The Washington Manual of Oncology, 3 Ed.

Bladder Cancer

Daniel Morgensztern • Bruce Roth

 I. PRESENTATION

11. Subjective. The most common presenting symptom of bladder cancer is hematuria, which is usually gross, intermittent, and total (present during the entire urine stream). Virtually all patients with bladder cancer have at least microscopic hematuria. Since the hematuria is usually intermittent, further evaluation after the first episode should be pursued even if the repeated subsequent urinalyses are negative. In a prospective study evaluating 1,930 patients with either microscopic or gross hematuria, 230 patients (11.9%) had bladder cancer, including 47 (4.8%) with microscopic and 183 (19.3%) with gross hematuria (J Urol 2000;163:524). Irritative lower urinary tract symptoms including frequency, urgency, and dysuria may indicate the presence of microscopic hematuria, and should prompt additional workup. Obstructive lower urinary tract symptoms such as incomplete emptying and decreased force of the urinary stream may occur in patients with tumor located at the bladder neck or prostatic urethra. Symptoms related to distant metastases are uncommon at presentation.
12. Objective. Most patients have no disease-specific findings in the physical examination. With more advanced disease, a pelvic mass may become palpable.
13. WORKUP AND STAGING
14. Workup. Evaluation of patients with hematuria includes urinalysis, cystoscopy, and imaging of the upper urinary tracts. Hematuria is considered to be clinically significant when there are more than three red blood cells (RBCs) per high power field (HPF). The gold standard for the diagnosis of bladder cancer is cystoscopy with transurethral resection of the bladder tumor (TURBT). Urine cytology, which has a low sensitivity but a very high specificity, should also be performed to increase the detection of upper urinary malignancies. Imaging studies help define the extent of the tumor and the presence of additional synchronous lesions. The most commonly used imaging test is CT urography, although intravenous pyelogram (IVP) may also be used in selected cases.
15. Pathology and staging
16. Pathology. Urothelial or transitional cell carcinomas are the most common histologic subtypes of bladder cancer, representing more than 90% of cases in the Western countries. The most common non-urothelial malignancies are squamous cell carcinomas, adenocarcinoma, and small cell carcinomas. Pathologic features such as identification of the “nested” variant of urothelial carcinoma, as well as the presence of sarcomatoid or plasmacytoid elements predicts for a more aggressive clinical course.
17. Staging. Bladder cancer may be broadly subdivided into three categories including non-muscle–invasive, muscle-invasive, and metastatic tumors. Noninvasive tumors belong to stages 0 to I and are divided into Ta (noninvasive papillary carcinoma), T1 (invasion of the subepithelial connective tissue), and Tis (carcinoma in situ). Stage II is defined as invasion of the muscularis propria, and stage III indicates the invasion of perivesical tissue, either microscopically or macroscopically as a vesical mass or invasion of adjacent organs. Invasion of the pelvic or abdominal wall indicates T4b, which is classified as stage IV. Involvement of regional or iliac lymph nodes and the presence of distant metastases also indicate stage IV. The prognosis and goals of therapy are distinct for each category, ranging from prevention of relapse in non-muscle–invasive tumors to palliation in those with metastatic disease.

 III. NON-MUSCLE–INVASIVE BLADDER CANCER. Approximately 75% of the bladder tumors are non-muscle–invasive. The treatment of choice for these tumors is TURBT with bimanual examination under anesthesia. The resection should sample the muscle to evaluate for invasion. Without additional therapy after a complete TURBT, more than half of the patients will have recurrence, with 10% of recurrences progressing to muscle-invasive disease. The most important factor for progression to muscle invasion is the tumor grade. Other risk factors for recurrence and progression include tumors larger than 3 cm, multifocal tumors, stage T1, and sessile lesions. Most patients with metastases have concurrent or prior diagnosis of muscle-invasive tumor, with the development of metastasis in patients without history of previous muscle invasion being rare. The use of immediate intravesical chemotherapy using mitomycin, thiotepa, or epirubicin decreases the risk of recurrence (J Urol 2004;171:2186). The International Bladder Cancer Group recommends immediate intravesical chemotherapy for patients with low risk disease (solitary and primary tumor, low grade Ta). The most commonly used drug in this setting is mitomycin. Patients with intermediate (multiple or recurrent low grade tumors) or high risk (T1, Tis, or grade 3) should be treated with Bacillus Calmette–Guerin (BCG) with six weekly instillations starting after bladder healing from surgery (J Urol 2011;186:2158). Maintenance BCG is usually offered to patients after the 6-week induction. BCG has been associated with decreased risk for both recurrence and progression. A large randomized trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) showed that there was no benefit from maintenance BCG for 3 years compared to 1 year in patients with intermediate risk. For patients with high risk, 3 years of BCG decreased the risk of recurrence but not progressions or deaths (Eur Urol 2013;63:462). BCG is contraindicated in patients with bleeding, urethral stricture, active tuberculosis, urinary tract infection, immunosuppression, and within 14 days from TURBT (Semin Oncol 2012;39:559). Patients that are at high risk for progression, including those with multiple recurrences and high-grade T1, should be considered for immediate cystectomy.

 IV. MUSCLE-INVASIVE DISEASE. The standard therapy for patients with muscle-invasive bladder cancer is radical cystectomy with removal of the bladder, adjacent organs, and pelvic lymph node dissection followed by urinary diversion through an ileal conduct or an internal urinary reservoir. The survival after radical cystectomy depends on the tumor extension and lymph node status. For patients who refuse cystectomy or who have comorbidities that prohibit a major surgical intervention, “bladder-sparing” approaches utilizing a combination of radiotherapy and chemotherapy have been studied and found to be effective (J Clin Oncol 1998:16;3576).

1. Neoadjuvant chemotherapy theoretically provides benefit via the treatment of occult metastatic disease and has been tested in multiple trials. The Southwest Oncology Group (SWOG) 8710 randomized 317 patients to muscle-invasive bladder cancer stages T2–T4a to radical cystectomy alone or preceded by three cycles of methotrexate 30 mg/m² on days 1, 15, and 22, vinblastine 3 mg/m² on days 2, 15, and 22, and doxorubicin 30 mg/m² plus cisplatin 70 mg/m² on day 2 (M-VAC) (N Engl J Med 2003;349:859). The median overall survival by intention-to-treat analysis was increased in the neoadjuvant M-VAC arm (77 vs. 46 months, p = 0.06). The BA06 30894 trial randomized 900 patients with muscle-invasive bladder cancer staged T2–T4a to three cycles of neoadjuvant cisplatin 100 mg/m² on day 2 and methotrexate 30 mg/m² plus vinblastine 3 mg/m² on days 1 and 8 (CMV) followed by definitive standard management according to enrolling site (radical cystectomy or radiation therapy) or local therapy alone (Lancet 1999;354:533). The 10-year overall survival increased from 30% in the control group to 36% in the neoadjuvant CMV (hazard ratio [HR] 0.84, p = 0.037). In a meta-analysis including 3,005 patients enrolled into 11 randomized trials comparing neoadjuvant chemotherapy to local therapy alone, the former was associated with an increase in the 5-year overall survival from 45% to 50% (HR 0.86, p = 0.02) (Lancet 2003;361:1927). Since the combination of cisplatin and gemcitabine (GC) has been associated with similar outcomes compared to M-VAC in patients with advanced disease, it is also commonly used in the neoadjuvant setting despite the lack of prospective data, particularly since retrospective analyses have shown similar rates of pathologic complete response and survival between the two regimens (Cancer 2008;113:2471; Urology 2012;79:384).
2. Adjuvant chemotherapy. Due to the lack of completed randomized studies with adequate sample sizes, there is no level I evidence of benefit with this approach, with conflicting results from the reported studies (Eur Urol2012;62:523). The ABC meta-analysis evaluated data from 491 patients in six trials, showing a 25% reduction in the risk of death with adjuvant chemotherapy, with most of the benefit observed in patients with pathological T3–T4 disease or lymph node involvement (Eur Urol 2005;48:189). More recently, updated data from an EORTC intergroup randomized phase III trial demonstrated that immediate postoperative chemotherapy in high risk individuals resulted in a 22% reduction in the risk of death, although this was non-statistically significant given the size of the trial (660 patients). Therefore, patients who did not undergo neoadjuvant chemotherapy should at least have a discussion regarding the use of adjuvant chemotherapy, particularly in patients with high risk features such as extravesical involvement or positive lymph nodes.
3. Radiation therapy. In many countries, external-beam radiation is considered standard therapy for muscle-invasive bladder cancer. In the BA06 30894 trial, the local therapy consisted of radiation, surgery, or both at the discretion of the treating physicians. Radiation was used in 50% of the patients, including 42% as the only modality for local therapy. Although the local therapies were not compared, there was no evidence for a preferential benefit from neoadjuvant chemotherapy in either group. Due to the high risk for local relapse in patients with pathological T3 or T4 disease, these patients may be considered for adjuvant radiotherapy. Since neoadjuvant radiation therapy does not improve survival compared to surgery alone, it is not indicated in this setting.
4. Bladder preservation options are alternatives to radical cystectomy in selected patients with stage T2 or T3a who are not fit for surgery or who are not interested in such an aggressive approach, which is associated with a significant morbidity. These patients may be treated with transurethral resection (TUR) alone, TUR followed by adjuvant chemotherapy, radiotherapy, or chemoradiotherapy. Another option is partial cystectomy, which allows the complete resection of the bladder tumor with wide surgical margins. In medically operable patients, trimodality therapy with maximal TUR followed by chemoradiotherapy appears to be associated with the best outcomes. The presence of persistent or recurrent muscle-invasive bladder cancer after any form of bladder preservation represents a formal indication for radical cystectomy (BJU Int 2013;112:13).
5. METASTATIC DISEASE. A number of single agents have been found to produce a significant number of partial remissions. Unfortunately, these remissions tend to be brief, in the range of a few months. These findings led investigators to pursue combinations of active single agents, and these efforts have led to a number of active combinations in the treatment of bladder cancer. The most active classes of drugs for bladder cancer are cisplatin, taxanes, and gemcitabine, which form the backbone for most of the chemotherapy regimens.

 The currently recommended regimens for patients with advanced bladder cancer and eligible for cisplatin therapy include GC and dose-dense M-VAC (DD-MVAC). A large clinical trial randomized 405 patients to GC (gemcitabine 1,000 mg/m² on days 1, 8, and 15 plus cisplatin 70 mg/m² on day 2) to standard dose M-VAC for a maximum of six cycles (J Clin Oncol 2000;18:3068). The study showed no significant differences in response rate (55% in both arms), time to progression (7.4 months in both arms), and median overall survival (13.8 months with GC and 14.8 months in MVAC). Since GC was associated with lower rate of toxicities, it became a more commonly used regimen than M-VAC. The EORTC 30924 randomized 263 patients with untreated unresectable or metastatic bladder cancer to standard M-VAC or DD-MVAC (methotrexate 30 mg/m² on day 1, vinblastine 3 mg/m² on day 2, doxorubicin 30 mg/m² on day 2, and cisplatin 70 mg/m² on day 2, with granulocyte colony stimulating factor on days 3 to 7, repeating every 15 days) (Eur J cancer 2006;42:50). DD-MVAC was associated with increased response rates (64% vs. 50%, p = 0.009), median progression-free survival (9.5 vs. 8.1 months, HR 0.73, p = 0.017), and 5-year overall survival (21.8% vs. 13.5%, p = 0.042). Several drugs have activity in patients with bladder cancer and may be used in the second-line setting, including taxanes, ifosfamide, pemetrexed, and gemcitabine, if not previously used.

 Patients that are not candidates for cisplatin may be treated with gemcitabine combinations, most commonly with either carboplatin or taxanes (Int J Urol 2014;21:630).

 Biological agents targeting epidermal growth factor receptor (EGFR), HER-2, and angiogenesis, either alone or in combination with chemotherapy have shown promising preliminary results but until data from randomized clinical trials become available to demonstrate their benefit, the standard of care for bladder cancer remains chemotherapy alone. Recent data has also suggested significant activity of agents that inhibit the programmed cell death (PD-1) pathway (J Clin Oncol 2014;32:325s) and a large number of clinical trials confirming preliminary results are currently underway.

 VI. FOLLOW-UP. Specific follow-up recommendations depend on the clinical presentation of disease. Patients with noninvasive bladder cancer should have a repeated cystoscopy and urine cytology at 3 months for the first year of follow-up. After that, those with low grade cTa may have increasing intervals between the cystoscopies, whereas patients with T1, Tis, or high grade tumors should have cystoscopy and urine cytology every 3 to 6 months for the first 2 years. Patients with high grade tumors should be considered for imaging of the upper urinary tract with IVP, CT urography, or MRI urogram every 1 to 2 years. Patients with muscle-invasive bladder cancer treated with either radical cystectomy or bladder preservation should have urine cytology, chemistry, and imaging of the chest, abdomen, and pelvis every 3 to 6 months for 2 years, with further evaluations as indicated. Patients with associated Tis in the bladder or prostatic urethra should have urethral wash cytology every 6 to 12 months (J Natl Compr Cancer Netw 2013;11:446).

 VII. BACKGROUND

2014. Epidemiology. Bladder cancer is relatively common, with approximately 75,000 cases diagnosed in the United States in 2014. The median age at diagnosis is 65 years, and this disease is uncommon in patients younger than 40. It is more common in men than in women (3:1) and in Caucasians. Superficial tumors account for 75% of disease at diagnosis, whereas muscle-invasive disease accounts for 20% to 25%.
2015. Risk factors. The most well-defined risk factor for bladder cancer in the United States is cigarette smoking, responsible for about 50% of cases. Other risk factors include exposure to occupational carcinogens such as polycyclic aromatic hydrocarbons (PAHs) and benzene, and occupational exposure accounts for another 25% of cases in the United States. Chronic cystitis from prolonged indwelling catheters or in spinal cord patients is associated with an increased risk for bladder cancer, with a higher percentage of squamous histology. Infection with Schistosoma haematobium, a parasite found mostly in Africa, Middle East, and India, increases the risk of bladder cancer, primarily associated with squamous histology. Iatrogenic bladder cancer may occur due to pelvic radiation therapy or prolonged exposure to cyclophosphamide.

SUGGESTED READINGS

Brausi M, Witjes JA, Lamm D, et al. A review of current guidelines and best practice recommendations for the management of nonmuscle invasive bladder cancer by the International Bladder Cancer Group. J Urol 2011;86:2158–2167.

Clark PE, Agarwal N, Biagioli MC, et al. Bladder cancer. J Natl Compr Canc Netw 2013;11:446–475.

Smith ZL, Christodouleas JP, Keefe SM, et al. Bladder preservation in the treatment of muscle-invasive bladder cancer (MIBC): a review of the literature and practical approach to therapy. BJU Int 2013;112:13–25.

Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 2000;163:524–527.

Grossman H, Natale R, Tangen C, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003;349:859–866.

Meeks JJ, Bellmunt J, Bochner BJH, et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2012;62:523–533.

Powles T. Inhibition of PD-L1 by MPDL3280A and clinical activity with metastatic urothelial bladder cancer. J Clin Oncol 2014;32:325s.

Shipley WU, Winter KA, Kaufman DS, et al. Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 98-03. J Clin Oncol 1998;16:3576–3583.

Sio TT, Ko J, Gudena VK, et al. Chemotherapeutic and targeted biological agents for metastatic bladder cancer: a comprehensive review. Int J Urol 2014;21:630–637.

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;17:3068–3077.