What is the best course of treatment for a patient diagnosed with bladder cancer?

Treatment of Bladder Cancer

The optimal treatment for bladder cancer depends critically on disease stage: non-muscle-invasive disease (Ta, T1, CIS) requires transurethral resection with risk-stratified intravesical therapy, while muscle-invasive disease (T2-T4a) mandates radical cystectomy with neoadjuvant cisplatin-based chemotherapy, and metastatic disease requires systemic platinum-based chemotherapy or immunotherapy based 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, ensuring the specimen includes lamina propria and detrusor muscle for accurate staging 1
• The resection must include both tumor base and edges sent separately to pathology 2
• Approximately 75% of bladder cancer patients present with NMIBC (Ta-T1) 1

Risk-Stratified Adjuvant Therapy

Low-Risk Disease (Low-grade Ta):

• Single immediate intravesical chemotherapy (mitomycin C) within 24 hours of resection reduces recurrence by 11% 2
• This represents adequate treatment for most low-risk tumors 1

Intermediate and High-Risk Disease (High-grade Ta, T1, CIS):

• Intravesical BCG therapy is the preferred adjuvant treatment over chemotherapy alone 1, 2
• BCG should be administered according to standard induction protocols 1
• T1 tumors are generally managed with intravesical BCG therapy 1

BCG-Unresponsive Disease

The ESMO guidelines define three critical BCG failure categories 1:

1. BCG-relapsing: recurrence of high-grade disease after achieving disease-free state at 6 months
2. BCG-intolerant: disease persistence due to inability to receive adequate BCG
3. BCG-unresponsive: combination of BCG-refractory and BCG-relapsing within 6 months

Management of BCG-Unresponsive Disease:

• Radical cystectomy should be performed in high-grade tumors (T1/HG, Ta/HG, CIS) unresponsive to BCG due to high progression risk 1
• For patients unwilling or unable to undergo cystectomy, thermochemotherapy can achieve 2-year disease-free survival in 47% 1
• BCG re-induction achieved similar disease control to thermochemotherapy and can be considered 1
• Intravenous pembrolizumab showed 41% complete response rate at 3 months in BCG-unresponsive CIS patients (KEYNOTE-057 trial) but requires more robust data before stronger recommendations 1

Muscle-Invasive Bladder Cancer (MIBC)

Standard Treatment Approach

Radical Cystectomy:

• Radical cystectomy with pelvic lymph node dissection (PLND) is the standard treatment for MIBC cT2-T4a, N0 M0 1
• Standard PLND includes removal of lymphatic tissues around common iliac, external iliac, internal iliac, and obturator regions up to the ureteral crossing 1
• Extended lymphadenectomy includes presacral and common iliac vessels above the crossing ureters, though optimal extent remains unestablished 1

Neoadjuvant Chemotherapy:

• Three to four cycles of cisplatin-based neoadjuvant chemotherapy should be given for MIBC before cystectomy 1
• This approach is strongly preferred over adjuvant chemotherapy 1
• Cross-sectional imaging should occur after chemotherapy before radical cystectomy 1

Locally Advanced Disease (T3-T4)

T3a, T3b Disease:

• Primary treatment is radical cystectomy with consideration of cisplatin-based neoadjuvant chemotherapy 1
• Bladder preservation is not an option except in highly selected cases due to low tumor-free rates 1
• Tumors with pathologic T3/T4, nodal involvement, or vascular invasion have >50% systemic relapse risk and may be considered for adjuvant therapy 1

T4a, T4b Disease:

• Patients with unresectable disease (fixed bladder mass) or positive nodes are considered for chemotherapy alone or chemotherapy with radiotherapy 1
• For node-negative disease on CT: 2-3 courses of chemotherapy ± radiotherapy, followed by cystoscopy and CT 1
• If tumor responds, options include cystectomy or consolidation chemotherapy ± radiotherapy 1

Bladder-Preservation Approaches

Patient Selection Criteria:

• Ideal candidates have tumors amenable to visible complete resection, no hydronephrosis, no prostatic urethral invasion, and no diffuse CIS 1
• Trimodality therapy (TURBT + radiotherapy + chemotherapy) is the preferred bladder-preservation approach 1
• This is reasonable for patients seeking alternatives to cystectomy or medically unfit for surgery 1

Treatment Protocol:

• Aggressive TURBT followed by concurrent chemoradiotherapy 1
• Typically 45 Gy to pelvis and bladder with ~20 Gy boost to disease sites 1
• Cisplatin administered on days 1 and 21 as radiosensitizer, or 5-FU with various schedules 1
• Cystoscopy with bladder biopsy performed midway through treatment; if disease persists, cystectomy recommended 1

Critical Caveat: Bladder preservation with TURBT alone may be curative only in highly selected cases: solitary lesion <2 cm, minimal muscle invasion, no CIS, no palpable mass, no hydronephrosis 1

Advanced/Metastatic Disease

First-Line Treatment Based on Cisplatin Eligibility

Cisplatin-Eligible Patients:

• Cisplatin-containing combination chemotherapy is standard 1
• Gemcitabine-cisplatin is most widely used 1
• Dose-dense MVAC or MVAC with G-CSF are acceptable alternatives 1
• Maintenance avelumab for tumors not progressing on chemotherapy 1

Cisplatin-Ineligible, PD-L1-Positive Patients:

• Atezolizumab or pembrolizumab as first-line therapy 1

Cisplatin-Ineligible, PD-L1-Negative/Unknown:

• Gemcitabine-carboplatin 1

Second-Line and Beyond

After Platinum Progression:

• Pembrolizumab is first choice after platinum failure 1
• Enfortumab-vedotin as subsequent option 1
• Erdafitinib for FGFR-altered tumors 1
• Other immune checkpoint inhibitors (atezolizumab) as alternatives 1

Follow-Up Protocols

Post-TURBT for NMIBC

• Cystoscopy at 3-month intervals for first year 1
• If negative, every 6 months thereafter 1
• Upper-tract imaging (IVP, retrograde pyelogram, or CT/MRI urography) at 1-2 year intervals 1

Post-Cystectomy for MIBC

• Serial imaging studies to exclude metastatic disease 1
• Monitoring dictated by pathologic stage and risk factors 1

Critical Pitfalls to Avoid

1. Inadequate initial TURBT: Failure to include muscle in specimen leads to 49% understaging risk; repeat TUR strongly recommended if no muscle present 2
2. Delayed cystectomy in BCG-unresponsive disease: High progression risk mandates definitive surgical intervention 1
3. Omitting neoadjuvant chemotherapy in MIBC: Neoadjuvant approach is strongly preferred over adjuvant therapy 1
4. Inappropriate bladder preservation attempts: Patients with T3 disease, diffuse CIS, hydronephrosis, or prostatic involvement are poor candidates 1
5. Second attempt at bladder preservation after invasive relapse: Not advisable; proceed to radical cystectomy 1