Bladder Cancer Treatment & Management

The treatment of non–muscle-invasive (Ta, T1, carcinoma in situ [CIS]) and muscle-invasive bladder cancer should be differentiated. Treatments within each category include both surgical and medical approaches. The 2011 EAU and the 2011 NCCN guidelines for non–muscle-invasive cancer both strongly recommend stratifying recurrence risk and progression risk and using risk tables to determine appropriate treatment.^{[55, 56]}

Ploeg et al found that more effective therapeutic approaches to target recurrent muscle-invasive bladder cancer are needed because of the extremely poor survival prognosis for patients initially treated with surgery or radiotherapy. Factors that predict survival after disease recurrence include location of recurrence, treatment for recurrence, and age at diagnosis of recurrence.^[59]

Patients with low-grade, low-stage disease may receive expectant treatment or may benefit from a single instillation of intravesical chemotherapy. Both guidelines also recommend one immediate instillation of chemotherapy as the entire adjuvant treatment for patients at low risk of recurrence and progression.^{[55, 56]}

Bacillus Calmette-Guérin (BCG) immunotherapy or other intravesical chemotherapies may be used for patients with recurrent disease or those at intermediate risk, although it is not necessary for all high-risk patients.^{[60, 61, 62, 63, 64, 65]} Patients with T1-high grade or CIS are advised to undergo intravesical BCG immunotherapy because of the substantial risk of disease recurrence and progression.

For patients with TaT1 tumors at intermediate risk of progression and intermediate or high risk of recurrence, EAU guidelines recommend one immediate instillation of chemotherapy followed by at least 1 year of intravesical BCG treatment or by further instillations of chemotherapy. Patients with TaT1 tumors and high risk of progression should receive 1 year of BCG treatment rather than further chemotherapy, as should patients with bladder CIS.^[55]

Endoscopic treatment with transurethral resection of bladder tumor (TURBT) is the first-line treatment to diagnose, to stage, and to treat visible tumors. TURBT is not effective for CIS because the disease is often so diffuse and difficult to visualize that complete surgical removal may not be feasible. It is critically important to surgically remove all non–muscle-invasive disease prior to beginning intravesical therapy. When a combination of papillary tumor and CIS is present, the papillary tumor is removed before treatment of the CIS is initiated.

As many as 20% of patients initially diagnosed with CIS may have unrecognized invasion beyond the lamina propria. Thus, they may not respond to intravesical therapy. These patients are candidates for radical cystectomy or radiation therapy and/or chemotherapy. Radiation therapy with or without chemotherapy is of limited benefit in patients with pure CIS but can be useful in some patients with muscle-invasive transitional cell carcinoma (TCC).

The criterion standard for the treatment of patients with stage T2-T4 disease is radical cystoprostatectomy for men and anterior pelvic exenteration for women. Additionally, all patients should undergo bilateral pelvic lymphadenectomy.

The treatment of localized small cell carcinoma is neoadjuvant chemotherapy followed by radical cystectomy or external beam radiation therapy. Chemotherapy using a platinum-based protocol is applied to metastatic disease. In addition, adjuvant therapy may be used in cases of stage III and IV disease that were treated with radical cystectomy.^{[33, 43, 66]}

Adenocarcinomas respond poorly to radiation and chemotherapy. Radical cystectomy is the treatment of choice. Lymphomas may be effectively treated with chemotherapy or radiation.

For patients with squamous cell carcinoma and those with squamous differentiation, a study by Ehdaie et al found no difference between the two groups regarding cancer specific survival or overall survival between those treated with radical cystectomy and pelvic lymph node dissection.^[67]

In 1999, the American Urological Association issued evidence-based guidelines for the management of noninvasive bladder cancer. In December 2007, a revision of the guidelines was published based on a comprehensive review of the available literature, as well as individual panel member experience.^[68] Thus, some of the published recommendations are not evidence-based but a product of practitioner experience. The panel determined 5 index-patient scenarios for which recommendations could be formulated.

The panel defined standard guideline statements for which (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions and (2) there is virtual unanimity about which intervention is preferred. They defined recommendation guidelines for which (1) the health outcomes of the alternative interventions are sufficiently well known to permit meaningful decisions and (2) an appreciable but not unanimous majority agrees on which intervention is preferred.

Finally, they defined option guidelines for which (1) the health outcomes of the interventions are not sufficiently well known to permit meaningful decisions or (2) preferences are unknown or equivocal. Options can exist because of insufficient evidence or because patient preferences are divided and may or should influence choices made.

Treatment guidelines statements

For all index patients, the standard is for the physician to discuss treatment options with the patient. The discussion should include the advantages and disadvantages and adverse effects of intravesical treatment, especially in regard to each particular agent.

Index patient no. 1 is a patient who presents with an abnormal growth of the urothelium prior to the establishment of a cancer diagnosis. Standard intervention is as follows:

• A biopsy specimen is obtained for pathologic analysis
• Under most circumstances, all visible tumor should be completely eradicated
• If bladder cancer is confirmed, surveillance cystoscopy should be implemented; however, no ideal interval or duration for surveillance cystoscopy has been determined

As an option for index patient no. 1, an initial single dose of intravesical chemotherapy may be administered immediately following tumor resection. (Immediate use of an intravesical agent is an option rather than a standard because of the lack of pathologic confirmation of disease at the time of resection, as well as potential side effects, costs, and patient preference. Additionally, intravesical agents are not of benefit in the setting of muscle-invasive disease.)

Index patient no. 2 is a patient with small-volume low-grade Ta bladder cancer. The recommendation in this patient is that an initial single dose of intravesical chemotherapy may be administered immediately postoperatively.

(The published guidelines explain that single-dose mitomycin C resulted in 17% fewer recurrences than tumor resection alone when all risk groups were considered, but the risk of recurrence and disease progression in individuals with low-grade Ta disease is "relatively low... and there is no evidence that multiple adjuvant instillations of either BCG or chemotherapy have additional benefit in patients at initial diagnosis of Ta Grade 1 bladder cancer.")

Index patient no. 3 is a patient with multifocal and/or large-volume, histologically confirmed, low-grade Ta disease or a patient with recurrent low-grade Ta bladder cancer. The recommendation in this patient is to give an induction course of intravesical therapy with BCG or mitomycin C, with the goal being prevention or delay of recurrence.

(The published guidelines reported a decreased probability of recurrence with either BCG or mitomycin C compared with tumor resection alone. Additionally, the report indicated no statistical advantage of either agent with respect to the incidence of tumor recurrence.)

An option for index patient no. 3 is to consider maintenance BCG or mitomycin C. (The guidelines note that, while maintenance BCG or mitomycin C is more effective in decreasing recurrence than induction alone, one must consider side effects, discomfort, lack of a uniform dosing schedule, and cost factors that may outweigh the benefits of this approach.)

Index patient no. 4 is a patient with initial histologically confirmed high-grade Ta, T1, and/or Tis bladder cancer. For patients with lamina propria invasion (T1) but without muscularis propria in the specimen, the standard is to perform repeat resection prior to additional intravesical therapy.

An induction course of BCG followed by maintenance therapy is recommended as treatment in these patients. In high-risk patients, BCG has proven superior to mitomycin C in terms of disease-free intervals, regardless of maintenance therapy. No significant data indicate any benefit in terms of disease progression.

As an option for index patient no. 4, cystectomy should be considered for initial therapy in select cases. No data indicate an advantage of intravesical therapy with regard to disease progression; thus, clinical factors, including tumor size, multifocality, grade, presence of CIS, angiolymphatic invasion, and prostatic urethral involvement, are all factors to be considered in this option.

Index patient no. 5 is a patient with high-grade Ta, T1, and/or CIS bladder cancer that has recurred after prior intravesical therapy. The standard in patients with lamina propria invasion (T1) but without muscularis propria in the specimen is to perform repeat resection prior to additional intravesical therapy.

Cystectomy should be considered as a therapeutic alternative in these patients. (High-risk individuals in whom initial intravesical therapy fails are at high risk of progression to invasive disease, and definitive therapy may be in their best interest.)

As an option for index patient no. 5, further intravesical therapy may be considered. (Repeat intravesical therapy may be indicated in individuals with late recurrence after previous complete response to an intravesical agent. Data are insufficient regarding the role of combined-agent therapy regimens.)

Intravesical instillation of Bacillus Calmette-Guérin (BCG) is used in the treatment of high-risk Ta, T1, and CIS urothelial carcinoma of the bladder. Immunotherapy with BCG is the most effective intravesical therapy for CIS and T1 tumors. It is less effective in reducing the 5-year recurrence rate for low-grade and low-stage urothelial carcinoma (see Table 2, below).

Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG (Open Table in a new window)

The intravesical instillation of either BCG vaccine or chemotherapy is initiated approximately 2-4 weeks following endoscopic resection of any visible papillary tumors or bladder biopsies. The bladder is usually healed enough to avoid systemic distribution of the vaccine organism.

See Bacillus Calmette-Guérin Immunotherapy in the Treatment of Bladder Cancer for more information on this topic.

Interferon alfa or gamma has been used in the treatment of stages Ta and T1 and CIS urothelial carcinoma, either as a single-agent therapy or in combination with BCG.^[69] Its role has primarily been in post-BCG failure. Early results in nonrandomized retrospective series have reported a 42% response with tolerable adverse effects after BCG failure. However, no evidence has indicated that re-treating with BCG with interferon is superior to re-treating with BCG alone. Patients who have a recurrence within 12 months after 2 courses of BCG (preferably 6+3 treatments) do not benefit from treatment with BCG plus interferon. In addition, in a randomized study of BCG versus BCG plus interferon in BCG naive high- risk patients, the addition of interferon was equivalent to BCG alone.

Kamat et al found that fluorescence in situ hybridization results can identify patients at risk for tumor recurrence and progression who are undergoing BCG immunotherapy. This information could be useful in counseling patients about alternative treatment strategies.^[70]

See Treatment of Carcinoma In Situ for more information on this topic.

Surgical treatment of Ta and T1 disease and carcinoma in situ

Endoscopic treatment with transurethral resection of bladder tumor (TURBT) is the first-line treatment to diagnose, to stage, and to treat visible tumors. Electrocautery or laser fulguration of the bladder tumor is sufficient for low-grade, small-volume, papillary tumors. However, the 2011 EAU guidelines recommend resection of small tumors (< 1 cm) in a single piece that includes part of the underlying bladder wall.

Both the 2011 EAU and 2011 NCCN guidelines offer similar recommendations for surgical treatment.^{[55, 56]} Patients with bulky, high-grade, or multifocal tumors should undergo a second procedure to ensure complete resection and accurate staging 4-6 weeks after the initial TURBT. Both guidelines state that a second resection should be performed at this time if these or other factors, such as an absence of muscle tissue in the initial specimen, indicate that the initial TURBT was incomplete. Resection of large tumors (>1 cm diameter) should be performed in fractions, including muscle tissue.^{[55, 56]} Approximately 30% of stage T1 tumors are upgraded to muscle-invasive disease.

No further metastatic workup is needed for obviously superficial tumors. Because bladder cancer is a polyclonal field change defect, continued surveillance is mandatory.

The only surgical treatment for CIS is radical cystectomy. Eliminating visible lesions with resection is preferable prior to intravesical BCG, but some CIS lesions may not be readily visible. Patients who do not respond to BCG instillations often find cystectomy difficult to accept and, instead, want to continue trying various intravesical instillations.

The difficulty of accurately staging CIS preoperatively was demonstrated by Tilki and a group of international investigators at 8 centers in the United States, Canada, and Europe.^[71] These researchers reported that of 243 patients who were considered to have only CIS before cystectomy, only 117 (48.1%) were found to actually have CIS. No cancer (pT0) was discovered in 20 patients (8.2%). Urothelial cancer was the sole finding in 19 patients (7.8%). The disease was up-staged in 36% of the patients. The overall 5-year recurrence-free and cancer-specific survival was 74% and 85%, respectively.

See Transurethral Resection of Bladder Tumors for more information on this topic.

Radical cystectomy in non–muscle invasive bladder cancer

Radical cystectomy is typically reserved for muscle-invasive disease, but it is appropriately used to treat some cases of high risk, non–muscle-invasive bladder cancer. From 35-50% of patients who undergo cystectomy for Ta, T1, or CIS are discovered to have muscle-invasive disease, with 10-15% demonstrating microscopic lymph node metastasis. According to the 2011 NCCN guidelines, cystectomy should involve at least bilateral node dissection, including iliac and obturator nodes.^[56]

Cystectomy may be indicated for non–muscle-invasive disease. Indications include patients with (1) tumor bulk so substantial that complete eradication of tumor is not feasible endoscopically, (2) prostatic urethra involvement, and (3) CIS or T1-high-grade tumor persistence despite adequate intravesical management. Patients with T1-high-grade cancer in association with diffuse CIS are at especially high risk of progression, and they might be treated with early cystectomy based on a decision made by the physician and patient. The 2011 EAU guidelines recommend that immediate cystectomy be considered for such patients.^[55]

The CIS in upwards of 80% of affected patients progresses to muscle-invasive disease, with 20% of patients found to have muscle-invasive disease at the time of cystectomy. High-grade T1 tumors that recur despite BCG have a 50% likelihood of progressing to muscle-invasive disease. Cystectomy performed prior to progression yields a 90% 5-year survival rate. The 5-year survival rate drops to 30-50% in muscle-invasive disease. The EAU guidelines strongly advocate cystectomy in patients with early BCG failure.^[55]

The criterion standard for the treatment of patients with stage T2-T4 disease is radical cystoprostatectomy for men and anterior pelvic exenteration for women. See Radical Cystectomy for information on this topic.

Cystoprostatectomy involves removal of the bladder, peritoneal covering, perivesical fat, distal ureters, prostate, seminal vesicles, vas deferentia, and, sometimes, the membranous or entire urethra. Anterior pelvic exenteration consists of a bilateral pelvic lymphadenectomy, cystectomy, urethrectomy, hysterectomy, salpingo-oophorectomy, and partial anterior vaginectomy.

In experienced hands, robot-assisted radical cystectomy may offer the advantages of reduced blood loss, opiate requirement, and hospital stay. As this is a relatively new procedure, surgeons performing it need to provide detailed informed consent and a full description of potential complications and outcomes.^[72]

Pelvic lymphadenectomy

Approximately 25% of patients undergoing radical cystectomy have lymph node metastases at the time of surgery. Bilateral pelvic lymphadenectomy (PLND) should be performed in conjunction with radical cystoprostatectomy and anterior pelvic exenteration. PLND adds prognostic information by appropriately staging the patient and may confer a therapeutic benefit.

The boundaries of a standard PLND include the bifurcation of the common iliac artery and vein superiorly, the genitofemoral nerve laterally, the obturator fossa posteriorly, and the circumflex iliac vein (or node of Cloquet) inferiorly.

Extended PLND includes the lymph nodes in the presacral region and those surrounding the common iliac vessels to the level of the aortic bifurcation. The additional benefit of an extended PLND is controversial. Based on several retrospective studies, some experts believe that an extended dissection provides additional staging information and offers a survival benefit. However, no randomized trials to date have proven that an extended PLND is more beneficial than a standard PLND.

Urinary diversion

After cystectomy is performed, a urinary diversion must be created from an intestinal segment. Diversions can be incontinent or continent. Contraindications to performing continent urinary diversions are as follows:

• Multiple comorbid health problems
• Chronic renal insufficiency
• Hepatic dysfunction
• Advanced disease stage

The most common incontinent diversion is the ileal conduit (see the image below), which has been used for more than 40 years with excellent reliability and minimal morbidity. Conduits can be constructed from either ileum or colon.

A small segment of ileum (at least 15 cm proximal to the ileocecal valve) is taken out of gastrointestinal continuity but maintained on its mesentery, with care to preserve its blood supply. The gastrointestinal tract is restored with a small-bowel anastomosis. The ureters are anastomosed to an end or side of this intestinal segment and the other end is brought out as a stoma to the abdominal wall. Urine continuously collects in an external collection device worn over the stoma.

The most commonly used continent cutaneous urinary diversion is the Indiana pouch (see the image below). Introduced in 1987, the Indiana pouch is a urinary reservoir created from a detubularized right colon and an efferent limb of terminal ileum. The terminal ileum is plicated and brought to the abdominal wall. The ileocecal valve acts as a continence mechanism. The Indiana pouch is emptied with a clean intermittent catheterization 4-6 times per day.

The neobladder is another form of continent urinary diversion. In neobladder diversions (see the image below), various segments of intestine, including the ileum, ileum and colon, and sigmoid colon, can be used to construct a reservoir. The ureters are implanted to the reservoir, and the reservoir is anastomosed to the urethra.

This operation has been performed successfully in men for more than 20 years and, more recently, in women. The orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder. Patients have volitional control of urination and void by Valsalva.

Chemotherapy in muscle-invasive disease

Giving chemotherapy prior to radical cystectomy may improve cancer-specific survival, presumably by treating micrometastatic disease and pathologic downstaging. A meta-analysis of 11 trials showed an overall survival rate benefit of 5% among patients who received neoadjuvant chemotherapy. If locally advanced transitional cell carcinoma (TCC) is suspected based on clinical staging, the rationale for neoadjuvant chemotherapy prior to cystectomy may be even stronger.^[73]

However, some patients with node-negative disease are needlessly treated with chemotherapy; in addition, neoadjuvant chemotherapy significantly delays surgery.

Emerging retrospective data from multiple institutions suggest that an increased interval from the time of the diagnosis to radical cystectomy can adversely affect pathologic stage and survival.^[74] For example, at the University of Pennsylvania, patients who underwent radical cystectomy within 12 weeks of the diagnosis had a lower incidence of advanced pathologic stage (42% vs 84% with extravesical disease), lower incidence of positive lymph nodes, and an increased 3-year survival rate (62% vs 35%).^[75] Although all studies have been retrospective, sufficient data support the concept of prompt surgical intervention.

Neoadjuvant chemotherapy prior to either radical cystectomy or external beam radiotherapy is controversial. The Southwestern Oncology Group (SWOG) conducted a multicenter randomized prospective study that compared neoadjuvant therapy using a methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) combination with surgery alone, and concluded that neoadjuvant therapy conferred a treatment benefit compared with surgery alone.^[76]

However, several criticisms of this study exist. The study was purposely underpowered because of slow recruitment (317 patients over 11 y), because 20% of the patients who were to undergo cystectomy alone never underwent surgery, and because there was no comparison to neoadjuvant therapy alone or adjuvant therapy. In addition, a study that re-evaluated the SWOG data found that surgical factors significantly affected outcomes.^[77]

In one small series, the T4 tumors of 45% of affected patients responded to chemotherapy, making potentially curative cystectomy possible.

Although no definite evidence of benefit exists, patients with P3-P4 or N+ urothelial carcinoma in the United States are typically advised to receive adjuvant chemotherapy.

A phase III trial that assessed 976 patients using neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy found that risk of death was decreased by 16%.^[78]

Methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the standard treatment of metastatic bladder cancer. MVAC has an objective response rate of 57-70%, a complete response rate of 15-20%, and a 2-year survival rate of 15-20%.

Gemcitabine and cisplatin (GC) is a newer regimen and has been shown to be as effective as MVAC, but with less toxicity.^[79] GC is now considered a first-line treatment for bladder cancer.

Several novel compounds have shown activity against transitional cell bladder cancer and are now being tested in combination chemotherapy trials. Some of these promising agents are ifosfamide, paclitaxel, docetaxel, and carboplatin.

External beam radiation therapy has been shown to be inferior to radical cystectomy for the treatment of bladder cancer. The overall 5-year survival rate after treatment with external beam radiation is 20-40%, compared with a 90% 5-year survival after cystectomy for organ-confined disease. Nevertheless, external beam radiation therapy is used in various countries other than the United States for T2-T3 urothelial carcinoma of the bladder.

Neoadjuvant external beam radiation therapy has been attempted for muscle-invasive bladder cancer, with no improvement in survival rate.

In certain centers, a bladder-preserving strategy for T2-T3 urothelial carcinoma is applied using a combination of external beam radiation, chemotherapy, and endoscopic resection. Survival rates associated with this approach are comparable with those of cystectomy in selected patients. This combination has a widespread application that is limited by the complexity of the protocol, its toxicity, and a high mortality rate.

The mortality rate in the 2 largest US series with the longest follow-up study is 4-5%. In comparison, the mortality rate for most modern cystectomy series is 1-2%. Furthermore, in some series, local recurrence of bladder cancer is as high as 50-60% despite the completion of bladder-preserving therapy. A significant number of patients ultimately require salvage cystectomy, which is associated with significantly increased morbidity and decreased options for urinary diversions.

The morbidity of untreated bladder cancer is significant and includes hematuria, dysuria, irritative urinary symptoms, urinary retention, incontinence, ureteral obstruction, and pelvic pain.

Complications of radical cystectomy

The radical cystectomy perioperative mortality rate is 2-3%. However, the 6-month mortality may be as high as 5-7% in elderly patients. The 2 most common complications are small-bowel obstruction and ureteroenteric stricture (see Table 3 below).

Table 3. Most Common Complications of Radical Cystectomy (Open Table in a new window)

The reported overall early and late complication rate associated with radical cystectomy is approximately 30-40%. However, this may be an underestimation of the true complication rate because of a lack of standardized reporting in published studies.

Many patients who undergo a radical cystectomy have multiple comorbid health risk factors (eg, advanced age, cardiovascular disease, pulmonary disease). Despite these difficulties, this procedure may be performed safely in patients older than 80 years.

Complications of all types of urinary diversion include the following:

• Hyperchloremic metabolic acidosis
• Urinary tract infections
• Stomal-peristomal inflammation, hernia, or stenosis
• Urinary calculi
• Vitamin B-12 deficiency
• Ureterointestinal stenosis leading to hydronephrosis

After a radical cystectomy, all men are impotent if the parasympathetic nerves from the pelvic plexus (S2-S4) to the corpora cavernosum are not spared at the time of surgery. However, a nerve-sparing approach may be associated with potency rates of approximately 50-70%.

Orthotopic neobladder complications

With the recent advances in surgical technique, this procedure is commonly used in tertiary centers. Complications include daytime and nighttime urinary incontinence at rates of approximately 5% and 20%, respectively. Urinary incontinence may develop from multiple factors, including injury to the external urethral sphincter, increased urine production from solute absorption, and relaxation of the external sphincter, which is greater at night.

Smoking cessation decreases the risk of tumor recurrence and progression and improves overall health.

Increased water intake has been advocated because it may help dilute carcinogens and decrease the exposure of the urothelium to them. Conclusive benefit has not been shown.

Multivitamin or vitamin A supplementation has also been advocated, but data do not fully support this practice.

The high rate of disease recurrence and progression in non–muscle-invasive bladder cancer underscores the need for careful follow-up studies. According to the US National Cancer Institute, bladder cancer affects approximately 500,000 people in America. Because most still have an intact bladder, the number of patients under surveillance approaches this figure.

The 2011 EAU guidelines include schedules for follow-up cystoscopy, urinary cytology, and imaging in patients with TaT1 tumors, depending on risk of recurrence and progression. In follow-up in patients with no visible tumor in the bladder but positive cytology, the guidelines recommend biopsies and investigation of extravesical locations.^[55] The NCCN 2011 guidelines further specify that cystoscopy and urinary cytology should be performed every 3-6 months for 2 years and then at increasing intervals as appropriate.^[56]

See Surveillance for Recurrent Bladder Cancer for more information on this topic.