Bladder Cancer

Table II.

Pathologic T stage at the time of radical cystectomy	5 year OS (%)
pT2	66
pT3	35
pT4	27

The 5 and 10-year recurrence-free survival for patients with organ-confined, lymph node-negative tumors was 92% and 86% for P0 disease, 91% and 89% for Pis, 79% and 74% for Pa, and 83% and 78% for P1 tumors, respectively. Patients with muscle invasive (P2 and P3a), lymph node-negative tumors had 89%, 87%, 78% and 76% 5 and 10-year recurrence-free survival, respectively.

Patients with non-organ-confined (P3b, P4), lymph node-negative tumors demonstrated a significantly higher probability of recurrence compared to those with organ-confined bladder cancers. The 5 and 10-year recurrence-free survival for pT3b tumors was 62% and 61%, and for pT4 tumors was 50% and 45%, respectively. Among patients with lymph node tumor involvement, the 5 and 10-year recurrence-free survival for these patients was 35% and 34%, respectively, which was significantly lower than that for patients without lymph node involvement.

Partial cystectomy

Patients should be strongly counseled that a partial cystectomy for muscle-invasive transitional cell carcinoma may be associated with higher rates of local and systemic recurrence. Since functional bladder substitutes such as the orthotopic neobladder are widely available, partial cystectomies must be reserved only for select indications such as a urachal adenocarcinomas. In highly selected patients with muscle invasive bladder cancer partial cystectomies may be performed by an experienced urologic oncologist. The goals of a partial cystectomy are:

• To remove the bladder tumor completely.

• To maintain continence and adequate bladder capacity.

Partial cystectomies can be performed for patients with bladder tumors with the following characteristics:

• Small unifocal tumor.

• Tumors away from the ureteral orifices and bladder neck (e.g., tumors involving the dome of the bladder).

• Complete resection of the tumor is safe and feasible.

• Obtaining a surgical margin free of malignancy more than 2 cm from the primary bladder tumor is feasible.

• Bladder reconstruction after partial cystectomy is feasible and results in a functional bladder with adequate bladder capacity.

• Random biopsies elsewhere in the urothelium does not show high risk flat lesions (e.g urothelial carcinoma in situ, Tis).

• Urachal adenocarcinomas in the dome of the bladder.

These bladder tumor characteristics are present in a very small minority of patients with muscle invasive bladder cancer. All patients must have negative random bladder biopsies of the “normal” bladder regions. In addition, pre-operative MRI evaluation of the abdomen and pelvis should be performed to evaluate the local extent of the malignancy. Induction cisplatin-based combination chemotherapy should be considered for patients with muscle invasive bladder cancer candidates for a partial cystectomy. Finally, whenever possible, a radical cystectomy should be offered for patients with muscle-invasive transitional cell carcinoma, due to the field effect.

Extent of lymphadenectomy

A thorough bilateral pelvic lymph node dissection at the time of radical cystectomy (Figure 8) results in accurate pathologic staging, improves disease local-regional control and provides key information about management and prognosis. A more complete lymphadenectomy is associated with a higher likelihood of a complete resection, a higher chance of negative surgical margins and a lower local and systemic recurrence rate. Patients with micrometastatic disease to the pelvic lymph nodes may be cured by a thorough lymphadenectomy. On the other hand, patients with bulky involved lymph nodes are unlikely to be cured by an extended lymphadenectomy.

Figure 8.

Currently, there is no recommended minimum number of pelvic lymph nodes that should be resected. The optimal extent of bilateral pelvic lymphadenectomy is being established in a prospective randomized clinical trial. Patients with metastases to regional pelvic lymph nodes have a high risk for distant micrometastatic disease and development of gross visceral and skeletal metastases and should be strongly considered for adjuvant chemotherapy.

Types of urinary diversion

Two main classes of urinary diversions are performed at the time of radical cystectomy: non-continent and continent urinary diversions.

1. Ileal conduit urinary

The ileal conduit urinary diversion is a non-continent urinary diversion. It is the simplest and the most common type of urinary diversion performed. The ileal conduit is the standard type of urinary diversion to which newer types of urinary diversion are compared. The ileal conduit is a resected segment of ileum that serves as a simple passage of urine. It is anastomozed proximally to both ureters and distally to an externalized stoma through the abdominal wall. There is free and constant urinary flow via the ileal conduit into an external urinary bag applied around the abdominal wall stoma.

2. Orthotopic neobladder urinary diversion

Orthotopic neobladder is a type of continent urinary diversion. The neobladder is created from detubularized segments of small intestine. The neobladder is anastomozed proximally to both ureters and distally to the proximal urethra through a Foley catheter. Urinary continence is preserved as the native urethral sphincter and its function are preserved. In carefully selected patients, the orthotopic neobladder is the preferred form of urinary diversion.

3. Continent cutaneous urinary diversion

In the continent cutaneous urinary diversion an ileal pouch is anastomozed proximally to the ureters and distally to a detubularized, aperistaltic segment of ileum which in turn is anastomozed to the abdominal wall. The urine accumulates in the ileal pouch and needs to be drained by clean self-catheterization. The patient needs to perform life-long clean self-catheterization.

Continent urinary diversions are more complex, demanding, and longer surgical procedures compared to the standard ileal conduit urinary diversion (Figure 9). Patient selection for urinary diversion is complex and should be individualized. Relevant clinical factors that influence the choice of urinary diversion include:

Figure 9.

• Patient health.

• Weight.

• Renal function.

• Hepatic function.

• Local and regional extent of bladder cancer at the time of presentation.

• Patient ability and commitment to perform clean self-catheterization.

• Presence of gastrointestinal disease (e.g., inflammatory bowel disease).

Patients with significant renal or hepatic dysfunction, obesity, locally or regionally advanced bladder cancer are not considered candidates for orthotopic neobladder urinary diversion.

Induction cisplatin-based combination chemotherapy for muscle invasive bladder cancer

Half of all patients with muscle invasive bladder cancer have micrometastases at the time of radical cystectomy. Without additional therapy, the majority of these patients will develop gross metastases within the first two to three years after radical cystectomy and will die from distant metastatic disease. For these patients, radical cystectomy as a single treatment modality is not enough to achieve a long term remission.

The results of two prospective randomized controlled clinical trials and two meta-analyses demonstrate the safety and efficacy of induction (neoadjuvant) cisplatin-based combination chemotherapy administered before radical cystectomy for patients with muscle invasive (T2) or higher stage (T3, T4a) bladder cancer.

The goals of induction cisplatin-based combination chemotherapy are:

• Treatment of micrometastases.

• Down-staging of the primary bladder tumor.

• Decrease the rate of relapse.

• Improve overall survival.

At five years of follow up, induction cisplatin-based combination chemotherapy is associated with a 14% relative risk reduction in the rate of bladder cancer related death and a 5% absolute improvement in overall survival.

Induction cisplatin-based combination chemotherapy regimens

1. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (ddM-VAC)

Four cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (ddM-VAC) is a standard induction cisplatin-based combination chemotherapy regimen. Each cycle of induction chemotherapy is administered every 14 days:

• Methotrexate 30 mg/m² on day 1.

• Vinblastine 3 mg/m² on day 2.

• Doxorubicin 30 mg/m² on day 2.

• Cisplatin 70 mg/m² on day 2.

Myeloid growth factor support therapy for prevention of febrile neutropenia should be initiated on day 3 of each cycle:

• Filgrastim 5 mcg/kg subcutaneously daily on days 3 through 9, or Pegfilgrastim 6 mg subcutaneously on day 3.

Radical cystectomy should be performed between 4 and 10 weeks after completion of the fourth cycle of ddM-VAC. Up to 38% of patients who receive induction cisplatin-based combination chemotherapy do not have residual tumor in the bladder (pathologic complete response) at the time of radical cystectomy. Pathologic complete response at the time of radical cystectomy is associated with improved overall survival and recurrence-free survival.

Overall, induction cisplatin-based combination chemotherapy is safe. It does not decrease the patient’s chance of undergoing a radical cystectomy. No treatment related deaths have been reported in published prospective phase III randomized controlled clinical trials. Induction cisplatin-based combination chemotherapy does not increase the rate of postoperative complications. The dose-dense regimen is currently preferred over the prior standard M-VAC regimen due to its improved toxicity profile. Grade 3 neutropenia was the main toxicity and seen in 10% of patients. Ninety-five per cent were able to receive all 4 cycles.

2. Gemcitabine plus cisplatin (GC)

Gemcitabine plus cisplatin (GC) is a commonly prescribed induction chemotherapy regimen before radical cystectomy for patients with muscle invasive bladder cancer. This regimen includes three cycles of GC administered every 28 days:

• Gemcitabine 1000 mg/m² on days 1, 8, and 15

• Cisplatin 70 mg/m² on day 2

There are no published prospective randomized phase III clinical trials evaluating the safety and efficacy of induction GC followed by radical cystectomy for patients with muscle invasive bladder cancer. Despite this lack of evidence, induction GC is commonly prescribed before radical cystectomy.

Adjuvant cisplatin-based combination chemotherapy for muscle invasive urothelial carcinoma of the bladder

The role of adjuvant cisplatin-based combination chemotherapy administered after radical cystectomy is not clearly established. Published studies evaluating the safety and efficacy of adjuvant cisplatin-based combination chemotherapy are small and lack power to detect significant differences in overall survival or relapse-free survival. Recommendations about adjuvant cisplatin-based combination chemotherapy after radical cystectomy are based on expert opinion. In some patients with muscle invasive bladder cancer who did not receive induction chemotherapy before radical cystectomy, adjuvant cisplatin-based combination chemotherapy is recommended.

After radical cystectomy, three to four cycles of adjuvant M-VAC or GC administered every 28 days are recommended for patients with muscle invasive bladder cancer at very high risk for harboring micrometastatic disease. These include:

• Patients with tumor invasion into microscopic or macroscopic perivesical tissue, pathologic T3a or T3b.

• Patients with tumor invasion into adjacent organs, pathologic T4a.

• Patients with metastases to primary or secondary pelvic regional lymph nodes, pathologic N1, N2, or N3.

Trimodality therapy-selective bladder preservation for muscle invasive urothelial carcinoma of the bladder

Trimodality therapy and selective bladder preservation is an alternative to radical cystectomy for selected patients with muscle invasive bladder cancer. Trimodality therapy involves a complete TURBT of all visible tumor(s) followed by concurrent chemoradiotherapy to the bladder and regional lymph nodes, followed by three to four cycles of adjuvant cisplatin-based combination chemotherapy.

The goals of trimodality therapy are:

• Preserve the patient’s original bladder.

• Preserve bladder function.

• Decrease the rate of local, regional, and systemic relapse.

• Achieve local, regional and systemic remission.

• Achieve optimal overall survival.

External beam radiotherapy techniques in use are image guided radiotherapy and intensity modulated radiotherapy (IMRT). One of the most important factors determining the local and regional control with trimodality therapy is the total dose of radiotherapy delivered to the primary bladder tumor and to regional lymph nodes. The total dose of radiotherapy to the primary bladder tumor ranges from 55 Gy to 70 Gy. The dose of radiotherapy to regional lymph nodes ranges from 45 Gy to 50 Gy.

Systemic chemotherapy is administered concurrently with radiotherapy to radio sensitize and inhibit the repopulation of bladder cancer cells. The most frequently prescribed chemotherapeutic agent is cisplatin. Other chemotherapeutic agents frequently prescribed concurrently with radiotherapy include carboplatin, paclitaxel, 5-fluorouracil (5FU), mitomycin C and others.

In a prospective, randomized clinical trial, infusional 5FU plus mitomycin C given concurrently with radiotherapy to the bladder was associated with improved local regional control compared to radiotherapy alone in patients with muscle invasive bladder cancer. The chemotherapy regimen prescribed in this prospective randomized clinical trial was as follows:

• 5FU 500 mg/m² continuous intravenous infusion (CIV) during days 1 to 5 and 16 to 20 of radiotherapy (10 days total)

• Mitomycin C 12 mg/m² intravenous (IV) bolus infusion on day 1 of radiotherapy.

This non-platinum chemotherapy regimen is particularly useful in patients with renal dysfunction (GFR < 50 mL/min).

After completion of concurrent chemoradiotherapy, adjuvant cisplatin-based combination chemotherapy is prescribed for the treatment of probable micrometastatic disease. The most frequently prescribed adjuvant combination chemotherapy regimen is GC.

Adequate selection of patients for trimodality therapy is fundamental to achieve optimal outcomes. Eligible patients for trimodality therapy include those with the following clinical parameters:

• Small bladder tumor (< 5cm).

• Early T stage (T2 or lower T stage).

• Complete TURBT of all gross visible tumor(s).

• No evidence of regional pelvic lymph node involvement on contrast enhanced cross sectional imaging studies.

• Absence of tumor related obstructive uropathy, ureteral obstruction, or hydronephrosis.

Selected patients with resectable muscle invasive bladder cancer (primary bladder tumor T4a or lower T stage), pelvic or lower retroperitoneal lymph node metastases and no clinical or radiologic evidence of distant lymph node, visceral or skeletal metastases may be candidates for induction cisplatin-based combination chemotherapy followed by salvage radical cystectomy. These patients are not eligible for trimodality therapy.

Management of unresectable or metastatic bladder cancer

1. Systemic chemotherapy for unresectable or metastatic urothelial carcinoma of the bladder

Bladder cancer is a chemosensitive epithelial malignancy. Cisplatin-based combination chemotherapy is the mainstay of treatment for metastatic or unresectable bladder cancer. The current standard first line treatment for patients with unresectable or metastatic bladder cancer and preserved renal function (GFR > 60 mL/min) is cisplatin plus gemcitabine. Up to six cycles of cisplatin plus gemcitabine is the current standard first line therapy for patients with metastatic or unresectable bladder cancer. Each cycle of cisplatin plus gemcitabine is administered every 28 days as follows:

• Gemcitabine 1000 mg/m² IV on days 1, 8, and 15.

• Cisplatin 70 mg/m²IV on day 2.

Response to chemotherapy is evaluated with contrast enhanced cross sectional imaging studies (CT scan or MRI) every two to three cycles of chemotherapy (Figure 10).

Figure 10.

Patients with metastatic or unresectable bladder cancer treated with first-line methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) combination chemotherapy have a similar median overall survival and objective response rates compared to patients treated with first-line gemcitabine plus cisplatin (GC). MVAC is associated with more frequent and severe side effects compared to gemcitabine plus cisplatin. These include severe mucositis (oral mucosal ulceration, diarrhea), myelosuppression, febrile neutropenia, severe fatigue and decline of quality of life. Gemcitabine plus cisplatin is considered the current standard first line combination chemotherapy regimen for patient with metastatic or unresectable bladder cancer.

The second-generation platinum agent carboplatin is not equivalent to cisplatin in the treatment of metastatic or unresectable bladder cancer. The role of first-line carboplatin-based combination chemotherapy for metastatic or unresectable bladder cancer is not clearly established. In patients with preserved renal function (GFR > 60 mL/min) cisplatin plus gemcitabine is the standard first line chemotherapy regimen. Carboplatin should not be prescribed in patients eligible for cisplatin-based combination chemotherapy.

2. Second-line chemotherapy for metastatic or unresectable bladder cancer

Second-line chemotherapy may be considered for the following groups of patients with metastatic or unresectable bladder cancer:

• Patients who have radiographic progression during or after completion of first-line cisplatin-based combination chemotherapy.

• Patients with disease resistant or refractory to first-line cisplatin-based combination chemotherapy.

• Patients who developed severe toxicity or unmanageable side effects caused by first line cisplatin-based combination chemotherapy.

Clinical factors influencing the decision to prescribe second-line chemotherapy include:

• Performance and nutritional status of the patient.

• Rate of progression of metastatic or unresectable disease during or after completion of first line combination chemotherapy.

• Extent of metastatic or unresectable disease.

• Patient preference.

Goals of second-line chemotherapy include:

• Palliation of symptoms.

• Improvement of quality of life.

• Prolongation of life.

Currently, there is no standard second-line single agent or combination chemotherapy regimen for patients with metastatic or unresectable bladder cancer who have progression after first line chemotherapy. Ideally, these patients should be enrolled in prospective randomized clinical trials evaluating the safety and efficacy of new antineoplastic or targeted therapies.

When prescribing second-line systemic therapy it is important to avoid combination chemotherapy regimens associated with high rates of severe side effects that could have a negative impact on the patient’s quality of life. In general, single-agent chemotherapy is associated with lower rates of toxicity and side effects compared to combination chemotherapy. In addition to second-line chemotherapy, all patients should receive optimal supportive care.

Commonly prescribed second-line single-agent chemotherapy for patients with metastatic or unresectable bladder cancer include:

• Paclitaxel 175 mg/m² IV every 21 days.

• Docetaxel 75 mg/m² IV every 21 days.

• Pemetrexed 500 mg/m² IV every 21 days.

• Gemcitabine 1200 mg/m² IV on Days 1, 8, 15 every 28 days.

Commonly prescribed second-line combination chemotherapy regimens for patients with metastatic or unresectable bladder cancer include:

• Paclitaxel 175 mg/m² IV on day one plus gemcitabine 1000 mg/m² on days one and eight every 21 days.

• Paclitaxel 200 mg/m² continuous IV infusion over 24 hours on day one plus ifosfamide 1000 mg/m² IV on days one, two, three and four every 21 days. Pegfilgrastim 6 mg subcutaneous on day five (TIP).

• Docetaxel 40 mg/m² IV plus gemcitabine 800 mg/m² IV both on days one and eight every 21 days.

New chemotherapeutic agents undergoing evaluation in prospective clinical trials include vinflunine, ixabepilone as well as others.

3. Immunotherapy for patients with metastatic or unresectable bladder cancer

The role of immunotherapy has long been established in non-muscle-invasive bladder cancer. The localized inflammatory response to intravesical BCG appears to be the source of its anti-tumor activity.

For advanced or metastatic urothelial carcinomas, there is now an established role for immune checkpoint inhibitors. Currently, 5 antibodies targeting the PD1/PD-L1 axis are FDA approved for this indication.

The PD-1 inhibitor pembrolizumab is approved for the treatment of patients with advanced or metastatic urothelial carcinomas who have progressed on or following prior platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. This approval is based on improved overall survival (OS) with pembrolizumab compared to cytotoxic chemotherapy.

The anti-programmed death-1 ligand (PD-L1) monoclonal antibodies atezolizumab, durvalumab and avelumab and the anti-PD-1 monoclonal antibody nivolumab have been granted accelerated approval by the FDA for the treatment of patients with advanced or metastatic urothelial cancer who have progressed on or following prior platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. The accelerated approval is based on tumor response rates (RR) and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Atezolizumab and pembrolizumab have also been granted accelerated approval by the FDA as first line therapies for patients with advanced or metastatic urothelial carcinomas ineligible for cisplatin-based combination chemotherapy.

Tumor PD-L1 expression by immunohistochemistry (IHC) may identify those cases most likely to respond to PD1/PD-L1 inhibition. However, PD-L1 IHC testing is not currently required for administration of any of the checkpoint inhibitors approved for the treatment of advanced or metastatic urothelial carcinomas.

Check point inhibitors for the treatment of advanced and metastatic urothelial carcinomas:

• Atezolizumab 1200 mg IV every 21 days continued until progression or unmanageable toxicity

• Durvalumab 10 mg/kg IV every 2 weeks continued until progression or unmanageable toxicity

• Avelumab 10 mg/Kg IV every 2 weeks continued until progression or unmanageable toxicity

• Nivolumab 240 mg IV every 2 weeks continued until progression or unmanageable toxicity

• Pembrolizumab 200 mg IV every 3 weeks continued until progression or unmanageable side effects

In a single arm phase 2 clinical trial atezolizumab demonstrated an objective response rate of 15%. Responses were durable for at least 6 months in 84% of responders. Patients expressing >5% PD-L1 on tumor cells had an improved ORR (26% vs. 9.5%). In patients ineligible for cisplatin-based combination chemotherapy, first-line atezolizumab was associated with an ORR of 23.5%.

A Phase 3 trial of pembrolizumab vs. chemotherapy in the second-line metastatic setting demonstrated an improved OS (10.3 vs. 7.4 months) and ORR (21.1 vs. 11.4%) for pembrolizumab over platinum-containing chemotherapy. In addition, a single-arm, open-label trial in 370 patients with metastatic urothelial carcinomas ineligible for cisplatin-based combination chemotherapy treated with pembrolizumab 300 mg IV every 3 weeks showed an ORR of 28.6% at a median follow-up of 7.8 months.

The safety and efficacy of the various FDA-approved check point inhibitors for advanced or metastatic urothelial carcinomas is similar. Choice of a specific check point inhibitor is based on factors such as clinician experience and familiarity with a particular agent, insurance coverage, cost, frequency of administration, and patient preference. Survival outcomes in prospective randomized phase 3 clinical trials may influence the decision to prescribe a particular check point inhibitor in the future.

The safety and efficacy of checkpoint inhibitors as first-line therapy for patients with advanced or metastatic urothelial carcinomas are under investigation in large phase 3 randomized clinical trials. In addition, multiple clinical trials are evaluating the safety and efficacy of different check point inhibitors for multiple indications including neoadjuvant therapy, adjuvant therapy, and treatment of patients with non-muscle-invasive urothelial carcinoma of the bladder in combination with intravesical BCG.

Immune-mediated side effects of check point inhibitors require early recognition and timely management. Common toxicities from check point inhibitors include:

• Fatigue (up to 50%, all grades)

• Gastrointestinal (low-grade nausea, vomiting, diarrhea; 5-15%)

• Anorexia

• Rash or pruritus

• Pyrexia

Infrequent but serious immune related side effects including pneumonitis, autoimmune endocrinopathies (hypo- or hyperthyroidism, hypophysitis), colitis and hepatitis have been reported. Depending on the severity of toxicity, treatment is either withheld or permanently discontinued. There are no dose reductions. The mainstay of management of moderate to severe immune related side effects is systemic corticosteroids. A typical approach is prednisone 1 to 2 mg/kg/day. Once toxicity has improved to grade 1 in severity, a 4-6 week taper is initiated. Oral budesonide has also been used for treatment of colitis. Only if symptoms remain controlled after taper completion is the immunotherapeutic agent re-initiated.

In severe cases, other immune-modulating agents such as TNF inhibitors may be indicated. Consultation with appropriate medical services (endocrinology, pulmonary medicine, gastroenterology) for assistance with diagnosis and treatment may be considered. As a consequence of these toxicities, immune checkpoint inhibitors are generally avoided in patients with pre-existing autoimmune disease or requiring chronic high-dose steroids.

For patients with treatment-related hypothyroidism or adrenal insufficiency, replacement with levothyroxine and hydrocortisone plus fludrocortisone, respectively, is given and the immunotherapy is generally continued.

4. First-line triple agent combination chemotherapy for patients with metastatic or unresectable bladder cancer

First-line combination chemotherapy with three different chemotherapeutic agents is not superior to standard front line cisplatin plus gemcitabine for patients with metastatic or unresectable bladder cancer. The safety and efficacy of first-line triple agent combination systemic therapy with novel chemotherapeutic or targeted agents needs to be evaluated in well-designed prospective randomized clinical trials.

5. Systemic chemotherapy for patients with metastatic or unresectable bladder cancer not eligible for cisplatin-based combination chemotherapy

Patients with advanced bladder cancer with the following characteristics are not considered eligible for cisplatin-based combination chemotherapy:

• GFR less than 60 ml/min.

• Grade 2 or higher hearing loss.

• New York Heart Association heart failure class III or higher.

• Pre-existing moderate to severe or severe peripheral neuropathy.

At the present time, there is no standard first-line chemotherapy regimen for patients with metastatic or unresectable bladder cancer and concomitant renal insufficiency (GFR < 60 mL/min). Placement of a percutaneous nephrostomy tube or insertion of ureteral stent in patients with tumor-related obstructive uropathy may improve renal function and allow treatment with cisplatin-based combination chemotherapy. A standard first line combination chemotherapy regimen for patients with metastatic or unresectable bladder cancer and chronic renal insufficiency (GFR< 60 mL/min) needs to be established in prospective randomized clinical trials.

A commonly prescribed front-line combination chemotherapy for patients with advanced bladder cancer and GFR of 30 to 60 ml/min includes:

• Carboplatin AUC 5 on day one plus gemcitabine 1000 mg/m² on days one and eight every 21 days.

A commonly prescribed front-line combination chemotherapy for patients with advanced bladder cancer and GFR less than mL/min includes:

• Paclitaxel 175 mg/m² IV on day one plus gemcitabine 1000 mg/m² on days one and eight every 21 days.

6. Maintenance systemic chemotherapy for patients with advanced bladder cancer

The role of maintenance systemic therapy (chemotherapy or targeted therapy) after completion of first-line cisplatin-based combination chemotherapy is unknown. The safety and efficacy of maintenance systemic therapy for patients with unresectable or metastatic urothelial carcinoma of the bladder is under evaluation in prospective randomized clinical trials.

7. Post-chemotherapy salvage radical cystectomy for patients with bladder cancer with regional lymph node metastases

A proportion of patients with advanced bladder cancer with metastases to regional pelvic or lower retroperitoneal lymph nodes and absence of visceral or skeletal metastases may benefit from post-chemotherapy salvage radical cystectomy. In some retrospective studies, 30-40% of such patients achieved a long-term remission with salvage radical cystectomy performed after cisplatin-based combination systemic chemotherapy.

The selection of patients for salvage radical cystectomy performed after induction cisplatin-based combination chemotherapy should be performed by a multidisciplinary team on a case-by-case basis. Patient preferences should be considered in the decision to proceed with post-chemotherapy salvage radical cystectomy.

Potential candidates for post-chemotherapy salvage radical cystectomy include patients with the following clinical characteristics:

• Resectable primary bladder tumor including tumors invading into adjacent organs (T4a).

• Pelvic or lower retroperitoneal lymph node metastases (lymph node involvement at the level or below the level of the iliac, lower para-aortic or lower para-caval lymph nodes).

• Patients with adequate functional and nutritional status.

• No clinical or radiologic evidence of distant lymph node, visceral or skeletal metastases after completion of induction chemotherapy.

Patients with bladder tumors invading into the pelvic or abdominal wall (T4b), with lymph node involvement above the lower para-aortic or lower para-caval lymph nodes or with visceral or skeletal metastases have unresectable bladder cancer. These patients are not eligible for post-chemotherapy salvage radical cystectomy.

What other therapies are helpful for reducing complications?

Growth factor support therapy: neutropenia

Primary prophylaxis of neutropenic fever with growth factor support therapy (e.g., filgrastim or pegfilgrastim) is not routinely prescribed in patients with bladder cancer receiving induction (neoajuvant), adjuvant, or palliative chemotherapy.

Patients who develop neutropenic fever after chemotherapy should receive growth factor support therapy with subsequent cycles of chemotherapy:

• Filgrastim 5 mg/kg SC daily starting 24 hours after infusion of chemotherapy and until the absolute neutrophil count (ANC) is more than 1000 for two to three consecutive days.

• Pegfilgrastim 6 mg SC 24 hours after infusion of chemotherapy. Do not prescribe pegfilgrastim within 14 days before the next chemotherapy infusion.

Growth factor support therapy: anemia

Erythropoietin stimulating agents (e.g., erithropoietin, darbepoietin) should not be prescribed in patients receiving potentially curative induction (neoadjuvant) or adjuvant cisplatin-based combination chemotherapy. In this setting, transfusion of packed red blood cells may be needed in patients who develop symptomatic or severe anemia.

Management of bone metastases

Short-course palliative external beam radiotherapy may be considered for painful bone metastatic lesions.

The parenteral bisphosphonate zoledronic acid or the monoclonal antibody denosumab are indicated for patients with bladder cancer with metastases to bones. Denosumab targets the receptor activator of nuclear factor kappa-B ligand (RANKL).

• Zoledronic acid 4 mg IV every four weeks.

• Denosumab 120 mg SC every four weeks.

Dose reductions of zoledronic acid are needed in patients with renal dysfunction. In patients with advanced renal insufficiency (GFR < 30 mL/min), zoledronic acid should not be prescribed. Patients receiving zoledronic acid or denosumab should take oral calcium and vitamin D supplementation.

Osteonecrosis of the jaw is a potential complication of treatment with zoledronic acid or denosumab. A careful exam of the oral cavity should be done in patients receiving these agents.

Antiemetic therapy

Cisplatin-based combination chemotherapy is highly emetogenic. Cisplatin can cause acute and delayed emesis. Medications for the prevention of acute nausea should include selective 5-HT3 antagonists (e.g., palonosetron, ondansetron, granisetron, or donasetron), a corticosteroid (e.g., dexamethasone), plus a neurokinin 1 (NK1) receptor antagonist (e.g., aprepitant).

Preventive therapy of emesis after highly emetogenic chemotherapy:

Day 1: acute antiemetic therapy administered before infusion of chemotherapy

• Aprepitant 125 mg PO.

• 5 HT3 antagonist antiemetic agent e.g. palonosetron 0.25 mg IV.

• Dexamethasone 12 mg PO or IV.

Day 2 and 3

• Aprepitant 80 mg PO daily.

Day 2, 3 and 4: delayed antiemetic therapy

• Dexamethasone 8 mg PO daily.

Days 1-4: breakthrough antiemetic therapy (prn)

• Lorazepam 0.5-2 mg IV, PO, or sublingual every 6 hours.

• Prochlorperazine 10 mg PO every 6 hours or prochlorperazine 25 mg suppositories every 12 hours or metoclopramide 10-40 mg PO or IV every 6 hours.

An oral H2 blocker (e.g., ranitidine) or a proton pump inhibitor (e.g., omeprazole) should be prescribed for the prevention of corticosteroid-related upper gastrointestinal toxicity. Patients receiving lorazepam should be monitored for oversedation.

What should you tell the patient and the family about prognosis?

Non-muscle invasive bladder cancer

The five-year risk of local recurrence after initial treatment of non-muscle invasive urothelial carcinoma of the bladder is 60-70%. Patients with non-muscle invasive urothelial carcinoma of the bladder have a 20-30% risk of progression to a higher disease stage or pathologic grade.

Patients with low-grade papillary tumors (Ta) commonly recur locally but rarely progress to muscle invasive disease. These patients have a survival similar to individuals without bladder cancer. Patients with tumors invading the submucosa (lamina propria) of the bladder wall (T1) are a heterogeneous group. Patients with low-grade tumors have an indolent clinical course characterized by local recurrence(s) without progression to a higher disease stage or grade. In contrast, patients with high grade T1 tumors have an aggressive clinical course with progression to muscle invasion or development of distant metastatic disease.

Clinical and pathologic characteristics of non-muscle invasive urothelial carcinoma of the bladder associated with an aggressive clinical course and progression to higher disease stages include:

• Tumor invasion of the deep portion of the lamina propria (T1b).

• High-grade histology.

• Presence of lymphovascular invasion (LVI).

• Presence of extensive urothelial carcinoma in situ (Tis).

• More than three bladder tumors at the time of TURBT.

• Size of bladder tumor more than 3 cm.

• First local recurrence within three months after initial TURBT.

• Two or more recurrences in less than 12 months after initial TURBT.

• Incomplete resection of tumor due to diffuse involvement of the bladder urothelium or unfavorable location of tumor (near a ureteral orifice or in a bladder diverticulum).

• Recurrence after intravesical chemotherapy or immunotherapy.

Muscle invasive bladder cancer

The ten-year recurrence-free survival after radical cystectomy for patients with muscle invasive bladder cancer depends on the pathologic staging at the time of radical cystectomy:

• Patients with organ-confined muscle invasive disease: 80% or higher.

• Patients with muscle invasive disease and extension into perivesical fat tissue: 50%.

• Patients with muscle invasive disease and regional metastases to pelvic lymph nodes: 30%.

Clinical, surgical, and pathologic factors influencing the risk of recurrence after radical cystectomy:

• Depth of tumor invasion into the bladder wall (T stage).

• Primary tumor with high-grade histology.

• Presence of lymphovascular invasion (LVI) in the primary tumor is associated with overall survival in patients with regional node-negative disease at the time of radical cystectomy.

• Immunohistochemical expression of protein factors involved in cell cycle regulation in the primary bladder tumor: p53, p27, p21, retinoblastoma protein (pRb), and cyclin E. (Altered expression of three or more protein factors is associated with an unfavorable risk of recurrence.)

• Surgical margin status: positive surgical margin is associated with a poor prognosis.

• Presence or absence of regional lymph node metastasis (N stage).

• Extent of lymph node dissection at the time of radical cystectomy: fewer than 10 resected lymph nodes is associated with a higher rate of recurrence.

• Number of metastatic lymph nodes at the time of cystectomy.

• Ratio of metastatic regional lymph nodes to total number of resected lymph nodes.

• Presence of extracapsular invasion in metastatic lymph nodes.

• Expertise of the urologist performing the radical cystectomy (better outcomes with experienced urologic oncologists).

• Volume of cases of the institution where radical cystectomy is performed (better outcomes in high-volume tertiary centers).

Thirty-eight per cent of patients who receive induction cisplatin-based combination chemotherapy do not have a residual tumor in the bladder (pathologic complete response) at the time of radical cystectomy. Pathologic complete response at the time of radical cystectomy is associated with improved overall survival and recurrence-free survival.

Metastatic or unresectable urothelial carcinoma of the bladder

The great majority of patients with metastatic or unresectable urothelial carcinoma of the bladder have incurable disease. The most common sites of metastatic spread include the lymphatic system, liver, lungs, and bones. Most metastases are diagnosed during the first two to three years after radical cystectomy. The median overall survival for patients with metastatic urothelial carcinoma of the bladder treated with cisplatin-based combination chemotherapy is 15 months. The five-year survival rate is 13%. Established clinical prognostic factors in patients with metastatic or unresectable urothelial carcinoma of the bladder receiving cisplatin-based combination chemotherapy include:

• Performance or functional status.

• Presence or absence of visceral or skeletal metastases.

Patients with metastatic bladder cancer without visceral metastases treated with front line cisplatin-based combination chemotherapy have a median overall survival of 18 months and a five-year overall survival of 21%. In contrast, patients with visceral metastases treated with cisplatin-based combination chemotherapy have a median overall survival of 10 months and a five year survival of 7%. Patients with a baseline Karnofsky performance status of 80 to 100 treated with cisplatin-based combination chemotherapy have a median overall survival of 16 months compared to 8 months in patients with Karnofsky performance status of 70.

What if scenarios.

Management of micropapillary variant of urothelial carcinoma of the bladder

Micropapillary variant of urothelial carcinoma of the bladder (Figure 11) is an aggressive form of bladder cancer. It is associated with a rapid progression and development of widespread distant metastatic disease. Under-staging is common. Contrast-enhanced cross sectional imaging studies of the chest, abdomen, and pelvis should be obtained in all patients. A bone scan is indicated if the serum alkaline phosphatase is elevated. Induction cisplatin-based combination chemotherapy followed by radical cystectomy should be strongly considered in patients with muscle invasive micropapillary variant of urothelial carcinoma of the bladder.

Figure 11.

Management of pure small cell carcinoma of the bladder

Pure small cell carcinoma of the bladder is a rare and aggressive type of bladder cancer. It represents less than 1% of all malignant bladder tumors. Small cell carcinoma of the bladder is associated with a rapid growth, progression to higher stages of disease, and development of distant metastases. There is no standard of care for patients with small cell carcinoma of the bladder. Small cell carcinoma of the bladder is a chemosensitive disease. Temporary responses to a combination of cisplatin plus etoposide can be seen. Some patients with organ-confined disease may have delay of recurrence or achieve a remission with three to four cycles of induction cisplatin plus etoposide followed by radical cystectomy.

Four to six cycles of first line platinum-based combination chemotherapy are prescribed to patients with metastatic or unresectable small cell carcinoma of the bladder. A commonly prescribed first line regimen is:

• Cisplatin 80 mg/m² IV on day 1 plus etoposide 80 mg/m² IV on days 1, 2, and 3 every 21 days.

Management of pure squamous cell carcinoma of the bladder

Pure squamous cell carcinoma of the bladder represents less than 5% of bladder cancers in the U.S. In Western countries risk factors include long term catheterization, chronic or recurrent infection and non-functional bladder. Squamous cell carcinoma of the bladder is an aggressive form of bladder cancer. Patients usually present with locally advanced or metastatic disease (extravesical extension of tumor, metastases to pelvic lymph nodes, viscera, or bones).

Management by a multidisciplinary team is needed. Treatment should be individualized. In patients with locally advanced but resectable squamous cell carcinoma of the bladder, induction (neoadjuvant) chemotherapy or concurrent chemoradiotherapy followed by radical cystectomy is a management option.

Combination chemotherapy for squamous cell carcinoma of the bladder:

• Cisplatin 75 mg/m² IV on day 1 plus continuous intravenous infusion of 5FU 1000 mg/m²/day on days 1 to 4 (96 hour 5FU infusion) every 21 days.

Radiosensitizing chemotherapy administered concurrently with external beam radiotherapy (chemoradiotherapy) to the bladder:

• Cisplatin 25 mg/m² IV on days 1 and 2 administered each week of external beam radiotherapy.

Follow-up surveillance and therapy/management of recurrences.

Surveillance after treatment of bladder cancer

Periodic office cystoscopy and urine cytology are the current standard surveillance tests after treatment for bladder cancer is completed.

1. Cystoscopy

Periodic office flexible cystoscopy is the “gold standard” surveillance test to detect recurrent or residual bladder tumors.

Disadvantages of cystoscopy:

• Invasive.

• Costly.

• Flat high-grade lesions and urothelial carcinoma in situ (Tis) can be missed.

• Inability to detect urothelial carcinoma of the upper urinary tract.

2. Urine cytology

Urine cytology is one of the standard surveillance tests for the detection of recurrent or residual bladder tumors.

Strengths of urine cytology:

• Specificity more than 90%.

• Non-invasive.

• Sample easy to obtain.

• Best test to detect high-risk bladder lesions including high-grade tumors and urothelial carcinoma in situ (Tis).

• High negative predictive value for high-grade bladder tumors.

Disadvantages of urine cytology:

• Low sensitivity to detect low-grade bladder tumors.

• Reliability depends on the level of expertise of the cytopathologist.

• Need for experienced cytopathologist.

3. Cross-sectional imaging studies

Contrast-enhanced cross-sectional imaging studies (CT scan or MRI) of the abdomen and pelvis should be obtained every three to six months during the first two years of surveillance for patients who have completed treatment for muscle invasive bladder cancer and who have adequate renal function. Patients with high risk of recurrence or progression to gross metastatic disease (T3 or T4 tumors, high grade histology, micropapillary variant, presence of regional nodal metastasis) need cross sectional imaging studies every three to four months during the first two years of surveillance.

In contrast, patients with low risk of recurrence or progression to gross metastatic disease (T1 or T2 tumors, no evidence of regional nodal metastasis, low-grade histology) need cross-sectional imaging studies every six months during the first two years of surveillance.

After two years of surveillance, the frequency of cross-sectional imaging studies varies and depends on the specific risk of recurrence or progression to gross metastatic disease. In general, during the third and fourth years of surveillance, cross-sectional imaging studies should be obtained every six to twelve months. In patients with impaired renal function, cross-sectional imaging studies of the abdomen and pelvis without contrast enhancement should be obtained.

A dedicated evaluation of the upper urinary tract is mandatory each time surveillance cross-sectional imaging studies are obtained.

Surveillance after treatment of non-muscle invasive bladder cancer

After complete TURBT, 70-80% of patients with non-muscle invasive bladder cancer have recurrence of tumor involving the bladder urothelium. Surveillance is indicated after treatment of non-muscle invasive bladder. The goal of surveillance is to detect bladder tumor recurrence at an early stage. Standard tests used for surveillance are office cystoscopy, urine cytology, and imaging of the upper urinary tract. After treatment of non-muscle invasive bladder cancer, office cystoscopy should be performed every three months during the first two years of surveillance, at less frequent intervals during years three and four, and annually thereafter. Urothelial carcinoma in situ (Tis) are flat, high-grade bladder tumors that are difficult to detect and commonly missed by cystoscopy. Urine cytology has a higher sensitivity and specificity in the detection of flat high-grade Tis tumors compared to cystoscopy. Imaging of the upper urinary tract every one to two years is recommended after treatment of high-grade bladder tumors.

Surveillance after radical cystectomy for muscle invasive bladder cancer

After treatment of muscle invasive bladder cancer the following tests are recommended every four to six months for two years and at increasing intervals thereafter:

• Urine cytology

• Serum electrolyte and creatinine levels

• Contrast enhanced cross sectional imaging studies (CT scan or MRI) of the abdomen and pelvis

• Chest X-ray

Cytology of urethral washing is recommended every 6-12 months for the first 2 years of surveillance and at increasing intervals thereafter.

Surveillance after bladder preservation treatment for muscle invasive bladder cancer

The following tests are recommended every four to six months for two years and at increasing intervals after bladder preservation treatment for muscle invasive bladder cancer:

• Urine cytology

• Serum electrolytes and creatinine levels

• Contrast enhanced cross sectional imaging studies (CT scan or MRI) of the abdomen and pelvis

• Chest X-ray

• Cystoscopy

• Random biopsies of the bladder are performed periodically in some centers

Management of local tumor recurrence after treatment of non-muscle invasive urothelial carcinoma of the bladder (Ta, T1, and Tis)

Endoscopic resection is the first step in the management of recurrent or persistent non-muscle invasive bladder tumors. After TURBT, a course of induction intravesical BCG or mitomycin C is indicated. Follow up cystoscopic evaluation at 12 weeks should be performed. A second consecutive course of intravesical BCG or mitomycin C may be prescribed to patients who respond to initial induction intravesical therapy. Maintenance intravesical BCG may be considered for patients who have a complete response after one or two courses of induction intravesical BCG or mitomycin C.

Patients with residual bladder tumor at a 12-week cystoscopic evaluation performed after a second consecutive course of induction intravesical therapy should undergo a TURBT. After endoscopic resection of the residual bladder tumor, intravesical therapy with a different chemotherapeutic agent (e.g. valrubicin) or combination intravesical immunotherapy with BCG plus interferon-2B may be considered.

Management of patients with positive urine cytology and no cystoscopic or radiologic evidence of identifiable recurrent bladder tumor

Patients with a positive urine cytology found during surveillance should undergo a cystoscopy. In the absence of identifiable tumor, biopsies of different regions of the bladder urothelium and the prostate gland should be obtained. In addition, bilateral ureteroscopy and cytology from both ureters should be obtained. Patients with urothelial carcinoma found on biopsy should receive induction intravesical BCG. Patients with a complete response at a 12-week cystoscopic evaluation may be considered for maintenance intravesical BCG. Patients with residual tumor or disease refractory to induction intravesical BCG at a 12-week cystoscopic evaluation may receive intravesical mitomycin C or may undergo a radical cystectomy.

Management of patients with progression to muscle invasive urothelial carcinoma of the bladder

All patients with non-muscle invasive urothelial carcinoma of the bladder who have progression to muscle invasive disease should undergo a radical cystectomy. Intravesical valrubicin is approved by the US Food and Drug Administration (FDA) for the treatment of BCG refractory Tis in patients who decline radical cystectomy.

Management of patients with recurrence of urothelial carcinoma of the bladder after radical cystectomy

The rate of locoregional recurrence after radical cystectomy in contemporary radical cystectomy series is 6% to 13%. Most locoregional recurrences occur 8 to 18 months after radical cystectomy.

Clinical prognostic factors associated with recurrence after radical cystectomy include:

• High pathologic stage of primary tumor (T stage)

• High histologic grade

• Regional lymph node involvement

• Less extensive pelvic lymphadenectomy at the time of radical cystectomy (<12 resected lymph nodes is associated with a higher risk of recurrence)

• Positive surgical margins at the time of radical cystectomy

• Presence of lymphovascular invasion in the primary bladder tumor

• Surgery performed by experienced urologic oncologists at large-volume tertiary centers is associated with a lower rate of local and regional recurrence

Locoregional and systemic recurrence of urothelial carcinoma of the bladder after radical cystectomy is associated with a poor prognosis. The great majority of patients with locoregional and systemic recurrence of bladder cancer after radical cystectomy have incurable disease. The median survival of patients with locoregional recurrence of bladder cancer after radical cystectomy is 4 to 8 months. In the majority of patients, treatment of locoregional recurrence is palliative and not curative. Treatment options include radiotherapy, concurrent chemoradiotherapy, and systemic chemotherapy.

Most systemic recurrences of urothelial carcinoma of the bladder occur within the first 36 months after radical cystectomy. The most common sites of systemic recurrence are the lymphatic system (pelvic, retroperitoneal, and intrathoracic lymph nodes), liver, lungs, and bones. The goals of therapy for patients with systemic recurrence of bladder cancer are to improve symptoms, improve quality of life, and prolong survival.

Cisplatin-based combination chemotherapy is the treatment of choice for chemotherapy naive patients. Cisplatin-based combination chemotherapy is a treatment option for patients who responded previously to induction cisplatin-based combination chemotherapy or for patients who had systemic relapse more than 6 months after completion of adjuvant cisplatin-based combination chemotherapy.

Single-agent paclitaxel or pemetrexed may be considered for patients who had disease refractory to induction cisplatin-based combination chemotherapy or for patients with systemic relapse within six months of completion of adjuvant cisplatin-based combination chemotherapy. Timely recognition and management of chemotherapy-related side effects is fundamental. Best supportive care is crucial.

Pathophysiology

Ta and Tis have distinct molecular pathways and clinical course. Two distinct molecular pathways of oncogenesis and tumor progression are recognized in urothelial carcinoma of the bladder (Ta).

Non-muscle invasive papillary urothelial carcinoma oncogenesis molecular pathway

Seventy percent of Ta have activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3). Activating mutations of the HRAS gene are also frequent in Ta tumors (30% to 40%). Activation of FGFR3 leads to activation of the Ras-mitogen activated protein kinase (MAPK) signaling transduction pathway.

Urothelial carcinoma in situ and muscle invasive urothelial carcinoma of the bladder oncogenesis molecular pathway

Alterations of the p53 and the retinoblatoma (RB) cell cycle regulation pathways are frequent in urothelial carcinoma in situ (Tis). More than half of patients with Tis have mutations of the TP53 and the RB genes. Mutation of the TP53 tumor suppressor gene leads to functional and structural alteration of the p53 protein.

Mutation of the RB gene leads to functional alteration of cell cycle regulatory nuclear phosphoprotein Rb. Alterations of the p53 and RB cell cycle regulation pathways lead to cell proliferation, angiogenesis, and metastasis. Activation and overexpression of the epidermal growth factor receptor (EGFR) and HER2 are common in muscle invasive urothelial carcinoma of the bladder. Overexpression of EGFR and HER2 is associated with an aggressive clinical behavior and poor outcome.

Angiogenesis

Tumor angiogenesis is fundamental in invasive urothelial carcinoma of the bladder. Angiogenesis allows the maintenance of oxygen and nutrient supply to proliferating urothelial carcinoma cells. Regulation of angiogenesis is complex. It involves the interaction of multiple stimulatory and inhibitory proteins and interaction with other signal transduction pathways.

Downstream activation of the MAPK-ERK signal transduction pathway leads to up-regulation and expression of vascular endothelial growth factor (VEGF). VEGF is a key pro-angiogenic stimulatory ligand of the vascular endothelial growth factor receptor (VGFR). Estimation of microvessel density in the primary bladder tumor is a histologic measurement of angiogenesis. Tumor microvessel density is an independent prognostic factor of disease-free and overall survival in invasive urothelial carcinoma of the bladder.

Epigenetic changes

Epigenetic alteration of genes is important in urothelial carcinoma of the bladder. Epigenetic changes involve reversible alteration in gene function without changes in the genetic sequence. Aberrant methylation of CpG islands in the promoter regions of tumor suppressor genes leads to silencing of transcription. Epigenetic alteration of genes involved in cell cycle regulation, proliferation, angiogenesis, and apoptosis are increasingly recognized in urothelial carcinoma of the bladder.

Concomitant epigenetic silencing of whole chromosomal regions in a subset of urothelial carcinomas of the bladder has been recently reported. Silencing of whole chromosomal regions occurred in association with histone H3K9 and K27 hypermethylation and H3K9 hypoacetylation. Bladder tumors with epigenetic silencing of whole chromosomal regions showed a urothelial carcinoma in situ-associated gene expression signature, had a higher grade and stage, and usually did not have mutations of the FGFR3 gene. It is anticipated that silencing of multiple chromosomal regions leads to concomitant inactivation of tumor suppressor genes and plays an important role in the oncogenesis of urothelial carcinoma in situ and muscle invasive urothelial carcinoma of the bladder.

Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.

No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.