Surgical approaches to superficial bladder cancer
Transurethral resection. Most patients with superficial bladder cancer can be treated adequately with transurethral resection (TUR). In patients with noninvasive, high-grade tumors, a repeated transurethral resection of a bladder tumor (TURBT) and post-resection examination under anesthesia are pivotal to rule out muscle-invasive bladder cancer (present in 30% to 50%) and similarly has been shown to improve treatment response/outcomes to intravesical induction BCG therapy. Such endoscopic procedures preserve bladder function, entail minimal morbidity, and can be performed repeatedly. Survival rates of more than 70% at 5 years are expected. Although TUR removes existing tumors, it does not prevent the development of new lesions. Patients should be monitored closely thereafter. Usually repeat cystoscopic evaluation is completed every 3 to 4 months.
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 used 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
• Non–muscle-invasive 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 for 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 on 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 improved survival in patients at time of nephroureterectomy.
In the United States, four intravesical agents are commonly used: thiotepa, an alkylating agent; BCG, an immune modulator/stimulator; and mitomycin and 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. Recently, in a phase III prospective trial, a full induction course of BCG and 3 years of maintenance therapy has been shown to provide a benefit in terms of recurrence-free survival for patients with high-risk non–muscle-invasive bladder cancer.
In a meta-analysis comparing intravesical BCG and chemotherapy (mitomycin, 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 entails 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 used 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 endoscopic or segmental resection. The tumor specifics that help determine which patients are best suited for radical surgical resection vs an endoscopic/segmental resection approach pertain to the anatomic location, multifocality, grade, and tumor extent within the upper tract.
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, because 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 adherence are indications to abandon conservative management and perform nephroureterectomy.
Primary radiation or chemoradiation therapy. Radiation therapy, preferably with chemotherapy, may be used following a maximal TURBT in select curative-care patients for bladder preservation in place of cystectomy or for treatment of patients who not surgical candidates. James et al recently reported a phase III trial that confirmed improved locoregional disease-free survival and a trend toward improved overall survival with the addition of fluorouracil (5-FU) and mitomycin C to radiation for bladder preservation. Other trials have shown improved local control using cisplatin with or without 5-FU or paclitaxel with radiation compared with radiation alone. Efstathiou et al reported on a phase III study of bladder preservation with or without neoadjuvant chemotherapy following TUR, conducted by the Radiation Therapy Oncology Group, that revealed no advantage to the use of MCV (methotrexate, cisplatin, and 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 rate equivalent to that achieved with initial radical cystectomy while allowing for bladder preservation in approximately two-thirds of 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 using 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, using multifield techniques. Image-guided techniques including cone beam CT can be useful.
The most frequently used 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 using 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 select 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.
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 uses 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 is inferior 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, 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, 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 and cisplatin exhibited survival equivalent to that with 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 inferior 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, which can be given with creatinine levels up to six times the upper limit of normal.