Treatment
Surgical approaches to superficial bladder cancer
Transurethral resection. Most patients with superficial bladder cancer can be treated adequately with transurethral resection (TUR). Such procedures preserve bladder function, entail minimal morbidity, and can be performed repeatedly. Survival rates > 70% at 5 years are expected. Although TUR removes existing tumors, it does not prevent the development of new lesions. Patients should be followed closely thereafter.
Laser. The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser has achieved good local tumor control when used in the treatment of superficial bladder tumors. However, it has not been adopted for general use because of its limitations in obtaining material for staging and grading of tumors.
Partial cystectomy. Partial cystectomy is an infrequently utilized treatment option for patients whose tumors are not accessible or amenable to TUR but are solitary in location and away from the trigone.
Radical cystectomy. Radical cystectomy is generally not used for the treatment of superficial bladder tumors. A 2007 retrospective series of patients with no viable tumor at the time of radical cystectomy (pT0) would suggest that up to 9% of these patients may develop a recurrence following surgery. On multivariate analysis, the presence of lymphovascular invasion and concomitant carcinoma in situ on the transurethral bladder tumor resection specimen predicted poorer overall and recurrence-free survival, respectively. The indications for radical cystectomy include:
• Unusually large tumors that are not amenable to complete TUR, even on repeated occasions
• Some high-grade tumors
• Multiple tumors or frequent recurrences that make TUR impractical
• Symptomatic diffuse carcinoma in situ (Tis) that proves unresponsive to intravesical therapy
• Prostatic stromal involvement
• Superficial bacillus Calmette-Guerin (BCG)-refractory high-grade disease.
Intravesical therapy. The indications for intravesical therapy include:
• Stage T1 tumors, especially if multiple
• Multifocal papillary Ta lesions, especially grade 2 or 3
• Diffuse Tis
• Rapidly recurring Ta, T1, or Tis disease.
A 2007 analysis found that following radical cystectomy, patients remain at risk of upper tract recurrence, with a previous report estimating the incidence of upper tract recurrence at 2.5%. Only urethral tumor involvement was predictive of upper tract recurrence. Despite routine surveillance of the upper urinary tracts, 78% of these recurrences were detected only upon development of symptoms, with the median survival following recurrence being only 1.7 years. Furthermore, the detection of asymptomatic upper tract recurrences via routine surveillance strategies did not predict lower pathologic stage, absence of nodal metastasis, or the improved survival in patients at time of nephroureterectomy.
In the United States, four intravesical agents are commonly used: thiotepa(Drug information on thiotepa), an alkylating agent; BCG, an immune modulator/stimulator; and mitomycin(Drug information on mitomycin) and doxorubicin(Drug information on doxorubicin), both antibiotic chemotherapeutic agents. The dose of BCG varies with the strain (50 mg [Tice] or 60 mg [Connaught]). Mitomycin doses range from 20 to 40 mg. Although all four agents reduce the tumor recurrence rate, BCG is the most effective particularly for high-grade disease. For the treatment of papillary Ta and T1 lesions, BCG and mitomycin have the greatest efficacy (complete response rate: approximately 50%). For the treatment of Tis, BCG is extremely effective.
In a meta-analysis comparing intravesical BCG and chemotherapy (mitomycin, epirubicin(Drug information on epirubicin), doxorubicin, or sequential mitomycin/doxorubicin), intravesical BCG was superior in reducing the risk of short- and long-term treatment failure for Tis. Therefore, intravesical BCG appears to be the agent of choice for Tis.
Surgical approaches to invasive bladder cancer
The standardized treatment for invasive bladder cancer (stage II or higher) is radical cystectomy and extended pelvic lymph node dissection.
Radical cystectomy. Candidates for radical cystectomy include:
• Patients with muscle-invasive tumor
• Patients with high-grade, invasive, lamina propria tumors with evidence of lymphovascular invasion, with or without Tis
• Patients with diffuse Tis or recurrent superficial cancer who do not respond to intravesical therapy.
In men, radical cystectomy with extended pelvic lymph node dissection and removal of the bladder, seminal vesicles, and prostate. In women, radical cystectomy entails pelvic lymph node dissection and anterior exenteration, including both ovaries, fallopian tubes, uterus, cervix, anterior vaginal wall, bladder, and urethra.
Partial cystectomy. Partial cystectomy is an infrequently utilized treatment option that should only be considered when there is a solitary lesion in the dome of the bladder and when random biopsy results from remote areas of the bladder and prostatic urethra are negative.
Urethrectomy. Urethrectomy is routinely included in the anterior exenteration performed in female patients. Urethrectomy in male patients is performed if the tumor grossly involves the prostatic urethra or if prior TUR biopsy results of the prostatic stroma are positive. Delayed urethrectomy for positive urethral cytology or biopsy is required in about 10% of male patients.
Urinary reconstruction. Urinary reconstruction may involve any one of the following: intestinal conduits (eg, ileal, jejunal, or colonic), continent cutaneous diversion (eg, Indiana, Florida, or Kock pouch), or orthotopic reconstruction (in both male and female patients).
Surgical approaches to ureteral and renal pelvic tumors
Optimal surgical management of urothelial malignancies of the ureter and renal pelvis consists of nephroureterectomy with excision of a bladder cuff. Some tumors may respond well to local resection, and tumor specifics may allow for a more conservative intervention, particularly for low-grade tumors.
Upper ureteral and renal pelvic tumors. These tumors (because of similar tumor behavior and anatomic aspects) may be considered as a group, whereas lower ureteral tumors may be considered as a separate group.
Upper ureteral and renal pelvic tumors are best treated with nephroureterectomy and bladder cuff excision. Solitary, low-grade upper tract tumors may be considered for segmental excision or ureteroscopic surgery if close surveillance is feasible. Care should be exercised, however, as multicentricity is more probable, and the risk of recurrence is greater than for lower ureteral lesions.
Lower ureteral lesions. These tumors may be managed by nephroureterectomy and bladder cuff excision, segmental resection, and neovesical reimplantation or by endoscopic resection. A 15% recurrence rate is seen after segmental resection or endoscopic excision. Careful follow-up is mandatory. Disease progression, the development of a ureteral stricture precluding periodic surveillance, and poor patient compliance are indications to abandon conservative management and perform nephroureterectomy.
Radiation therapy for bladder cancer
Primary radiation or chemoradiation therapy. Radiation therapy, preferably with chemotherapy, may be used follwing a maximal TURBT in selected curative-care patients for bladder preservation in place of cystectomy or for palliation for patients who not surgical candidates. A recently reported phase III trial (James ND et al: N Engl J Med 2012) confirmed improved locoregional disease-free survival and a trend towards improved overall survival with the addition of 5-FU and mitomycin C to radiation for bladder preservation. Other trials have shown inproved local control using cisplatin(Drug information on cisplatin) with or without fluorouracil(Drug information on fluorouracil) (5-FU) with radiation as compared with radiation alone. A phase III study of bladder preservation (Efstathiou JA et al: J Clin Oncol 2009) with or without neoadjuvant chemotherapy following TUR, conducted by the Radiation Treatment Oncology Group (RTOG), revealed no advantage to the use of MCV (methotrexate, cisplatin, and vinblastine(Drug information on vinblastine)) before radiation therapy and concurrent cisplatin. The favorable outcome without neoadjuvant chemotherapy may make bladder preservation a more acceptable option for a wider range of patients. Several phase II trials and retrospective series have also shown a survival equivalent to that achieved with initial radical cystectomy while allowing for bladder preservation in many patients. Updates from institutions in Europe and the United States on more than 600 patients with long-term follow-up support the durability of outcomes previously reported. The extent of TUR and the absence of hydronephrosis are important prognostic factors in studies of bladder-conserving treatment.
Radiation dose and technique. Initially, a pelvic field is treated to 4,000 to 4,500 cGy utilizing a three-dimensional conformal technique, with daily or twice-daily fractionation. Cystoscopy with bladder biopsies is performed. If a complete response is confirmed, the bladder tumor site is then boosted to a total dose approximating 6,480 cGy, utilizing multifield techniques.
Chemotherapy regimens for bladder carcinomaThe most frequently utilized systemic chemotherapy regimens for urothelial carcinoma are shown in Table 2.
Radiation therapy for renal pelvic and ureteral cancers
In patients with renal pelvic and ureteral lesions who have undergone nephroureterectomy and bladder cuff excision, postoperative local-field irradiation is offered if there is periureteral, perirenal, or peripelvic extension or lymph node involvement. A dose of approximately 4,500 to 5,580 cGy is delivered utilizing multifield techniques.
Palliative irradiation. Palliative radiation therapy is effective in controlling pain from local and metastatic disease and in providing hemostatic control. A randomized study comparing 3,500 cGy in 10 fractions vs 2,100 cGy in three hypofractionated treatments revealed high rates of relief of hematuria, frequency, dysuria, and nocturia in both regimens. In selected cases of bladder cancer, aggressive palliation to approximately 6,000 cGy may be warranted to provide long-term local tumor control. Concurrent chemotherapy should be considered.
Neoadjuvant/adjuvant chemotherapy
Perioperative chemotherapy to improve overall survival and reduce the risk of recurrence before or after cystectomy is a debated topic. Data from two randomized trials of cisplatin-based chemotherapy administered in the neoadjuvant setting provide evidence of a survival benefit. Despite these data, it appears that many, if not most, patients with muscle-invasive bladder cancer in the United States do not receive chemotherapy before surgery, or rather do so in the adjuvant setting.
Multiple underpowered randomized trials of different designs have given various chemotherapy regimens after cystectomy. Many of these trials had inadequate power or methodologic flaws that limited interpretation. Therefore, the role of adjuvant chemotherapy remains undefined. Despite this, the US bladder cancer community increasingly utilizes adjuvant chemotherapy by extrapolating a “perioperative” benefit from the neoadjuvant experience. Perioperative cisplatin-based chemotherapy should now be considered a standard of care. In the perioperative setting, carboplatin(Drug information on carboplatin) is an inferior agent to cisplatin and should not be offered in this setting.
Chemotherapy for advanced disease
Treatment of advanced metastatic urothelial cancer is generally considered to be palliative. Response rates are high with cisplatin-containing regimens (50% to 60%), but the duration of response is short, and median survival is 12 to 14 months. A small subset of patients (5% to 10%; usually with only lymph node metastases) can have a complete response to chemotherapy. This small subset of patients should be considered for post-chemotherapy retroperitoneal lymph node dissection [RLND] provided no additional sites of metastases are suspected on complete metastatic evaluation. A randomized trial showed an advantage for a regimen of M-VAC (methotrexate, vinblastine, Adriamycin [doxorubicin], and cisplatin) over cisplatin alone with regard to progression-free and overall survival, but with high rates of myelosuppression. In another randomized trial, the combination of gemcitabine(Drug information on gemcitabine) (Gemzar) and cisplatin exhibited equivalent survival to M-VAC in metastatic bladder cancer but was clinically better tolerated. Thus, cisplatin plus gemcitabine has become a common standard of care in this setting. Similar data do not exist for the perioperative setting. Although carboplatin is an inferior agent to cisplatin in bladder cancer, this agent can be used if a contraindication to cisplatin exists (eg, neuropathy, poor renal function). Since many patients cannot receive cisplatin because of renal impairment, some nonrandomized studies (eg, a phase II study by Carles et al) have examined the subsitution of oxaliplatin(Drug information on oxaliplatin) (Eloxatin), which can be given with creatinine levels up to six times the upper limit of normal [ULN].
