Bethesda Handbook of Clinical Oncology, 2nd Edition



Bladder Cancer

Manish Agrawal

William L. Dahut

Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland

Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland


In 2003, approximately 57,400 patients were estimated to have developed bladder cancer, and 12,500 patients were estimated to have died from it. Bladder cancer is a disease of the elderly; most people diagnosed with this disease are older than 60 years, and it is the second most prevalent cancer in men 60 years of age or older. The incidence of bladder cancer is more common in men than in women (3:1) and more common in whites than in blacks (2:1).


  • Cigarette smoking:The most common cause of bladder cancer is cigarette smoking; smokers have twice the risk of developing bladder cancer than do nonsmokers. There is a strong correlation between the amount and duration of cigarette smoking and bladder cancer.
  • Occupational exposures:Occupational exposures to chemical carcinogens are associated with an increased risk of bladder cancer. In particular, workers exposed to arylamines in the dye, paint, rubber, and leather industries are at an increased risk. Truck, taxi, and bus drivers along with hairdressers are other workers whose occupations have been recently implicated as risk factors.
  • Analgesics:The abuse of analgesics, in particular, phenacetin, is associated with an increased risk of urothelial cancers, with the greatest risk for the renal pelvis.
  • Treatment-related risks:Treatment-related risks include pelvic radiation (for cervical, ovarian, and prostate cancer) and treatment with cyclophosphamide.
  • Chronic infections:Chronic infection due to Schistosoma haematobium causes squamous metaplasia and increases the risk of squamous cell carcinoma (SCC) in endemic areas such as Egypt.
  • Others:Other less-established and more controversial risk factors include drinking water, artifical sweeteners, coffee consumption, and chronic cystitis.


Transitional Cell Carcinoma (TCC) accounts for 90% to 95% of all bladder tumors found in the United States. Five percent to 10% of bladder tumors are SCC, and 1% to 2% are adenocarcinomas. Carcinoma in situ (CIS) usually presents as diffuse urothelial involvement in patients with superficial bladder tumors. CIS increases the risk for subsequent invasive disease and recurrence regardless of whether it occurs alone or in association with superficial bladder tumors.



Painless gross or microscopic hematuria is seen in 85% of patients. Symptoms of bladder irritability are seen in 20% of patients. Patients with invasive disease may have flank pain because of ureteral obstruction, bladder mass, or lower extremity edema. Constitutional symptoms such as weight loss, abdominal pain, or bone pain may be present in patients with advanced disease.


  • The diagnostic workup of a patient with suspected bladder cancer includes intravenous pyelography, urinary cytologic studies, and cystoscopy with full evaluation of the bladder mucosa and urethra.
  • Computerized tomography (CT) scan of the abdomen and pelvis is performed to detect local extension and involvement of abdominal lymph nodes. A chest x-ray is used as an initial screening tool for detecting pulmonary metastases.
  • A bone scan is recommended for patients with an elevated alkaline phosphatase level or bone pain.


The staging of bladder cancer (Fig. 15.1 and Table 15.1) is the most important independent prognostic variable for progression and overall survival. Bladder cancers are divided into


superficial and invasive cancers. Superficial bladder cancers are tumors that involve only the mucosa (Ta) or submucosa (T1) and flat CIS (Tis) and account for 75% of bladder cancers. Most superfical bladder cancers recur within 6 to 12 months, with the same stage, but 10% to 15% of patients can develop invasive or metastatic disease.

TABLE 15.1. Tumor–node–metastasis (TNM) Staging of Bladder Cancer

Primary tumor (T)

   The suffix “m” should be added to the appropriate T category to indicate multiple lesions.

      The suffix “is” may be added to any T to indicate the presence of associated carcinoma in situ

   TX: Primary tumor cannot be assessed

   T0: No evidence of primary tumor

   Ta: Noninvasive papillary carcinoma

   Tis: Carcinoma in situ: “flat tumor”

   T1: Tumor invades subepithelial connective tissue

   T2: Tumor invades muscle

      T2a: Tumor invades superficial muscle (inner half)

      T2b: Tumor invades deep muscle (outer half)

   T3: Tumor invades perivesical tissue

      T3a: microscopically

      T3b: macroscopically (extravesical mass)

   T4: Tumor invades any of the following: prostate, uterus, vagina, pelvic wall, or abdominal wall

      T4a: Tumor invades the prostate, uterus, vagina

      T4b: Tumor invades the pelvic wall and abdominal wall

Regional lymph nodes (N)

   Regional lymph nodes are those within the true pelvis; all others are distant lymph nodes

   NX: Regional lymph nodes cannot be assessed

   N0: No regional lymph node metastasis

   N1: Metastasis in a single lymph node, ≤2 cm in greatest dimension

   N2: Metastasis in a single lymph node, >2 cm but = 5 cm in greatest dimension; or multiple lymph nodes, none >5 cm in greatest dimension

   N3: Metastasis in a single lymph node >5 cm in greatest dimension

Distant metastasis (M)

   MX: Distant metastasis cannot be assessed

   M0: No distant metastasis

   M1: Distant metastasis

Stage grouping

   Stage 0a: Ta N0 M0

   Stage 0is: Tis N0 M0

   Stage I: T1 N0 M0

   Stage II: T2a N0 M0 or T2b N0 M0

   Stage III: T3a N0 M0 or T3b N0 M0 or T4a N0 M0

   Stage IV: T4b N0 M0 or any T N1–N3 M0 or any T Any N M1


FIG. 15.1. Clinical staging of carcinoma of the bladder.

Invasive bladder cancers are tumors that invade the muscularis propria, perivesical tissues, or adjacent structures. Patients with muscle-invasive disease have a 50% likelihood of having occult distant metastases at the time of diagnosis. The usual sites of metastases are pelvic lymph nodes, liver, lung, bone, adrenal glands, and intestine.




  • The major prognostic factors are the tumor stage at the time of diagnosis and degree of differentiation of the tumor.
  • Five-year relative survival rates for patients with superficial, muscle-invasive, and metastatic bladder cancer are 95%, 50%, and 6%, respectively.
  • Old age, expression of p53, aneuploidy, tumor multifocality, and palpable mass are other adverse prognostic factors.


Carcinoma In Situ

Transurethral resection (TUR) followed by intravesical bacille Calmette-Guérin (BCG) therapy is the most common treatment for CIS of the bladder (Fig. 15.2). It produces complete response rate in 70% to 80% of patients and a 5-year disease-free survival in more than 75% of patients. Intravesical chemotherapeutic agents such as thiotepa, doxorubicin, gemcitabine, and mitomycin produce complete response rates in 30% to 50% of patients and a 5-year disease-free survival in 20% to 40% of patients.


FIG. 15.2. Treatment of bladder cancer. *Cytoscopy and urine cytology q3mo × 2 years, followed by q6mo × 2 years, and then yearly for life. †Computerized tomography scan q6mo, intravenous pyelogram or ultrasound q12mo, cytoscopy and urine cytology q3mo × 1 year and then q6mo, serum creatinine and liver function test, and vitamin B12 q3–6mo.

Superficial Bladder Cancer

  • The treatment of superficial bladder cancer has two goals: to eradicate existing disease and provide prophylaxis against tumor recurrence.
  • TUR is the primary therapy for superficial bladder cancer. Approximately 80% of these patients survive for 5 years if treated with TUR alone, but in 70% to 80% of these patients, tumor recurrence develops within 12 months.
  • Adjuvant intravesical therapy permits high local drug concentrations to be achieved within the bladder, potentially destroying the remaining cancer cells. In high-risk patients, the tumor recurrence rate is decreased to about 20% with adjuvant intravesical BCG therapy.

Muscle-invasive Bladder Cancer

  • Radical cystectomy with bilateral pelvic lymph node dissection is the standard therapy for muscle-invasive bladder cancer. In men, the surgery involves radical cystoprostatectomy, and a total urethrectomy is indicated if there is involvement of the prostatic urethra. In women, radical cystectomy involves wide excision of the bladder, urethra, uterus, adnexa, and anterior vaginal wall.
  • Recent studies have shown that bladder-sparing options, which include aggressive TUR in combination with radiotherapy and chemotherapy, can be considered in select patients with T2 or T3a disease without compromising survival; however, this approach remains investigational.
  • External beam radiotherapy with or without radiation-sensitizing agents such as cisplatin or 5-fluorouracil is an option for poor surgical candidates. Randomized trials have not shown any benefit for preoperative radiotherapy followed by radical cystectomy over radical cystectomy alone.
  • There is no accepted standard of care for postoperative chemotherapy in the treatment of muscle-invasive bladder cancer. Several randomized trials have shown conflicting results, with some showing a survival advantage with adjuvant chemotherapy and others reporting no benefit. The negative trials have been criticized for being insufficiently powered, for using suboptimal chemotherapy, and for premature closure. Randomized controlled trials are under way—European Organization for Research and Treatment of Cancer (EORTC), The Cancer and Leukemia Group B (CALGB), Eastern Cooperative Oncology Group (ECOG)—to address this question, and eligible patients should be encouraged to enter these






important trials. Outside the context of a clinical trial, physicians and patients must discuss and evaluate the decision for adjuvant chemotherapy depending on the clinical scenario.

  • Neadjuvant chemotherapy has been studied in numerous randomized clinical trials with conflicting results. The largest trial was of 975 patients conducted by the Medical Research Council and the EORTC. Patients were randomized to three cycles of neoajuvant CMV (cisplatin, methotrexate, and vinblastine) or to no chemotherapy, followed by management of the primary lesion with surgery or radiation or both. The 3-year survival benefit was 5.5% for the treatment arm but did not reach statistical significance because the trial was powered to detect a 10% increase in survival. A U.S. Intergroup trial (SWOG-8710) randomized 317 patients to neoajuvant M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) versus no chemotherapy and found an improvement in overall survival in the chemotherapy arm (77 months versus 46 months). Three other trials (Italian Bladder Tumor Study Group, Nordic-164, Nordic 2) did not find any benefit to neoadjuvant chemotherapy in their preliminary report. On the basis of the two large trials, there is an emerging opinion that in select patients, there may be a benefit to neoadjuvant chemotherapy. Eligible patients should be enrolled in clinical trials, and outside of clinical trials, each clinical situation should be evaluated individually.

Stage IV Bladder Cancer

  • Cisplatin, methotrexate, paclitaxel, docetaxel, and gemcitabine are the most active single agents in treatment of bladder cancer, with response rates of 30% to 45%.
  • Combination chemotherapy with the M-VAC regimen has been shown in randomized trials to be superior to single-agent cisplatin (1) and the three-drug regimen CISCA (cyclophosphamide, cisplatin, and doxorubicin) (2) (Tables 15.2 and 15.3). M-VAC has a response rate of 40% to 72%. The major drawback of using the M-VAC regimen is that it is associated with significant toxicity including neutropenia, sepsis, mucositis, and renal failure.
  • More recently, the combination of gemcitabine plus cisplatin was compared to M-VAC in a randomized trial of 405 patients with stage IV TCC bladder cancer. The response rate, time to treatment failure, and median survival were similar for both regimens. However, there was less toxicity with the cisplatin plus gemcitabine arm in comparison to the M-VAC arm.
  • Alternative treatment regimens incorporating docetaxel, gemcitabine, and paclitaxel as first-line agents are being actively studied and have shown response rates of 40% to 70%, with potentially less toxicity (Table 15.4) in phase II studies.

TABLE 15.2. Combination Chemotherapy Regimens in Advanced Urothelial Carcinoma


Treatment description

Cycle duration



AUC, graphically represented area under the plasma concentration versus time curve for carboplatin; GFR, glomerular filtration rate. In clinical application, urinary creatinine clearance during 24 h approximates the GFR; i.v., intravenously; PO, orally; s.c., subcutaneously; WBC, white blood cell.
Antineoplastic regimen included primary prophylaxis with antihistamines and corticosteroids against hypersensitivity reactions before taxoid (paclitaxel or docetaxel) administration.
Calvert formula: Total dose (mg) = [Target AUC (mg/mL/min)] × [GFR (mL/min) + 25].
Adapted from Calvert AH, Newell DR, Gumbrell LA, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989;7:1748–1756, with permission.


Cyclophosphamide, 650 mg/m2 i.v. d 1 (total dose/cycle, 650 mg/m2)
Doxorubicin, 50 mg/m2 i.v. d 2 (total dose/cycle, 50 mg/m2)
Cisplatin, 100 mg/m2 i.v. d 2 (total dose/cycle, 100 mg/m2)

21–28 d


6, 7


Methotrexate, 30 mg/m2 i.v. d 1 and 8 (total dose/cycle, 60 mg/m2)
Vinblastine, 4 mg/m2 i.v. d 1 and 8 (total dose/cycle, 8 mg/m2)
Cisplatin, 100 mg/m2 i.v. infusion over 4 h on d 2, ≥12 h, after methotrexate and vinblastine (total dose/cycle, 100 mg/m2)

21 d



Docetaxel + cisplatinaa

Docetaxel, 75 mg/m2 slow i.v. infusion over 1 h, d 1 (total dose/cycle, 75 mg/m2)
Cisplatin, 75 mg/m2 i.v. d 1 (total dose/cycle, 75 mg/m2)

21 d



Gemcitabine + cisplatin

Gemcitabine, 1,000 mg/m2i.v. d 1, 8, and 15 (total dose/cycle, 3,000 mg/m2)
Cisplatin, 75 mg/m2 i.v. d 1 (total dose/cycle, 75 mg/m2)

28 d




Ifosfamide, 1,500 mg/m2/d i.v. for d 1–3 (total dose/cycle, 4,500 mg/m2
Mesna, 300 mg/m2 i.v., 30 min before ifosfamide, and then 
Mesna, 300 mg/m2 i.v. 4 and 8 h after ifosfamide, 
Mesna, 600 mg/m2 PO 4 and 8 h after ifosfamide 
Paclitaxel, 200 mg/m2 i.v. infusion over 3 h, d 1 (total dose/cycle, 200 mg/m2
Cisplatin, 70 mg/m2 i.v. d 1 (total dose/cycle, 70 mg/m2)

28 d

Regimen includes primary hematopoietic growth factor support with filgrastim, 5 µg/kg or per d, s.c.




Methotrexate, 30 mg/m2 i.v. d 1, 15, and 22 (total dose/cycle, 90 mg/m2
Vinblastine, 3 mg/m2 i.v. d 2, 15, and 22 (total dose/cycle, 9 mg/m2
Doxorubicin, 30 mg/m2 i.v. d 2 (total dose/cycle, 30 mg/m2
Cisplatin, 70 mg/m2 i.v. d 2 (total dose/cycle, 70 mg/m2)

28 d

Withhold methotrexate and vinblastine on d 15 and 22 if WBC count is <2.5 × 103/µL and platelets <100 × 103/µL

4, 5


Paclitaxel + carboplatina

Paclitaxel, 200 mg/m2 i.v. infusion over 3 h, d 1 (total dose/cycle, 200 mg/m2
Carboplatin i.v. after paclitaxel; dosage is calculated by the Calvert formula to achieve a target AUC of 5 mg/mL/min (Calvert reference)b

21 d



TABLE 15.3. Randomized Trials in Patients with Advanced Urothelial Carcinoma

Randomized trial

Overall response rate

Median survival

M-VAC vs. cisplatin (1)

39% vs. 12%

12.5 mo vs. 8.2 mo

M-VAC vs. CISCA (2)

65% vs. 46%

48 wk vs. 36 wk

M-VAC vs. cisplatin (3) + gemcitabine

46% vs. 49%

13.8 mo vs. 14.8 mo

TABLE 15.4. Newer Agents in Untreated Advanced Urothelial Carcinoma Patients

Phase II trials

No. of evaluable patients

Overall response rate (%)

Docetaxel + cisplatin (4)



Gemcitabine + paclitaxel (5)



Ifosfamide + paclitaxel + cisplatin (6)



Paclitaxel + carboplatin (7)



Paclitaxel + cisplatin + Gemcitabine (8)






  1. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study [published erratum appears in J Clin Oncol1993;11:384]. J Clin Oncol 1992;10:1066–1073.
  2. Logothetis CJ, Dexeus FH, Finn L, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol1990;8:1050–1055.
  3. 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.
  4. Sengelov L, Kamby C, Lund B, et al. Docetaxel and cisplatin in metastatic urothelial cancer: a phase II study. J Clin Oncol1998;16:3392–3397.
  5. Meluch AA, Greco FA, Burris HA, et al. Paclitaxel and gemcitabine chemotherapy for advanced transitional-cell carcinoma of the urothelial tract: a phase II trial of the Minnie pearl cancer research network. J Clin Oncol2001;19(12):3018–3024.
  6. Bajorin DF, McCaffrey JA, Hilton S, et al. Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional-cell carcinoma of the urothelial tract: final report of a phase II trial evaluating two dosing schedules. Cancer2000;88(7):1671–1678.
  7. Redman BG, Smith DC, Flaherty L, et al. Phase II trial of paclitaxel and carboplatin in the treatment of advanced urothelial carcinoma.J Clin Oncol1998;16:1844–1848.
  8. Bellmunt J, Guillem V, Paz-Ares L, et al. Spanish Oncology Genitourinary Group. Phase I-II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. J Clin Oncol2000;18(18):3247–3255.

Suggested Readings

Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: a systematic review and meta-analysis. Lancet 2003;361(9373):1927–1934.

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

Harker WG, Meyers FJ, Freiha FS, et al. Cisplatin, methotrexate, and vinblastine (CMV): an effective chemotherapy regimen for metastatic transitional cell carcinoma of the urinary tract: a Northern California Oncology Group study. J Clin Oncol 1985;3:1463–1470.

Levin RM, Crawford DE. Bladder, renal pelvis, and ureters. In: Haskell CM, ed. Cancer treatment, 4th ed. Philadelphia, PA: WB Saunders, 1995:567–588.

Logothetis CJ, Dexeus FH, Chong C, et al. Cisplatin, cyclophosphamide and doxorubicin chemotherapy for unresectable urothelial tumors: the MD Anderson experience. J Urol 1989;141:33–37.

NCCN. Urothelial cancer practice guidelines., 2004

Sher HI, Shipley WU, Herr HW. Cancer of the bladder. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: principles and practice of oncology, 5th ed. New York: Lippincott–Raven Publishers, 1997:1300–1322.

Sternberg CN, Yagoda A, Scher HI, et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985;133:403–407.

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