What is the recommended staging system and treatment approach for bladder cancer?

Staging of Bladder Cancer

Recommended Staging System

Bladder cancer is staged using the TNM (Tumor, Node, Metastasis) system from the American Joint Committee on Cancer (AJCC), 8th edition, which provides the framework for all treatment decisions. 1

The TNM system encompasses:

• T stage: Depth of tumor invasion through bladder wall layers (Ta, Tis, T1-T4) 1
• N stage: Number and location of metastatic regional lymph nodes (N0-N3) 1
• M stage: Presence of distant metastases 1

Key 8th Edition Updates

The 8th edition introduced critical reclassifications that directly impact treatment algorithms 1:

• Stage IIIA: T3-T4a with N0, OR T1-T4a with single regional lymph node metastasis (N1) 1
• Stage IIIB: T1-T4a with multiple regional lymph node metastases (N2-N3) 1
• Common iliac lymph nodes: Now classified as regional (N3) rather than distant metastases 1

This nodal reclassification matters because patients with N1 disease have significantly better prognosis than those with N2-N3 involvement and benefit from aggressive curative-intent treatment 1.

Diagnostic Workup for Staging

Initial Evaluation

After cystoscopic identification and biopsy confirmation 1:

• Transurethral resection of bladder tumor (TURBT) with bimanual examination under anesthesia to assess depth of invasion and obtain muscle in the specimen 1
• Selected mapping biopsies and prostatic urethral biopsy if sessile tumor, carcinoma in situ (CIS), or high-grade disease suspected 1
• Second-look TURBT mandatory for high-grade T1 tumors to ensure complete resection and accurate staging 1

Imaging Protocol

For muscle-invasive bladder cancer (MIBC, ≥T2), obtain CT abdomen and pelvis with contrast as the primary staging modality 1:

• CT identifies: Extravesical extension, lymphadenopathy, and distant metastases (lung, liver, bone) 1
• CT limitations: Cannot distinguish inflammatory changes from tumor, cannot assess depth of bladder wall invasion, misses microscopic disease in normal-sized lymph nodes 1

MRI pelvis provides superior local staging accuracy and should be considered when precise T-staging will change management decisions 2:

• Multiparametric MRI with diffusion-weighted imaging improves detection of muscle invasion and extravesical extension 2
• VI-RADS (Vesical Imaging-Reporting and Data System) standardizes MRI interpretation for bladder cancer 2

Enhanced Cystoscopy Options

Blue light cystoscopy (BLC) with hexyl-aminolevulinate improves detection of non-muscle-invasive lesions, particularly flat CIS that is frequently missed by white light cystoscopy 1:

• Reduces recurrence rates (OR 0.5, p<0.00001) and delays time to first recurrence by 7.39 weeks 1
• Most beneficial for detecting multifocal disease and CIS 1

Treatment Approach by Stage

Non-Muscle-Invasive Bladder Cancer (Ta, T1, Tis)

Approximately 75% of newly diagnosed cases present as non-muscle-invasive disease 1:

Low-risk disease (Ta, low-grade):

• TURBT alone with surveillance cystoscopy 1

High-risk disease (T1 high-grade, CIS, multifocal):

• TURBT followed by intravesical BCG immunotherapy (standard of care) 1, 3
• Consider radical cystectomy for BCG-unresponsive disease 1, 3

Muscle-Invasive Bladder Cancer (Stage II and IIIA: T2-T4a, N0-N1)

Neoadjuvant cisplatin-based combination chemotherapy followed by radical cystectomy with pelvic lymphadenectomy is the reference standard treatment 1:

• Preferred regimens (Category 1 evidence) 1:
  • Gemcitabine + cisplatin
  • Dose-dense MVAC with growth factor support
• Neoadjuvant chemotherapy improves disease-specific and overall survival compared to surgery alone 1

Bladder preservation alternative for selected patients 1:

• Maximal TURBT followed by concurrent chemoradiotherapy (60-66 Gy) 1
• Optimal candidates: Tumors without hydronephrosis, visibly complete or maximally debulking TURBT possible 1
• Radiosensitizing regimens: Cisplatin/5-FU, cisplatin/paclitaxel, 5-FU/mitomycin C, or cisplatin alone (doublet preferred) 1

Stage IIIB Disease (T1-T4a, N2-N3)

Treatment lacks strong prospective data but downstaging chemotherapy or chemoradiotherapy can be effective 1:

• Consider induction chemotherapy for pathologic downstaging 1
• Selected patients responding to systemic therapy may be candidates for consolidative cystectomy with lymphadenectomy or definitive radiotherapy 1, 4

Stage IV Disease (M1 or T4b)

For patients with ECOG 0-1: Enfortumab vedotin + pembrolizumab is preferred first-line treatment (median OS 31.5 vs 16.1 months with chemotherapy, HR 0.47) 4

For cisplatin-eligible patients: Platinum-based combination chemotherapy (gemcitabine/cisplatin or MVAC) prolongs survival 1, 5

For ECOG 2 or cisplatin-ineligible patients 4:

• Consider carboplatin-based regimens or single-agent therapy if preserved renal function
• Early palliative care with palliative radiotherapy for symptom control (bleeding, pain, obstruction): 8 Gy × 1,21 Gy × 3,20 Gy × 5, or 36 Gy × 6 fractions 4

Critical Staging Pitfalls

Clinical staging by TURBT and examination under anesthesia frequently understages patients compared to final pathology at cystectomy, primarily due to underestimation of invasion depth and lymph node involvement 2:

• Ensure adequate muscle sampling in TURBT specimen to distinguish T1 from T2 disease 1
• Perform second-look TURBT for high-grade T1 tumors—residual disease found in up to 50% of cases 1

Lymph node staging limitations 1, 6:

• Size-based criteria miss microscopic metastases in normal-sized nodes 1
• Neither 6th nor 7th edition TNM nodal staging performs well as prognostic tool 6
• Number of positive lymph nodes (>6) is more prognostic than anatomic location 6

Cisplatin eligibility assessment is mandatory before treatment planning 4, 5:

• Measure serum creatinine, BUN, creatinine clearance, and electrolytes (magnesium, sodium, potassium, calcium) 5
• Never substitute carboplatin for cisplatin in perioperative setting—not equivalent efficacy 4
• Cisplatin contraindicated with pre-existing renal impairment, myelosuppression, or hearing impairment 5