What are the treatment options for a patient diagnosed with bladder cancer?

Treatment Options for Bladder Cancer

Treatment for bladder cancer is fundamentally determined by whether the tumor is non-muscle-invasive (NMIBC) or muscle-invasive (MIBC), with approximately 75% of patients presenting with NMIBC and 25% with MIBC at diagnosis. 1

Initial Diagnostic Workup

Before treatment can be initiated, proper staging is essential:

• Transurethral resection of bladder tumor (TURBT) with bimanual examination under anesthesia is the cornerstone of diagnosis and initial treatment, with complete resection of all visible tumor when possible 1, 2
• Adequate muscle sampling in the resected specimen is critical for accurate staging—absence of detrusor muscle in the pathology specimen necessitates repeat TURBT for high-grade disease or any T1 lesion 1, 2
• Upper tract imaging with CT urography or MRI urography must be performed to exclude synchronous upper tract urothelial carcinoma, which occurs in 2.5% of patients 1, 2
• Bladder biopsies from suspicious areas or random mapping biopsies should be obtained in patients with positive cytology or history of high-grade NMIBC, as concurrent carcinoma in situ (CIS) is an adverse prognostic factor 1

Treatment Algorithm for Non-Muscle-Invasive Bladder Cancer (NMIBC)

Low-Risk NMIBC (Ta, Low Grade, Single Tumor <3cm)

• TURBT alone is typically sufficient for low-risk disease 2
• Single immediate postoperative intravesical chemotherapy instillation may reduce recurrence risk 2

Intermediate and High-Risk NMIBC

• Intravesical BCG immunotherapy is the gold standard for high-risk NMIBC (high-grade Ta, T1, or CIS) 2, 3, 4
• BCG induction consists of 6 weekly instillations starting 2-4 weeks after repeat TURBT 2
• BCG maintenance therapy with 3 weekly instillations at 3,6,12,18,24,30, and 36 months is recommended for high-risk disease 2
• For BCG-unresponsive high-risk NMIBC with CIS, pembrolizumab (single agent) is FDA-approved for patients ineligible for or who have elected not to undergo cystectomy 5

BCG-Unresponsive Disease

This represents a challenging population where radical cystectomy should be strongly considered as the definitive treatment to prevent progression to muscle-invasive disease 2, 3

Treatment Algorithm for Muscle-Invasive Bladder Cancer (MIBC)

Localized MIBC (T2-T4a, N0, M0)

Radical cystectomy with bilateral pelvic lymph node dissection is the gold standard treatment for localized MIBC 1, 2, 6

Neoadjuvant Chemotherapy

• Cisplatin-based combination chemotherapy before radical cystectomy improves survival compared to surgery alone 2
• This should be administered to eligible patients with MIBC prior to cystectomy 2

Surgical Approach

• Radical cystoprostatectomy (in males) or anterior pelvic exenteration (in females) with bilateral pelvic lymph node dissection including at minimum common iliac, internal iliac, external iliac, and obturator nodes 1, 2
• Urinary diversion is required, either through an external collection bag or internal neobladder reconstruction 2

Segmental (Partial) Cystectomy

• Reserved only for solitary lesions in locations amenable to segmental resection with adequate margins 1
• No carcinoma in situ should be present 1
• Bilateral pelvic lymphadenectomy must still be performed 1

Bladder Preservation (Trimodality Therapy)

• Maximal TURBT followed by concurrent chemoradiation can be considered in select patients 6, 3
• This approach requires radiosensitizing chemotherapy combined with radiation therapy 3
• Incomplete initial TURBT is a contraindication to bladder preservation therapy 1

Treatment for Advanced/Metastatic Bladder Cancer

First-Line Therapy

• Pembrolizumab in combination with enfortumab vedotin is FDA-approved for locally advanced or metastatic urothelial cancer 5
• Cisplatin-based combination chemotherapy remains a standard option for platinum-eligible patients 7, 8
• Cisplatin as a single agent is FDA-approved for transitional cell bladder cancer not amenable to local treatments 7

Platinum-Ineligible Patients

• Pembrolizumab as a single agent is FDA-approved for patients not eligible for any platinum-containing chemotherapy 5

Second-Line and Beyond

• Pembrolizumab monotherapy for patients with disease progression during or following platinum-containing chemotherapy 5
• Antibody-drug conjugates and targeted therapies have expanded treatment options in recent years 3, 8, 4

Special Histologic Variants

Small-Cell/Neuroendocrine Component

• Neoadjuvant chemotherapy using small-cell lung cancer regimens followed by local treatment (cystectomy or radiotherapy) 1

Pure Squamous Cell Carcinoma

• Cystectomy, radiation therapy, or alternative agents such as 5-FU, taxanes, and methotrexate commonly used for squamous cell carcinomas of other sites 1

Adenocarcinoma

• Radical or segmental cystectomy is preferred 1
• Conventional MVAC chemotherapy is not effective; chemotherapy or radiation should be individualized 1

Urachal Carcinoma

• Complete urachal resection with en-bloc resection of the urachal ligament and umbilicus 1

Critical Pitfalls to Avoid

• Inadequate muscle sampling during initial TURBT leads to understaging—always ensure detrusor muscle is present in the specimen 1, 2
• Failing to perform upper tract imaging misses synchronous upper tract disease in 2.5% of patients 1
• Delaying cystectomy in BCG-unresponsive high-risk NMIBC increases risk of progression to incurable disease 2, 3
• Omitting neoadjuvant chemotherapy in eligible MIBC patients reduces survival benefit 2
• Not obtaining prostatic urethral biopsies in males with trigone/bladder neck tumors or positive cytology without visible tumor can miss prostatic involvement 1, 2