Sections

Treatment

Approach Considerations

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 surgical and medical approaches.^[81]European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines for non–muscle-invasive cancer strongly recommend stratifying risk of recurrence and progression and using risk tables to determine appropriate treatment.^{[1, 69]}

The two principal treatment choices in muscle-invasive bladder cancer are radical cystectomy and transurethral resection of bladder tumor (TURBT) followed by concurrent radiation therapy and systemic chemotherapy (trimodality therapy). Each choice has its advocates.

Chedgy and Black propose that radical cystectomy should be considered the gold-standard treatment for muscle-invasive bladder cancer. They cite recommendations from European and United States guidelines, as well as published literature showing a 75% 5-year cancer-specific survival for all stages of bladder cancer treated with cystectomy, while noting that the published literature on trimodality therapy shows evidence of inferior survival and frequent treatment failure, with almost one-third of patients eventually requiring a salvage cystectomy.^[82]

Nevertheless, Chedgy and Black consider cystectomy and trimodality therapy to be complementary. They observe that many patients considered ineligible for radical cystectomy may be candidates for trimodality therapy, especially if radiosensitization is performed with 5-fluorouracil and mitomycin.^[82]

In contrast, Mitin recommends considering trimodality therapy as the first option for patients with muscle-invasive bladder cancer, with cystectomy reserved for patients who are unable or unwilling to undergo bladder preservation or for salvage in the case of local recurrence. Mitin cites literature demonstrating similar or better outcomes compared with cystectomy and excellent quality of life, with low rates of radiation-induced adverse effects.^[83]

Trimodality therapy carries a significant local recurrence rate, however, which necessitates thorough and frequent cystoscopic follow-up. Local recurrence requiring salvage cystectomy is usually identified within the first 3 years. Morbidity and mortality rates with salvage cystectomy are remarkably similar to those with first-line radical cystectomy, but reconstructive options with salvage cystectomy may be limited by the presence of irradiated bowel, which may be unacceptable for a continent reservoir or a neobladder creation.^[83]

In the future, treatment selection for muscle-invasive bladder cancer is likely to be based on testing of tumors for biomarkers that indicate treatment sensitivity. Patients with resistant tumors would be offered upfront cystectomy, while those with chemoradiation-sensitive tumors would be offered bladder-preserving therapy, with regimens selected on the basis of genetic analysis.^[83]For example, presence of the MRE11A single-nucleotide polymorphism rs1805363 has been associated with worse cancer-specific survival after radiation therapy, with a gene-dosage effect observed, but not after cystectomy.^[84]

Immunotherapy and chemotherapy

Patients with low-grade, low-stage disease may receive expectant treatment or may benefit from a single instillation of intravesical chemotherapy. Both EAU and NCCN guidelines also recommend 1 immediate instillation of chemotherapy as the entire adjuvant treatment for patients at low risk of recurrence and progression.^{[1, 69]}

Bacillus Calmette-Guérin (BCG) immunotherapy or other intravesical chemotherapies may be used for patients with recurrent disease or those at intermediate risk. Patients at high risk, with T1–high grade or CIS, are advised to undergo intravesical BCG immunotherapy because of the substantial likelihood of disease recurrence and progression.^{[85, 86, 87, 88, 89, 90]}

The EAU guidelines recommend that patients with intermediate- and high-risk tumors receive intravesical BCG after TURBT to reduce the risk of tumor recurrence. For optimal efficacy, BCG must be given on a maintenance schedule; 3-year maintenance is more effective than 1-year to prevent recurrence of high-risk tumors, but not of intermediate-risk tumors.^[69]

In 2016, the US Food and Drug Administration (FDA) granted accelerated approval of atezolizumab, the first cancer immunotherapy that acts as an inhibitor of programmed cell death ligand 1 (PD-L1), for the treatment of urothelial carcinoma. Nivolumab, another PD-L1 inhibitor, was approved by the FDA in 2017. For more information, see Chemotherapeutic Regimens for Metastatic Bladder Cancer, below.

Surgery and radiation therapy

Endoscopic TURBT is the first-line intervention to diagnose, stage, and 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.

The EAU guidelines recommend the use of fluorescence-guided resection, as it is more sensitive than conventional white-light cystoscopy for detection of tumors.^{[91, 92, 93]}The added detection rate with fluorescence-guided cystoscopy is 20% for all tumors and 23% for CIS.^[94]The FDA has approved the use of blue-light cystoscopy with 5-aminolevulinic acid (Cysview) in patients suspected or known to have non–muscle-invasive bladder cancer on the basis of prior cystoscopy.^[95]

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.

Level 1 evidence supports the use of preoperative (neoadjuvant) chemotherapy in patients with muscle-invasive bladder cancer. In addition, a series of studies have shown substantial benefit for adjuvant chemotherapy in these patients. Booth and Tannock have noted that few patients in North America receive neoadjuvant therapy, however, and suggest that neoadjuvant or adjuvant therapy should be provided to all patients with muscle-invasive bladder cancer who are sufficiently fit to receive it.^[96]

Lymph node dissection

Much controversy exists regarding the optimal extent of the lymph node dissection that should accompany cystectomy. It is clear that at minimum, a meticulous standard dissection should be performed.

While a number of retrospective studies demonstrate no difference in overall survival with standard versus extended lymph node dissection, a growing body of evidence suggests that more extended node dissection may improve survival in both lymph node–positive and lymph node–negative disease. The first prospective, randomized trial to address this question, sponsored by the Southwest Oncology Group (SWOG), is currently enrolling patients.^[97]

Small cell carcinoma

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.^{[50, 61, 98]}

Adenocarcinoma and lymphoma

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

Squamous cell carcinoma

For patients with squamous cell carcinoma (SCC), the main treatment is cystectomy because these tumor tend to be chemoresistant. Adjuvant radiation therapy has been reported in patients with locally advanced disease or positive margins.

See Bladder Cancer Treatment Protocols for more information on this topic. Go to Oncology Decision Point for expert commentary on bladder cancer treatment decisions and related guidelines.

Lifestyle measures

Smoking cessation decreases the risk of tumor recurrence and progression and improves overall health. Increased water intake has been advocated because it may help to dilute carcinogens and decrease the exposure of the urothelium to them, but conclusive benefit has not been shown. Multivitamin or vitamin A supplementation has also been advocated, but data do not fully support this practice.^[99]

Immunotherapy and chemotherapy

Bacillus Calmette-Guérin (BCG)

Intravesical instillation of 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)

Stage	Recurrence, %	Progression, %
Ta	55	11
T1	61	31
CIS	45	23
G1	61	2-4
G2	56	5-7
G3	50-70	30-40

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. By that time, the bladder has usually healed enough to avoid systemic distribution of the vaccine organism.

See Bacillus Calmette-Guérin Immunotherapy for Bladder Cancer for more information on this topic.

Gene therapy

In December 2022, nadofaragene firadenovec (Adstiladrin) became the first gene therapy approved for adults with bladder cancer. It is indicated for high-risk BCG-unresponsive non–muscle-invasive bladder cancer (NMIBC) with CIS, with or without papillary tumors. Nadofaragene firadenovec is a non-replicating adenoviral vector–based gene therapy that delivers a copy of a gene encoding a human interferon-alfa 2b (IFNα2b) to the bladder urothelium. Intravesical instillation results in cell transduction and transient local expression of IFNα2b protein that is anticipated to have antitumor effects.

Approval was supported by a phase 3, multicenter, open-label, repeat-dose study in adults with BCG-unresponsive NMIBC with Eastern Cooperative Oncology Grouip status of 2 or less. Among 151 patients included in the per-protocol efficacy analyses, 55 (53.4%) of 103 patients with CIS (with or without a high-grade Ta or T1 tumor) had a complete response within 3 months of the first dose and this response was maintained in 25 (45.5%) of 55 patients at 12 months.^[100]

Immunotherapy

Interferon alfa or gamma has been used in the treatment of stages Ta and T1 and CIS urothelial carcinoma, either as single-agent therapy or in combination with BCG.^[101]Its role has primarily been in treatment following 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 retreatment with BCG plus interferon is superior to retreatment 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.^[102]

Kamat et al found that the results of fluorescence in situ hybridization (FISH) assays 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.^[103]

Patients with BCG-refractory CIS may also be treated with intravesical valrubicin (Valstar), which is approved for this particular indication. However, any patient who has persistent or recurrent disease after BCG should be considered for radical cystectomy, given the high rate of disease progression.

Another option is pembrolizumab (Keytruda), which is indicated for treatment of BCG-unresponsive, high-risk, non–muscle-invasive bladder cancer with CIS with or without papillary tumors in patients who are ineligible for, or have elected not to undergo, cystectomy. Approval was supported by the KEYNOTE-057 study, which showed a complete response rate of 41% in patients who received pembrolizumab. The median duration of response was 16.2 months.^{[104, 105]}

Intravesical docetaxel appears to be a promising agent for BCG-refractory non–muscle-invasive bladder cancer; adding maintenance treatments of docetaxel may increase the duration of recurrence-free survival. Barlow et al reported that 32 of 54 patients with BCG-refractory bladder cancer showed a complete response to 6 weekly treatments of intravesical docetaxel.^[106]Median time to recurrence was 39.3 months in responders treated with maintenance docetaxel, compared with 19 months in those who did not receive maintenance therapy.

Surgery

TURBT

Endoscopic TURBT is the first-line means of diagnosing, staging, and treating visible tumors. Electrocautery or laser fulguration of the bladder tumor is sufficient for low-grade, small-volume, papillary tumors. However, the EAU guidelines recommend resection of small tumors (< 1 cm) in a single piece that includes part of the underlying bladder wall.^[69]

The EAU and NCCN guidelines offer similar recommendations for surgical treatment.^{[1, 69]}Patients with bulky, high-grade, or multifocal tumors should undergo a second procedure to ensure complete resection and accurate staging 2-6 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.^{[1, 69]}Approximately 30% of stage T1 tumors are upgraded to muscle-invasive disease.

Fluorescence-guided resection

The EAU guidelines recommend fluorescence-guided resection, as it is more sensitive than white-light cystoscopy alone for detection of tumors, particularly CIS.^{[107, 108, 109]}The FDA has approved blue-light cystoscopy with hexaminolevulinate (Cysview) as an adjunct to white-light cystoscopy in patients suspected or known to have non–muscle-invasive papillary cancer of the bladder on the basis of a prior cystoscopy. This technique is not a replacement for random bladder biopsies or other procedures used in the detection of bladder cancer and is not for repetitive use.

Blue-light cystoscopy with hexaminolevulinate detects more Ta/T1 bladder cancer lesions than does white-light cystoscopy alone.^{[107, 108, 109, 110, 111]}(See the image below.) Stenzl et al reported that in patients with Ta or T1 tumors, at least one of the tumors was seen only with fluorescent cystoscopy in 16% of patients.^[112]Improved detection leads to improved tumor resection, as every tumor detected is resected in the same TURBT.^[113]

Bladder cancer. (A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.

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

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

Radical cystectomy

Although radical cystectomy is typically reserved for muscle-invasive disease, it is also appropriately used to treat some patients with high-risk, non–muscle-invasive bladder cancer, including CIS. Indications in non–muscle-invasive disease include the following:

Tumor bulk so substantial that complete eradication of tumor is not feasible endoscopically
Prostatic urethra involvement
CIS or T1 high-grade tumor persistence despite adequate intravesical management

Eliminating visible lesions with resection is preferable prior to intravesical BCG, but some CIS lesions may not be readily visible. Blue-light cystoscopy may improve the detection of CIS.^[112]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.^[114]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; 20 patients (8.2%) had no cancer (pT0), and 19 patients (7.8%) had urothelial cancer only. 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.

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 NCCN guidelines, cystectomy should involve at least bilateral node dissection, including iliac and obturator nodes.^[1]

Patients with T1 high-grade cancer in association with diffuse CIS are at especially high risk of progression, and they may be treated with early cystectomy based on a decision made by the physician and patient. The EAU guidelines recommend that immediate cystectomy be considered for such patients.^[69]

CIS progresses to muscle-invasive disease in upwards of 80% of affected patients, 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.^[69]

Radical cystectomy

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, bilateral pelvic lymphadenectomy should be offered.

Cystoprostatectomy involves removal of the bladder, peritoneal covering, perivesical fat, , prostate, seminal vesicles, vasa deferentia, and, sometimes, the membranous or entire urethra. Total urethrectomy is rarely performed concomitantly for primary cancer of the bladder in the male since the vast majority of cases a negative urethral margin can be achieved. Those with a positive urethral margin on final pathology can be considered for a delayed urethrectomy.^[80]

Anterior pelvic exenteration consists of cystectomy, urethrectomy, hysterectomy, salpingo-oophorectomy, and partial anterior vaginectomy. Vaginal-sparing techniques can be considered in low stage patients, which will help with the preservation of sexual function.^[115]Additionally, there is evidence suggesting that removing the fallopian tubes alone may decrease the risk of ovarian cancer without impacting hormonal function.^{[116, 117]}

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.^[118]

Emerging retrospective data from multiple institutions suggest that a longer interval from the time of diagnosis to radical cystectomy can adversely affect pathologic stage and survival.^[119]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% with extravesical disease).^[120]

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. Furthermore, AUA guidelines recommend a standard lymphadenectomy, which includes the external and internal iliac and obturator lymph nodes.

PLND can be performed in a standard or an extended version. 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. For a supra-extended PLND, dissection can be continued to the level of the inferior mesenteric artery. In rare cases, patients with lymph node metastases have “skip lesions” (ie, positive nodes in the extended dissection with negative pelvic lymph nodes).

The additional benefit of an extended PLND is controversial. On the basis of 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 proved that an extended PLND is more beneficial than the standard procedure. In a randomized trial of extended versus limited lymph node dissection performed in Germany, extended node dissection failed to show a significant improvement in recurrence-free, cancer-specific, or overall survival.^[121]A Southwestern Oncology Group (SWOG) prospective, randomized trial comparing standard with extended pelvic lymphadenectomy has completed accrural and should report in 2022.^[97]

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

Incontinent urinary diversion

Conduits can be constructed from either ileum or colon. 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.

In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.

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In this procedure, 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.

Continent urinary diversion

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.

In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.

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The orthotopic 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.

In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.

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Neobladder diversions have 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.

A variety of other continent urinary reservoirs have been developed. These vary primarily in the continence mechanisms utilized.

Neoadjuvant chemotherapy in muscle-invasive disease

Cisplatin-based neoadjuvant chemotherapy has become the standard of care in muscle-invasive bladder cancer.^[70]Giving chemotherapy prior to radical cystectomy may improve cancer-specific survival, presumably by treating micrometastatic disease and pathologic downstaging.^[122]A meta-analysis of 11 trials showed an overall survival rate benefit of 5% in patients who received neoadjuvant chemotherapy.^[123]

If locally advanced TCC is suspected, based on clinical staging, the rationale for neoadjuvant chemotherapy prior to cystectomy may be even stronger. In a SWOG multicenter, randomized, prospective study of neoadjuvant therapy with a combination of methotrexate, vinblastine, doxorubicin, and cisplatin, the investigators concluded that neoadjuvant therapy conferred a treatment benefit compared with surgery alone for locally advanced bladder cancer.^[124] Median survival in patients treated with surgery was 46 months as compared to 77 months in patients assigned to receive neoadjuvant MVAC followed by cystectomy. ^[124]

However, several criticisms of this study exist. The study was underpowered because of slow recruitment (317 patients over 11 y), because 20% of the patients who were to undergo cystectomy alone never had the surgery, and because there was no comparison to neoadjuvant therapy alone or adjuvant therapy. In addition, a study that reevaluated the SWOG data found that surgical factors significantly affected outcomes.^[125]

The gemcitabine and cisplatin combination is frequently substituted for the classic MVAC. Studies have shown non-inferiority to the MVAC regimen. The American Urological Association (AUA) states that cisplatin plus gemcitabine is widely accepted by the oncology community as an alternative to MVAC because of its better tolerability.^[126]

A phase III trial that assessed 976 patients with muscle-invasive bladder cancer using neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) chemotherapy found that risk of death was decreased by 16%. Chemotherapy was followed by cystectomy and/or radiotherapy.^[127]

Advanced urothelial carcinoma that develops resistance to platinum-based chemotherapy has often also developed resistance to inhibitors of the epithelial growth factor receptor (EGFR) family of receptor tyrosine kinases. However, a review by Mooso et al notes that EGFR family inhibitors such as erlotinib may be of use in patients with no prior chemotherapy in whom EGFR or ERBB2 is over expressed.^[128]

Adjuvant chemotherapy in muscle-invasive bladder cancer

Although the evidence supporting adjuvant chemotherapy is less compelling than that for neoadjuvant chemotherapy, some patients may benefıt from adjuvant chemotherapy, such as those who underwent up-front radical cystectomy and have extensive tumor invasion of the bladder wall or lymph node involvement.^[70]

The AUA guidelines recommend offering adjuvant cisplatin-based chemotherapy to patients with non–organ-confined (pT3/T4 and/or N+) disease at cystectomy who are eligible for, but have not received, cisplatin-based neoadjuvant chemotherapy.^[80]

A phase III trial in 284 patients with pT3 to T4 or node-positive bladder cancer found insignificant improvement in overall survival with adjuvant cisplatin-based chemotherapy given within 90 days after cystectomy, compared with deferral of chemotherapy until relapse: after a median follow-up of 7 years, 66 of 141 patients (47%%) in the immediate chemotherapy arm had died, compared with 82 out of 143 (57%) in the deferred chemotherapy arm (P=0.13). However, patients who received iimmediate adjuvant chemotherapy had significantly longer progression-free survival (PFS): 5-year PFS was 47.6% in the immediate chemotherapy arm versus 31.8% in the deferred treatment arm (P< 0.0001).^[129]

This study did not meet its accrual goal of 644 patients and was terminated early. Nevertheless, it remains the largest randomized trial of adjuvant chemotherapy to date.^[70]

Systemic Regimens for Metastatic Bladder Cancer

First-line, platinum-based combinations are active in locally advanced and metastatic urothelial carcinoma. However, long-term outcomes, including disease-specific and overall survival, remain suboptimal.

Methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is a standard combination regimen for treatment of metastatic bladder cancer. MVAC has an objective response rate of 57-70% and a complete response rate of 15-20%. Median overall patient survival with this regimen is typically 13-15 months, and the 2-year survival rate is 15-20%.^{[130, 131, 132]}

Gemcitabine and cisplatin (GC) is a newer regimen that has been shown to be as effective as MVAC but with less toxicity.^[133]In particular, less nephrotoxicity is seen with GC than with MVAC.^[134]GC is now considered a first-line treatment for bladder cancer. Unfortunately, about 40-50% of patients with advanced urothelial carcinoma have coexisting medical issues that preclude the use of cisplatin-based therapy.

Programmed cell death inhibitors

Agents that inhibit programmed cell death 1 (PD-1) protein and its ligands PD-L1 and PD-L2, which are part of immune checkpoint pathways that regulate T-cell activation to escape antitumor immunity, have entered clinical practice as second-line therapy for metastatic urothelial carcinoma, and are beginning to establish a role as first-line agents in patients who are not candidates for cisplatin chemotherapy. Agents in this category include atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab.

Previously, second-line therapy had represented a significant unmet medical need. While vinflunine, a vinca alkaloid, was approved in Europe based on the results of a phase III trial versus best supportive care in the second-line setting, its efficacy is marginal.^[135]The median survival for patients treated with second-line therapy such as vinflunine or other agents, including the taxanes and pemetrexed, is only 6-9 months.

Atezolizumab

Atezolizumab (Tecentriq) is the first PD-L1 inhibitor approved for the treatment of urothelial carcinoma. In May 2016, the US Food and Drug Administration (FDA) granted accelerated approval of atezolizumab for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.^[136]In April 2017, atezolizumab’s indication was expanded to include use as initial treatment of locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin chemotherapy.

Approval of atezolizumab was based on the phase II IMvigor 210 trial (n=310), an open-label, multicenter, single-arm study with two cohorts. In the previously treated patients (cohort 2), the objective response rate (ORR) was 26% for the subgroup with the highest positivity for PD-L1, 18% for the subgroup with lower positivity, and 15% for all patients. Median overall survival was 7.9 months for all patients, 11.4 months for the highest-positivity subgroup, and 6.7 months for the lowest-positivity subgroup. Twelve-month overall survival was 36% for all patients, 48% for the high group, and 30% for the low group.^[136]

In the treatment-naive patients (cohort 1), the ORR was 23.5%. Complete responses were seen in 6.7%, and partial responses were seen in 16.8%.^[137]

The FDA has also approved a complementary diagnostic, the Ventana PD-L1 (SP142) assay, which can detect PD-L1 protein expression levels on tumor-infiltrating immune cells and help physicians determine which patients may derive the most benefit from treatment with atezolizumab.

In IMvigor 211, a confirmatory phase III study that compared atezolizumab with chemotherapy in patients whose bladder cancer had progressed on at least one prior platinum-containing regimen, overall survival was numerically, but not significantly, longer in the atezolizumab group than in the chemotherapy group (median 15.9 vs 8.3 months, respectively). However, the safety profile of atezolizumab was superior to that of chemotherapy, with lower rates of grade 3-4 treatment-related adverse events (20% vs 43%), and of adverse events leading to treatment discontinuation (7% vs 18%).^[138]

Nivolumab

Nivolumab (Opdivo) also gained accelerated approval for advanced or metastatic urothelial carcinoma from the FDA. Approval was based on the CheckMate-275, single-arm, phase II clinical trial (n=270). ORR, confirmed by an independent radiographic review committee using Response Evaluation Criteria in Solid Tumors 1.1, was 19.6% (52/265; 95% confidence index [CI]: 15.0-24.9). Seven patients had complete responses and 46 had partial responses. Estimated median response duration was 10.3 months, with responses ongoing at data cutoff.^[139]

The double-blind, randomized phase III CheckMate-274 trial demonstrated the efficacy and safety of adjuvant nivolumab in patients with muscle-invasive urothelial carcinoma after radical surgery (with or without neoadjuvant cisplatin-based combination chemotherapy). Median disease-free survival in the intention-to-treat population was 20.8 months with nivolumab versus 10.8 months with placebo. At 6 months, 74.9% of the 353 patients treated with nivolumab were alive and disease-free, versus 60.3% of the 356 patients treated with placebo (hazard ratio for disease recurrence or death, 0.70; P < 0.001). Among patients with a PD-L1 expression level of 1% or more, those percentages were 74.5% and 55.7%, respectively (hazard ratio, 0.55; 5; P < 0.001).^[140]

Avelumab

Avelumab (Bavencio) was also granted accelerated approval in 2017 for advanced urothelial carcinoma that progresses during or following platinum-containing chemotherapy. Approval was based on the JAVELIN solid tumor trial, which comprised 2 cohorts with 44 patients and 200 patients, respectively. The data from both cohorts were pulled together and showed that 161 patients with a follow-up of > 6 months had an overall response rate of 16.1%.^[141]

Pembrolizumab

Pembrolizumab (Keytruda) gained approval from the FDA for urothelial carcinoma in May 2017. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy. It is also indicated for patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Approval was based on the KEYNOTE-052 trial. As first-line treatment for patients who were ineligible to receive platinum-based chemotherapy, the ORR was 24% at the time of initial phase II data evaluation.^[142]

Pembrolizumab is the only drug with data from a phase III trial demonstrating overall survival benefit vs chemotherapy in the second-line setting for metastatic bladder cancer, with an overall response rate of 15-20% in an unselected patient population.^[80] The FDA approval for second-line therapy for advanced urothelial carcinoma was based on an international phase III trial (n=542). ORR was 10.3 months in the pembrolizumab recipients compared with 7.4 months in the chemotherapy group.^[143]

Fibroblast growth factor receptor inhibitors

Erdafitnib

Erdafitinib inhibits fibroblast growth factor receptor (FGFR) phosphorylation and signaling, and thereby decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. FGFRs regulate important biological processes including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis.

The FDA granted erdafitinib accelerated approval in April 2019 for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Approval was based on a multicenter, open-label, single-arm study (n=87) of patients in which the overall response rate was 32.2%, with 2.3% of patients having a complete response and almost 30% having a partial response.^[144]

Anti-nectin-4 monoclonal antibodies

Enfortumab vedotin

Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti–nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE). Once the antibody attaches to nectin-4 that is expressed on the tumor, the complex is internalized in the lysosome, which releases MMAE.

The FDA approved enfortumab vedotin in December 2019 for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. Approval was based on the single-arm, phase II EV-201 global trial, which enrolled 125 patients with locally advanced or metastatic urothelial cancer who had received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. The primary endpoint of confirmed ORR was 44% per blinded independent central review (55/125; 95% CI, 35.1-53.2). Of patients treated with the single agent enfortumab vedotin, 12% (15/125) experienced a complete response and 32% (40/125) experienced a partial response.^[145]

Radiation Therapy

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. However, no improvement in survival rate has been demonstrated.

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 peritreatment mortality rate of 4-5%, mostly due to nadir sepsis from the chemotherapy. In comparison, the mortality rate for most modern cystectomy series is 2-3%.

Overall, approximately 30% of patients treated with bladder-preserving therapy experience local recurrence of bladder cancer.^[83]A significant number of patients ultimately require salvage cystectomy, which may be associated with decreased options for urinary diversions.

Radical cystectomy

Radical cystectomy has a 2-3% perioperative mortality rate. However, the 6-month mortality may be as high as 7-8% in elderly patients. The two most common late 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)

Early Complications	Rate, %	Late Complications	Rate, %
Ileus	10	Small-bowel obstruction	7.4
Wound infection	5.5	Ureteroenteric stricture	7.0
Sepsis	4.9	Renal calculi	3.9
Pelvic abscess	4.7	Acute pyelonephritis	3.1
Hemorrhage	3.4	Parastomal hernia	2.8
Wound dehiscence	3.3	Stomal stenosis	2.8
Bowel obstruction	3.0	Incisional hernia	2.2
Enterocutaneous fistula	2.2	Fistula	1.3
Rectal injury	2.2	Rectal complications	< 1

The reported overall complication rate (including early and late complications) for 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 even in patients older than 80 years.

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. A nerve-sparing approach may be associated with potency rates of approximately 50-70%.

Urinary diversion

Complications of urinary diversion include the following:

Hyperchloremic metabolic acidosis - If the ileum or colon is used
Urinary tract infections (UTIs)
Stomal-peristomal inflammation, hernia, or stenosis
Urinary calculi
Vitamin B12 deficiency - For diversions affecting the terminal ileum
Ureterointestinal stenosis leading to hydronephrosis

Orthotopic neobladder complications

Owing to 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.

Long-Term Monitoring

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 National Cancer Institute, bladder cancer affects approximately 500,000 people in the United States. Because most still have an intact bladder, the number of patients under surveillance approaches this figure.

The EAU guidelines include schedules for follow-up cystoscopy, urinary cytology, and imaging in patients with Ta/T1 tumors, depending on risk of recurrence and progression. For follow-up in patients with no visible tumor in the bladder but positive cytology, the guidelines recommend biopsies and investigation of extravesical locations.^[69]

For follow-up after a radical cystectomy for muscle-invasive bladder cancer, NCCN recommendations are as follows^[1]:

Imaging: For the first two years, patients should undergo computed tomography (CT) or magnetic resonance imaging (MRI) urography (imaging of upper tracts plus axial imaging of abdomen and pelvis) every 3-6 months. Chest x-ray or CT every 3-6 months or fluorodeoxyglucose positron emission tomography/CT (FDG PET/CT) (category 2B) is recommended only if metastatic disease is suspected. In years 3 through 5, patients should have abdominal/pelvic CT or MRI annually. Chest x-ray annually or FDG PET/CT (category 2B) is recommended only if metastatic disease is suspected. After year 5, patients should have annual ultrasound to look for hydronephrosis; after more than 10 years, imaging is needed only if clinically indicated.
Blood tests: Kidney function testing (electrolytes and creatinine) is recommended every 3-6 months. A complete blood cell count (CBC) and comprehensive metabolic panel (CMP) should be performed every 3-6 months in patients who received chemotherapy. Liver function tests (LFTs) should be performed every 3-6 months. In year 2 through year 5, patients should have annual kidney function testing, LFTs, and vitamin B12 assays. After year 5, patients should have annual monitoring of vitamin B12 levels.
Urine tests: For the first two years following radical cystectomy, patients should have urine cytology every 6-12 months; consider urethral wash cytology every 6-12 months for patients with high-risk disease (eg, postitive urethral margin, multifocal CIS, prostatic urethal invasion). Cytology should be performed at the time of cystoscopy if bladder in situ.

For follow-up after a segmental (partial) cystectomy or bladder preservation, the NCCN recommendations are as follows^[1]:

Cystoscopy: Every 3 months for the first two years, every 6 months for years 3 and 4, annually for years 5 through 10. After 10 years, cystoscopy should be performed only if clinically indicated.
Imaging: Every 3-6 months for the first 2 years, patients with muscle-invasive bladder cancer should undergo CT or MRI urography (imaging of the upper tracts plus axial imaging of abdomen/pelvis), as well as chest x-ray or chest CT. Alternatively, FDG PET/CT (category 2B) may be performed, but only if metastatic disease is suspected. In years 3 through 5, patients should have those imaging studies annually (category 2B). After year 5, imaging is used if clinically indicated.
Blood tests: In the first year, patients should undergo kidney function testing and LFTs every 3-6 months, along with CBC and CMP if they received chemotherapy. Following the first year, patients should have kidney function testing and LFTs as clinically indicated.
Urine tests: For the first two years, patients should have urine cytology every 6-12 months. Following year 2, patients should have urine cytology only if clinically indicated.

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

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Media Gallery

In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.
In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.
In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.
Bladder cancer. The classic appearance of carcinoma in situ is as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.
Bladder cancer. Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.
Bladder cancer. Sessile lesions as shown usually invade muscle, although occasionally a tumor is detected at the T1-G3 stage prior to muscle invasion. Courtesy of Abbott and Vysis Inc.
Bladder cancer. Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.
Bladder cancer. Cross-section through the bladder, uterus, and vagina with squamous cell carcinoma of the bladder infiltrating through the bladder wall into the vaginal wall.
Bladder cancer. High power, Pap stain showing high grade urothelial carcinoma on a bladder wash cytology.
Bladder cancer, Intermediate power, H&E stain of urothelial carcinoma in situ. The superficial cells shed into the urine and correlate with those seen in cytologic bladder washing or urine cytology.
Bladder cancer. High power, H&E stain of high grade urothelial carcinoma. This tumor is now invasive into the muscularis propria (smooth muscle seen in center of image).
Bladder cancer. Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.
Bladder cancer. (A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.

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Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy

Cystoscopy Findings	Urine Cytology Findings	*FISH Findings**	Action
Negative	Negative	Negative†	Routine follow-up
Negative	Negative	Positive‡	Increased frequency of surveillance, whether FISH findings are false positive or anticipatory positive
Negative	Positive	Negative or positive	Cancer until proven otherwise Upper tract imaging with contrast Cystoscopy with random bladder and urethral biopsies, retrograde pyelography, selective ureteral washings, and/or ureteroscopy Evaluate urethra Increased frequency of surveillance upon negative findings
*FISH - Fluorescent in situ hybridization. †Negative predictive value 95%. ‡Positive predictive value 30%.

Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG

Stage	Recurrence, %	Progression, %
Ta	55	11
T1	61	31
CIS	45	23
G1	61	2-4
G2	56	5-7
G3	50-70	30-40

Table 3. Most Common Complications of Radical Cystectomy

Early Complications	Rate, %	Late Complications	Rate, %
Ileus	10	Small-bowel obstruction	7.4
Wound infection	5.5	Ureteroenteric stricture	7.0
Sepsis	4.9	Renal calculi	3.9
Pelvic abscess	4.7	Acute pyelonephritis	3.1
Hemorrhage	3.4	Parastomal hernia	2.8
Wound dehiscence	3.3	Stomal stenosis	2.8
Bowel obstruction	3.0	Incisional hernia	2.2
Enterocutaneous fistula	2.2	Fistula	1.3
Rectal injury	2.2	Rectal complications	< 1

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Author

Kara N Babaian, MD, FACS Assistant Professor, Director of Urologic Oncology, Division of Urology, Southern Illinois University School of Medicine

Kara N Babaian, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society of Clinical Oncology, American Urological Association, European Association of Urology, North Central Section of the American Urological Association (AUA), Society of Urologic Oncology, Society of Women in Urology

Disclosure: Participation in a clinical trial for: Janssen.

Coauthor(s)

Parker G Adams, BS DO Candidate, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

Parker G Adams, BS is a member of the following medical societies: American Urological Association

Disclosure: Nothing to disclose.

Courtney McClure, DO Resident Physician, Department of Urology, Ascension Healthcare

Disclosure: Nothing to disclose.

Brandon Tompkins, BS DO Candidate, Kansas City University of Medicine and Biosciences College of Osteopathic Medicine

Disclosure: Nothing to disclose.

Megan McMurray, DO Resident Physician, Department of Urology, Southern Illinois University School of Medicine

Megan McMurray, DO is a member of the following medical societies: American Association of Clinical Urologists, American Urological Association, Association of Women Surgeons, Society of Women in Urology

Disclosure: Nothing to disclose.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, American Urological Association, Association of Military Osteopathic Physicians and Surgeons, Endourological Society, Society of Laparoscopic and Robotic Surgeons, Society of University Urologists

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Endourological Society Board of Directors; President Elect North Central Section of the American Urological Association<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical.

Additional Contributors

Gary D Steinberg, MD, FACS Professor and Director, Perlmutter Cancer Center, Goldstein Bladder Cancer Program, NYU Langone Health, NYU Urology Associates

Gary D Steinberg, MD, FACS is a member of the following medical societies: American Association for Cancer Research, American College of Surgeons, American Society of Clinical Oncology, American Urological Association, International Society of Urology, Society of Laparoscopic and Robotic Surgeons, Society of Urologic Oncology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Heat Biologics; CG Oncology; PhotoCure; Merck; Roche/Genentech; Ciclomed; Taris Biomedical (now Janssen); MDxHealth; Fidia Farmaceuticals; Urogen, Ferring; Aduro; Boston Scientific; Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; others<br/>Member of Clinical Trial Protocol Committees for: for: Merck; BMS; Janssen; CG Oncology; Pfizer; PhotoCure; Fidia; Seagen; Protara.

Kush Sachdeva, MD Southern Oncology and Hematology Associates, Inspira Health Network

Disclosure: Nothing to disclose.

Bagi RP Jana, MD, MBA, MHA, FACP Professor of Cancer Medicine, MD Anderson Cancer Center; Professor of Medicine, University of Texas Medical Branch at Galveston

Bagi RP Jana, MD, MBA, MHA, FACP is a member of the following medical societies: American Cancer Society, American Medical Association, American Society of Clinical Oncology, SWOG

Disclosure: Nothing to disclose.

Acknowledgements

Sujeet S Acharya, MD Resident Physician, Department of Surgery, Section of Urology, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine