Bladder Cancer
Summary of Key Points
Incidence
• Worldwide, bladder cancer is diagnosed in approximately 380,300 cases each year and causes 150,200 deaths. In the United States, it is the sixth most common cancer, with an estimated 73,510 diagnoses and 13,750 deaths in 2012.
• Median age at diagnosis is 73 to 74 years. Many patients have comorbid illnesses such as cardiovascular disease at diagnosis.
• Cigarette smoking is the most significant risk factor, accounting for approximately 50% of bladder cancers in the United States. Occupational chemical exposure to polycyclic aromatic hydrocarbons and aromatic amines represents the next most important risk factor.
Staging Evaluation
• There is no clear role for screening.
• The primary manifesting symptom is painless gross hematuria. All patients with unexplained gross hematuria require evaluation.
• Cystoscopy with transurethral resection and urine cytology are the mainstay of diagnosis. Photodetection during cystoscopy is increasingly used to improve sensitivity of detecting bladder tumors.
• Upper tract evaluation is necessary to detect additional urothelial tumors and obstruction.
• Patients with muscle-invasive bladder cancer (MIBC) require metastatic workup.
Primary Therapy
• Transurethral resection of bladder tumor (TURBT) is the initial procedure and used to determine the clinical stage that drives subsequent treatment approaches.
• For patients with noninvasive bladder cancer (Ta, Tis, or T1), a complete TURBT may be sufficient. The addition of intravesical therapy reduces the risks of recurrence and progression to muscle-invasive cancer.
• Bacillus Calmette-Guerin (BCG) is the most effective agent for intravesical therapy in patients with high-grade noninvasive disease. An induction course of 6-weekly treatments, followed by maintenance therapy every 6 months for 2 to 3 years, may be used.
• For patients with MIBC, radical cystectomy with urinary diversion is the most commonly used treatment approach in the United States. However, there is significant undertreatment of elderly patients with MIBC likely because of concerns about tolerability of cystectomy.
• Trimodality bladder preservation therapy (TURBT followed by concurrent chemoradiation) is a well-tolerated and effective alternative for patients with MIBC, including elderly patients. Overall, 75% to 80% of patients maintain their native bladders long-term.
• Effective radiosensitizing chemotherapy agents include cisplatin-based regimens or 5-fluorouracil (5-FU) with mitomycin C.
Neoadjuvant and Adjuvant Therapy
• Despite aggressive local treatment, up to 50% of MIBC patients eventually develop local or distant recurrences.
• Neoadjuvant cisplatin-based chemotherapy prior to cystectomy provides a 5% to 10% absolute benefit in overall survival over cystectomy alone.
• Data on the potential benefit of adjuvant chemotherapy are conflicting, and treatment decisions should be individualized.
• Patients with pathological T3–T4 cancers and those with positive surgical margins are especially likely to develop local recurrences after cystectomy. Adjuvant radiation therapy may be considered for these patients.
Advanced Disease
• Cisplatin-based combination therapy is the standard treatment for patients with advanced bladder cancer. Gemcitabine/cisplatin (GC) or methotrexate/vinblastine/Adriamycin/cisplatin (MVAC) have similar efficacy, but the latter regimen is more toxic.
• Short-course radiation therapy can achieve a significant palliative benefit.
1. A 65-year-old man, previous 40-pack-year smoker who quit 5 years ago, developed painless gross hematuria and is diagnosed with bladder cancer. He has no other significant past medical history. Initial TURBT demonstrated high-grade urothelial carcinoma with muscularis propria invasion and carcinoma in situ. A CT scan demonstrates multiple bladder masses and mild right-sided hydronephrosis and no lymphadenopathy. A right ureteral stent is placed and his estimated glomerular filtration rate is 80 mL/min. What is the most appropriate treatment plan?
2. A 70-year-old man with no significant past medical history and newly diagnosed metastatic urothelial cancer is evaluated for treatment. His initial CT scan demonstrates enlarged pelvic, retroperitoneal, and mediastinal lymph nodes, multiple lung metastases, and a 3-cm bladder mass. A bone scan shows no evidence of osseous metastatic disease. He complains of a mild and intermittent dry cough, but is otherwise active. Routine blood work including complete blood count and comprehensive metabolic profile are within normal limits. His estimated glomerular filtration rate is 75 mL/min. Which of the following is the most appropriate treatment plan?
3. For patients with nonmetastatic bladder cancer, what is the most important risk factor for cancer progression?
4. A healthy 73-year-old woman presents with painless gross hematuria, and subsequent TURBT reveals high grade T1 disease. Muscle was present in the specimen and uninvolved. A CT urogram is negative for metastatic disease. What is the most appropriate next step?
A 3 weeks of BCG, followed by surveillance local cystoscopy
5. A 78-year-old patient with clinical T2 urothelial carcinoma, negative staging scans for nodal or distant metastasis, has chosen to pursue radiation-based bladder preservation therapy. He is not eligible for concurrent cisplatin because of poor renal function. Which of the following treatments is based on the strongest available evidence?
1. Answer: D. This patient has newly diagnosed muscle-invasive bladder cancer. Two large randomized trials and two meta-analyses have demonstrated a survival benefit for the use of neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy versus radical cystectomy alone in patients with muscle-invasive bladder cancer. Bladder-preservation strategies may be considered for cystectomy-eligible patients with unifocal tumors without significant carcinoma in situ or hydronephrosis, or in patients who are not candidates for radical cystectomy. In this patient with no significant medical history and adequate renal function, cisplatin-based neoadjuvant chemotherapy and radical cystectomy represents the most appropriate treatment plan.
2. Answer: A. The patient has metastatic urothelial cancer involving lymph nodes and lung. In metastatic urothelial cancer, visceral involvement and poor performance status are risk factors for shortened survival. Cisplatin-based chemotherapy is associated with a survival benefit in patients with metastatic urothelial cancer. The regimen of methotrexate, vinblastine, Adriamycin, and cisplatin (M-VAC) demonstrated a survival benefit in patients with metastatic urothelial cancer, and a subsequent randomized phase III study demonstrated similar outcomes including survival with the regimen of gemcitabine and cisplatin (GC), and GC was associated with better tolerability. Gemcitabine and carboplatin is a standard option in metastatic urothelial cancer patients who are not candidates for cisplatin-based therapy. Although taxanes have demonstrated activity in patients with metastatic urothelial cancer, single-agent paclitaxel is not associated with a survival benefit and would not be recommended in the first-line setting. Radical cystectomy is indicated in patients with localized disease.
3. Answer: B. The most important risk factor for bladder cancer progression is tumor grade. The 2004 WHO classification has replaced the older system (grades 1, 2, and 3) with “low grade” and “high grade” distinctions, in which the latter represents higher rates of progression. Although PUNLMP and low-grade papillary carcinoma demonstrate a low risk of progression (0% to 12%), high-grade papillary carcinoma will progress in up to 40% of patients, and may be even higher with micropapillary and nested variants.
4. Answer: C. Approximately 30% of patients with high-grade T1 disease on the first resection are found to have T2 disease on re-resection: 15% if muscle was present in the original specimen, but up to 40% if no muscle was present. Because of these high rates of upstaging, AUA guideline recommendations include a repeat TURBT for all patients with apparent T1 disease, even if muscle is present and uninvolved in the initial resection. Answer A represents maintenance BCG, which would not be appropriate for initial therapy of high-grade T1 disease. Answer B represents induction BCG, which would be appropriate if the patient is not upstaged after repeat TURBT. However, repeat TURBT is required before proceeding with induction therapy. Neoadjuvant chemotherapy (answer D) is not appropriate in the setting of high-grade T1 disease with no evidence of metastatic disease.
5. Answer: D. In the BC2001 trial, which randomized patients with muscle-invasive bladder cancer to radiation alone versus radiation with concurrent 5-FU and mitomycin C, concurrent chemoradiation improved local-regional disease-free survival (primary end point, P = 0.03), and also appeared to reduce the need for cystectomy (2-year rates 11.4% vs. 16.8% for radiation alone, P = 0.07) and improve overall survival (5-year survival 48% vs. 35% for radiation alone, P = 0.16). This trial provides level 1 evidence for the use of concurrent 5-FU and mitomycin C with radiation therapy. Gemcitabine has been studied in phase I and II studies. Carboplatin does not have proven efficacy in the setting of trimodality bladder preservation therapy. In a large series from Erlangen, patients who received radiation plus carboplatin had similar rates of complete response and overall survival as those who received radiation alone, which were significantly worse compared to patients who received cisplatin-based concurrent chemotherapy.
