What are the treatment options for bladder cancer?

Bladder Cancer Treatment

Treatment of bladder cancer must be stratified by stage: non-muscle invasive disease requires transurethral resection with risk-adapted intravesical therapy, muscle-invasive disease demands radical cystectomy with neoadjuvant cisplatin-based chemotherapy, and metastatic disease is treated with platinum-based chemotherapy or immunotherapy depending on cisplatin eligibility and PD-L1 status. 1

Non-Muscle Invasive Bladder Cancer (NMIBC)

Initial Management

• Complete transurethral resection of bladder tumor (TURBT) is the cornerstone of initial treatment for all bladder tumors. 2
• Repeat TURBT is mandatory when no muscle is present in the specimen, for any T1 lesion, or when initial resection does not allow adequate staging. 2
• Multiple selective and/or random biopsies should be performed when carcinoma in situ is suspected or known. 2

Risk-Stratified Intravesical Therapy

Low-Risk Tumors (Initial, low-grade, <3 cm):

• Single-dose intravesical chemotherapy within 24 hours of TURBT, or observation alone. 2
• Cystoscopy follow-up at 3 months, then at increasing intervals if negative. 2

Intermediate-Risk Tumors (Low-grade recurrent, multiple, or >3 cm):

• Multiple intravesical chemotherapy instillations with mitomycin. 2
• This approach reduces recurrence rates compared to TURBT alone. 2

High-Risk Tumors (Any high-grade non-muscle invasive tumor or CIS):

• BCG intravesical immunotherapy is the gold standard, preventing recurrences and reducing mortality by 23%. 2
• BCG should be administered as induction course followed by maintenance therapy. 1
• For BCG-unresponsive disease in patients who refuse or are ineligible for cystectomy, pembrolizumab or nadofaragen firadenovec can be considered, though data remain limited. 1, 3

Radical Cystectomy for NMIBC

• Cystectomy should be performed for CIS or high-grade T1 disease unresponsive to BCG due to high progression risk. 1
• Very-high-risk patients should be offered radical cystectomy as primary treatment. 1

Muscle-Invasive Bladder Cancer (MIBC)

Standard Treatment Approach

• Radical cystectomy with extended bilateral pelvic lymphadenectomy is the standard treatment for T2-T4a, N0 M0 disease. 1, 2
• Multidisciplinary tumor board discussion involving medical oncology, radiation oncology, and urology is essential before treatment decisions. 1

Neoadjuvant Chemotherapy

• Three to four cycles of cisplatin-based neoadjuvant chemotherapy (gemcitabine-cisplatin or dose-dense MVAC) should be administered before cystectomy for MIBC, providing a 5-6% absolute survival benefit. 1, 4, 2
• Cross-sectional imaging should be performed after chemotherapy completion and before cystectomy. 1
• This represents level 1A evidence and is strongly preferred over adjuvant approaches. 1, 4

Adjuvant Chemotherapy

• Adjuvant cisplatin-based chemotherapy should be considered for patients who did not receive neoadjuvant therapy and have high-risk pathologic features (pT3/pT4, node-positive disease, vascular invasion). 1, 4
• Evidence for adjuvant therapy is weaker than for neoadjuvant treatment; neoadjuvant chemotherapy is preferred. 1
• Adjuvant immunotherapy with checkpoint inhibitors shows inconsistent results and requires overall survival advantage before recommendation as standard therapy. 1

Bladder-Preserving Approaches

• Trimodality therapy (maximal TURBT + radiation + concurrent chemotherapy) is a reasonable alternative for patients seeking bladder preservation or medically unfit for surgery. 1
• Ideal candidates have initial T2 tumors <5 cm, no CIS, pT0 after repeat TURBT, no hydronephrosis, good performance status, and adequate bladder capacity. 1
• Concurrent cisplatin-based chemoradiation is the preferred radiosensitizing strategy. 4
• Up to 70% of patients achieve complete response, though 25% develop new lesions requiring additional treatment during follow-up. 1

Segmental Cystectomy

• May be considered for solitary lesions in locations amenable to segmental resection with adequate margins, without CIS present. 2

Advanced/Metastatic Bladder Cancer (Stage IV)

First-Line Therapy for Cisplatin-Eligible Patients

• Gemcitabine-cisplatin (GC) is the preferred first-line regimen due to equivalent efficacy with significantly less toxicity compared to MVAC. 1, 4, 5
• Dose-dense MVAC with growth factor support remains an acceptable alternative. 1, 4
• Median overall survival with platinum-based chemotherapy is 9-15 months. 1

First-Line Therapy for Cisplatin-Ineligible Patients

PD-L1 Positive Tumors:

• Atezolizumab or pembrolizumab monotherapy can be used as first-line treatment. 1, 3
• Pembrolizumab showed 24% overall response rate with 5% complete response in the KEYNOTE-052 trial. 1
• Important caveat: FDA issued safety alerts in 2018 regarding potential decreased survival with first-line checkpoint inhibitors in certain populations; careful patient selection is critical. 1

PD-L1 Negative or Unknown:

• Gemcitabine-carboplatin is the preferred regimen. 1, 4
• Single-agent taxane or gemcitabine are alternatives for patients with poor performance status. 1

Maintenance Therapy

• Avelumab maintenance should be administered to patients without disease progression after first-line platinum-based chemotherapy. 1
• This represents a significant advance with demonstrated survival benefit. 1

Second-Line Therapy

• Pembrolizumab is the preferred second-line option after platinum failure, with demonstrated survival benefit. 1, 3
• Enfortumab vedotin (antibody-drug conjugate) is highly effective in platinum-refractory disease. 1
• Erdafitinib can be used for tumors with FGFR alterations. 1
• Atezolizumab and other checkpoint inhibitors are alternative options. 1
• Vinflunine produces survival benefit in eligible patients progressing after platinum-based chemotherapy. 1

Locally Advanced Disease (T4b, N1-N3)

• Selected patients may be candidates for cystectomy and lymph node dissection or definitive radiotherapy following systemic therapy. 1
• Patients with radiologically suspicious node-positive disease (cN1) should be considered for preoperative platinum-based chemotherapy before surgery. 1

Critical Patient Selection Factors

Cisplatin Eligibility Criteria

• Renal function assessment is mandatory before initiating cisplatin-based therapy; creatinine clearance must be determined. 4
• Cisplatin-ineligible patients include those with creatinine clearance <60 mL/min, ECOG performance status ≥2, hearing loss, neuropathy, or heart failure. 1

Performance Status Considerations

• Patients with performance status 2 and poor renal function have very limited benefit from chemotherapy and require alternative strategies. 1, 4
• Performance status is critical for patient selection across all treatment modalities. 4

Cardiac Assessment

• Cardiac disease must be evaluated when selecting regimens, particularly those containing doxorubicin (MVAC). 4

Common Pitfalls and Caveats

• Underutilization of neoadjuvant chemotherapy remains a major problem despite level 1A evidence; it should be offered to all eligible MIBC patients. 1, 6
• Biomarker testing (PD-L1 status, FGFR alterations) should be performed in metastatic disease to guide therapy selection. 1
• For immunotherapy, biomarkers should match the specific drug (SP142 for atezolizumab; 22C3 for pembrolizumab) as recommended by regulatory agencies. 1
• BCG shortage has created challenges in NMIBC management; alternative intravesical therapies or early cystectomy should be considered when BCG is unavailable. 2
• Delay in cystectomy for BCG-unresponsive high-risk NMIBC significantly worsens outcomes; timely surgical intervention is critical. 1