemastix® testing. However, because hematuria per se is nonspecific, patients who test positive for hematuria need to undergo further tests to determine its etiology. Other noninvasive screening methods have been used, such as urine cytology or urine-based markers. Markers such as nuclear matrix protein 22, bladder tumor antigen, cytokeratins, and many others have widely variable sensitivity and specificity. Therefore, definitive diagnosis can be established only by cystoscopy and biopsy.
DIAGNOSIS AND STAGING WORKUP
■Diagnostic workup of a patient with suspected bladder cancer should begin with an office cystoscopy and urine cytology.
■If a bladder mass is detected, then the patient should undergo a transurethral resection of the bladder tumor (TURBT) for full primary tumor staging. The bladder tumor resection should include muscle in the specimen to fully assess the depth of tumor invasion. The TURBT is performed with an examination under anesthesia (EUA).
■The EUA is an important part of clinical staging, allowing for the detection of locally advanced bladder cancer by assessing for invasion into adjacent organs, extravesical extension, and abdominal or pelvic sidewall extension.
■The upper tracts should also be evaluated with computerized tomography (CT) urography, ureteroscopy, retrograde pyelogram, intravenous pyelography (IVP), or MR urogram. In patients with a positive cytology and a normal cystoscopy, it is especially important to fully investigate the upper tracts. When CIS is detected, multiple random biopsies may be performed to assess the extent of involvement.
■In patients with high-grade and/or invasive tumors radiologic assessment should be performed with a CT of the chest abdomen and pelvis or MR of the abdomen and pelvis and CT of the chest to assess for local lymph node involvement, upper tract disease, and distant metastases.
■The value of FDG/PET CT for initial staging is still under investigation but appears to be a good adjunct (not a substitute) to anatomical imaging with a high-resolution CT or MR.
■A 99mTc bone scan is recommended for patients with elevated blood alkaline phosphatase level or bone pain.
Staging and Tumor Grading
■The staging of bladder cancer (Table 15.1) is the most important independent prognostic variable for progression and overall survival (OS).
■Bladder cancers are classified as non–muscle invasive, muscle invasive, and metastatic (Fig. 15.1).
■Non–muscle-invasive bladder cancers are tumors that involve only the mucosa (Ta) or submucosa (T1) and flat CIS (Tis) and account for 70% of bladder cancers. Of the non–muscle-invasive bladder cancers, about 60% are Ta tumors, 30% are T1, and 10% are CIS. Most non–muscle-invasive bladder cancers recur within 6 to 12 months with the same stage, but 10% to 15% of patients may develop invasive or metastatic disease. Low-grade (grade 1 or 2, solitary) and lower stage (Ta) tumors have lower recurrence and progression rates than high-risk disease (T1, CIS, high grade [grade 3] or multifocal).
■Muscle-invasive bladder cancers are tumors that invade the muscularis propria (T2), perivesical tissues (T3), or adjacent structures (T4a). Patients with muscle-invasive disease have a 50% likelihood of occult distant metastases at the time of diagnosis.
■Muscle-invasive tumors that invade the abdominal or pelvic sidewall and are fixed or nonmobile during an EUA are staged as T4b tumors and are categorized as unresectable metastatic disease. Patients with node-positive disease have stage IV bladder cancer (see Fig. 15.1).
■In metastatic disease, the usual sites of metastases are pelvic lymph nodes, liver, lung, bone, adrenal glands, and intestine.
Tumor grade is a key prognostic factor in non–muscle-invasive tumors with regard to the potential risk of recurrence and progression. The 1973 World Health Organization (WHO) grading classification uses the designation for papilloma and grade 1, 2, 3 TCC. A revised grading classification was published in 2004 by WHO which added a new category for a tumor with particularly good prognosis; papillary urothelial neoplasm of low malignant potential. The designations were also changed from grade 1, 2, and 3 TCC to low-grade and high-grade urothelial carcinoma. Grade 2 lesions are now classified as either low or high-grade tumors. The 2004 WHO classification is potentially enhancing the prognostic significance of the pathologic grading categorizations of non–muscle-invasive urothelial tumors.
FIGURE 15.1 Treatment of bladder cancer by stage: The management of bladder cancer differs significantly depending on stage. This algorithm depicts the treatment of non–muscle-invasive, muscle-invasive and metastatic bladder cancer. *T4b, if tumor responds to systemic chemotherapy, consolidation with a radical cystectomy may be considered.
PROGNOSIS
■The major prognostic factors are tumor stage at the time of diagnosis and degree of tumor differentiation.
■Five-year survival rates for patients with non–muscle-invasive, muscle-invasive, and metastatic bladder cancer are 95%, 50%, and 6%, respectively. Median OS for non–muscle-invasive bladder cancer is 10 years, with a natural history characterized by recurrence of non–muscle-invasive tumor or progression to muscle-invasive disease. Non–muscle-invasive tumors recur in 60% to 70% of cases; about one-third of these progress to a higher stage or grade. Significant variability in OS occurs in patients with metastatic urothelial cancer undergoing first-line treatment with chemotherapy. In order to better predict OS in these patients, Memorial Sloan-Kettering Cancer Center (MSKCC) developed a prognostic model using two pretreatment risk factors: Karnorfsky performance status (KPS) less than 80% or the presence of visceral metastases (liver, lung, or bone). Based on the MSKCC prognostic risk group model, patients with no risk factors had a median survival of 33 months; 1 risk factor, 13.4 months; and 2 risk factors, 9.3 months (P = 0.0001). There is now a new model modified by MSKCC to include four pretreatment variable including visceral metastases, performance status, albumin, and hemoglobin. This new four-variable prognostic model for patients with metastatic urothelial carcinoma has a statistically significant superiority for predicting OS in patients with metastatic disease than the former two-variable model. The prognostic model can predict the survival probabilities at 1-, 2-, and 5-year and median OS in patients with metastatic urothelial carcinoma.
TREATMENT
Figure 15.1 shows an algorithm for treatment of bladder cancer.
Non–Muscle-Invasive Bladder Cancer
■TURBT remains the cornerstone of treatment for non–muscle-invasive disease, i.e., Ta, T1, and Tis bladder cancers. A second TURBT may be performed for high-grade tumors. In addition to observation after TURBT, intravesical therapy may be used. Close follow-up is recommended for high-risk tumors (high-grade Ta, CIS, and high-grade T1) with urine cytology and cystoscopy every 3 to 6 months for the first 2 years and longer subsequent follow-up intervals after 2 years as appropriate.
■Intravesical therapy is primarily used as an adjunct or prophylaxis after TURBT to lower the incidence of disease recurrence and/or progression. Intravesical chemotherapy is used for low-risk disease (low-grade Ta and T1) and intravesical bacillus Calmette-Guerin (BCG) therapy is recommended for high-risk disease (high-grade Ta, CIS, and high-grade T1). Intravesical chemotherapy: Chemotherapeutic agents used for intravesical instillation include thiotepa, doxorubicin, epirubicin, and mitomycin C. Data suggest that currently available intravesical chemotherapeutic agents are equally effective but differ in toxicity. Although no standardized dosing or scheduling has been established as the optimum delivery for intravesical chemotherapy, a meta-analysis showed one dose of cytotoxic chemotherapy reduced the risk of recurrence by 39%. Patients with low-grade solitary papillary tumors particularly benefited. Thus, in addition to observation after TURBT, an option for a low-grade, clinical stage Ta lesion would be administration of a single dose of intravesical chemotherapy within 24 hours of TURBT. Mitomycin C is the chemotherapy most often used. Immunotherapy with BCG has shown statistically significant clinical benefits, including induction of complete response (CR) in CIS (70% to 75%) and reduction of rates of recurrence in high-grade Ta of T1 (20% to 57%), but has shown no consistent reduction in tumor progression. Maintenance BCG has been shown to reduce recurrence, but optimal dose scheduling and duration have not been determined. A second induction of BCG therapy may be given, at 3-month follow-up, to recurrent/persistent tumors that responded to initial intravesical therapy. No more than two consecutive induction courses should be given. If disease recurs after two consecutive BCG inductions, then cystectomy is advised. Intravesical valrubicin is FDA approved for BCG-refractory patients who refuse or are intolerant of cystectomy. Other agents used in this population include gemcitabine and cotreatment with BCG and interferon α-2b.
■Early radical cystectomy indications include BCG-refractory CIS or high-grade lesions that recur after BCG immunotherapy. High-grade T1 and CIS lesions have a propensity to progress and even metastasize. Nonsurgical candidates may pursue a clinical trial with alternative therapies including chemoradiation.
Muscle-Invasive Bladder Cancer
■Radical cystectomy with bilateral pelvic lymph node dissection and distal ureterectomy is the standard therapy for muscle-invasive bladder cancer. In men, the surgery involves removal of the prostate gland, seminal vesicles, and proximal urethra. In women, it involves removal of the urethra, uterus, fallopian tubes, anterior vaginal wall and surrounding fascia.
■Trimodality therapy with chemotherapy, radiotherapy, and TURBT: Definitive chemoradiation is an alternative to radical cystectomy with the goal of bladder preservation. The two most common approaches include protocols developed at Mass General Hospital (MGH), the University of Paris, and the University of Erlangen. The MGH and University of Paris protocol patients undergo complete TURBT followed by an induction dose of chemoradiation therapy; the patients are then assessed for response. Only patients who achieve a CR then undergo consolidative chemoradiotherapy for bladder preservation, whereas patients who do not achieve a CR are referred for radical cystectomy with curative intent. In the University of Erlangen protocol, patients receive upfront full-dose chemoradiotherapy and then are evaluated for therapeutic response; patients who do not achieve a CR then undergo radical cystectomy. Cisplatin is the most common radiosensitizer used in trimodality therapy; however, cisplatin is not ideal, since many bladder cancer patients who are referred for radiotherapy have impaired renal function or poor performance status. The combination of fluorouracil and mitomycin C is good alternative for patients who are not cisplatin candidates. Patients with multifocal disease, CIS, or hydronephrosis are not ideal candidates for definitive treatments with trimodality therapy. Combined chemotherapy with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, without significant increase in adverse events.
■Neoadjuvant cisplatin-based chemotherapy prior to definitive therapy improves survival in bladder cancer patients with T2–T4a disease. The mature results of the Medical Research Council (MRC) and European Organization for the Treatment and Cure of Cancer (EORTC) trial of neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) prior to definitive cystectomy or radiotherapy showed an absolute survival benefit of 6% and a relative reduction in the risk of death resulting from bladder cancer of 16% at 10 years in 976 randomized patients with muscle-invasive bladder cancer. A similar survival benefit was seen in a U.S. Intergroup trial (SWOG-8710) of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) randomized study. A meta-analysis of over 3,000 bladder cancer patients with muscle-invasive bladder cancer who received cisplatin-based neoadjuvant chemotherapy also showed a survival benefit of 6% and a 14% risk reduction in mortality at 5 years Bladder cancer patients that are cisplatin eligible should receive neoadjuvant chemotherapy prior to definitive therapy. In the United States, gemcitabine and cisplatin (GC) are frequently used in the neoadjuvant setting instead of MVAC or CMV. GC is equivalent to MVAC in the metastatic setting but has not been studied in a randomized trial in the neoadjuvant setting. Peri-operative therapies for cisplatin-ineligible patients are still under investigation. There are no data supporting the administration of noncisplatin-based neoadjuvant chemotherapy such as carboplatin combinations.
■Adjuvant chemotherapy data for cisplatin-based chemotherapy are less compelling, and this should not be used as a replacement for neoadjuvant chemotherapy. However, there are patients who benefit from cisplatin-based adjuvant chemotherapy, including patients who did not received neoadjuvant chemotherapy and have extensive disease found on radical cystectomy. Unfortunately, patients with bladder cancer are usually elderly and tend to have multiple comorbidities; therefore, delivering adjuvant chemotherapy to these patients after a radical cystectomy can be challenging.
Metastatic Bladder Cancer
First-Line Therapy (Tables 15.2 and 15.3)
■First-line therapy: MVAC, dose-dense MVAC (ddMVAC), and GC chemotherapy are standard of care chemotherapy regimens for metastatic urothelial carcinoma. MVAC is one of the most active chemotherapy regimens for the treatment of metastatic bladder cancer, with response rates between 40% and 72%. However, toxicities associated with this regimen limit its widespread use.
■GC have been shown to be equivalent to MVAC in OS, time to treatment failure, and response rates, but less toxic than MVAC.
■A randomized study in metastatic disease of standard MVAC versus ddMVAC showed that by eliminating days 15 and 22 of methotrexate and vinblastine the regimen could be completed faster, with less toxicity and better outcome.
■A randomized controlled study of ddMVAC versus ddGC showed that both regimens were comparable in terms of OS and progression-free survival, with a better toxicity profile in the ddGC group. However, this study halted randomization early due to poor accrual.
■Triplet chemotherapy combination regimens such as paclitaxel, cisplatin, and gemcitabine(PCG) may have increased response, but their impact on survival is unclear (see Table 15.2). When compared to standard GC, the PCG group had more febrile neutropenia (13.2% vs. 4.3%; P < 0.001). There are no data showing that carboplatin can be efficaciously substituted for cisplatin. Before it closed prematurely due to poor accrual, an ECOG phase 3 study comparing MVAC with carboplatin and paclitaxel demonstrated a nonstatistically significant difference in median OS of 15.4 months for the MVAC arm versus 13.8 months for the carboplatin–paclitaxel arm (P = 0.65), with toxicity profiles favoring the carboplatin–paclitaxel arm. Therefore, carboplatin should be substituted for cisplatin only in patients deemed unfit for cisplatin.
Cisplatin Ineligible First Line
■Patients may be considered “unfit” for cisplatin if they have any one of the following: poor performance status, renal insufficiency, hearing loss, neuropathy, or class III heart failure.
■In patients unfit for cisplatin, a phase 2/3 randomized study examined gemcitabine and carboplatin versus M-CAVI (methotrexate, carboplatin, and vinblastine). The median OS was 9.3 months in the gemcitabine and carboplatin group versus 8.1 months in the M-CAVI group (P = 0.64). Severe toxicity was observed in 9.3% of gemcitabine and carboplatin arm versus 21.2% of the M-CAVI. These results demonstrated that there was no difference between these two carboplatin-based regimens related to survival outcome; however, there was more severe toxicity associated with the M-CAVI regimen.
Second-Line Therapy
■In the United States there is no FDA-approved therapy for bladder cancer patients after they progress from either cisplatin- or carboplatin-based first-line chemotherapy.
■In Europe, vinflunine is approved as second-line treatment in patients with metastatic bladder cancer based on a randomized phase 3 study of vinflunine plus best supportive care (BSC) versus BSC alone. In the intent-to-treat population, OS was not statistically significant (P = 0.287); however, multivariate cox analysis adjusted for prognostic factors did reveal a statistically significant difference in vinflunine plus BSC versus BSC alone. The median OS for vinflunine plus BSC was 6.9 months versus median OS for BSC alone at 4.3 months (P = 0.040).
■Response rates to chemotherapy in the second-line setting are low, ranging from 5% to 20%. Commonly used agents include single-agent taxanes or pemetrexed.
28.von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol.2000;18(17):3068-3077.
REVIEW QUESTIONS
1.A 73-year-old woman presents with gross hematuria. Urine cytology is positive for malignant cells and CT is negative except for thickening of the bladder wall. The patient undergoes an EUA and bimanual assessment reveals no palpable masses but cystoscopy shows a 3 cm tumor over the dome of the bladder wall. The biopsy of this lesion shows high-grade muscle-invasive urothelial carcinoma. Which of the following is the most appropriate surgery?
A.Partial cystectomy
B.Partial cystectomy and sentinel lymph node biopsy
C.Radical cystectomy and sentinel lymph node biopsy
D.Radical cystectomy and pelvic lymph node dissection, distal ureterectomy, and removal of the urethra, uterus, fallopian tubes, anterior vaginal wall, and surrounding fascia
2.A 70-year-old man is diagnosed with advanced bladder cancer with liver and bone involvement. He works as a construction worker and believes to have been exposed to asbestos in the past. He has a history of previous alcohol abuse, and a 50-pack-year history of smoking. His family history is significant for a brother who developed a germ cell tumor at the age of 30 years. Which of the following risk factors has been shown in clinical studies to have the highest association with the development of bladder cancer?
A.Asbestos exposure
B.Alcohol abuse
C.Brother with a germ cell tumor
D.Smoking history
3.A 66-year-old man undergoes a cystoscopy which reveals a 3 cm papillary tumor in the left lateral wall of the bladder as well as diffuse erythema of the remainder of the bladder wall. An EUA demonstrates a mobile bladder. Evaluation of the biopsy of the papillary lesion reveals high-grade papillary carcinoma, with no invasion. Biopsy of the erythematous areas reveals diffuse carcinoma in situ. Muscle is present in the biopsy specimen. Which of the following is the most appropriate therapy for this patient?
A.Intravesical BCG therapy
B.Cystectomy
C.Gemcitabine and Cisplatin chemotherapy
D.Intravesical gemcitabine therapy
4.A 72-year-old male smoker presents with intermittent painless gross hematuria and urinary frequency. Urine analysis is normal except for moderate red blood cells and trace white blood cells. Urine culture is negative. A course of antibiotics did not alleviate his symptoms. Complete blood count, electrolytes, and creatinine are normal. Prostate-specific antigen is 0.9. Which of the following would be the next appropriate diagnostic test?
A.Urine cytology and serum CEA
B.18-Fluorodeoxyglucose (FDG)-positron emission tomography (PET)
C.CT scan of the chest, abdomen, and pelvis
D.Urine cytology and cystoscopy
5.A 68-year-old man presents with gross hematuria. Urine cytology is positive for malignant cells. A cystoscopy reveals a 4 cm ulcerating bladder tumor. TURBT shows high-grade invasive urothelial carcinoma with muscle involvement. A CT scan demonstrates no masses or lymph nodes. He has renal impairment with a calculated creatinine clearance (CrCl) of 39 mg/dL. Which of the following treatments should be recommended?
A.Neoadjuvant chemotherapy with a non–cisplatin-containing regimens followed by radical cystectomy and pelvic lymph node dissection
B.Radical cystectomy and pelvic lymph node dissection
C.Radical cystectomy and pelvic lymph node dissection followed by adjuvant chemotherapy with a non–cisplatin-based regimen
D.Intravesical BCG therapy
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