Bladder Cancer Treatment Protocols

Treatment protocols for bladder cancer are provided below, including those for the following:

• Chemotherapy
• Immunotherapy
• Systemic neoadjuvant and adjuvant therapy.

Non–muscle-invasive bladder cancer (Ta, Tis, T1)

Non–muscle-invasive bladder cancer (NMIBC) is divided into 3 groups: Ta, Tis, and T1:

• Ta are noninvasive papillary lesions confined to the urothelium and have not penetrated the basement membrane.

• Tis tumors are defined as severe cellular dysplasias usually in the absence of tumor formation.

• T1 tumors are invasive cancers that have penetrated into underlying lamina propria but without any involvement of the muscularis propria.

Standard treatment for NMIBC is a complete transurethral resection of the bladder tumor (TURBT). Intravesical chemotherapy is generally used as prophylactic or adjuvant therapy after complete endoscopic resection; it is rarely used as therapy to eradicate residual disease that could not be completely resected

Postoperative adjuvant intravesical chemotherapy for non–muscle invasive bladder cancer ^{[1, 2, 3]}  

One postoperative intravesical dose (within 24 h, but usually immediately after resection) of the following has been shown to reduce recurrence, but not progression, of disease:

• Mitomycin 40 mg in 20 mL sterile water ^[4]   or
• Epirubicin 80 mg in 40 mL sterile water ^[5] or
• Thiotepa 30 mg in 15 mL sterile water ^[6]   or
• Doxorubicin 50 mg in 20 mL sterile water

Non–muscle invasive bladder cancer (high grade)

High-grade or T1 disease:

• For T1 tumors, TURBT alone is generally not adequate treatment; use of intravesical bacillus Calmette-Guerin (BCG) after TURBT is recommended ^[7]

Intravesical adjuvant immunotherapy for non–muscle-invasive bladder cancer ^{[1, 8, 2]} :

• BCG 81 mg (TheraCys) or 50 mg (TICE BCG) in 50 mL sterile saline instilled into the bladder through a catheter and held for 2 h; instilled weekly for 6 wk ^[4]

• Maintenance therapy: 81 mg intravesically given on days 1, 8, and 15 of months 3, 6, 12, 18, 24, and 36 after initiation

BCG-unresponsive non–muscle-invasive bladder cancer:

• Pembrolizumab is indicated for treatment of BCG-unresponsive, high-risk NMIBC with carcinoma in situ (CIS) with or without papillary tumors in patients who are ineligible for, or have elected not to undergo, cystectomy. ^[9]  
• Pembrolizumab 200 mg IV q3wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression
• Valrubicin is indicated for intravesical therapy of BCG-refractory CIS of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. ^[10]
• Valrubicin 800 mg added to 55 mL sterile saline instilled into the bladder through a catheter and held for 2 h; instilled weekly for 6 wk 
• Gene therapy: Nadofaragene firadenovec 75 mL instilled into bladder at a concentration of 3 × 10 ¹¹ viral particles (vp)/mL once q3months ^[11]  

Muscle-invasive bladder cancer

T2-T4 without metastatic disease:

• TURBT is the initial treatment recommendation to help identify the stage of the bladder cancer.

• All muscle-invasive tumors are categorized as high-grade urothelial carcinomas. ^[12]

• Radical cystectomy is the primary treatment for T2 and T3 tumors, with consideration for neoadjuvant chemotherapy.

• Clinical evidence has demonstrated a overall survival benefit of neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), compared with cystectomy alone. ^[13]

• Current clinical data conflict on the role of adjuvant therapy in invasive bladder cancer, and additional trials are required; however, results from trials show delays of recurrence, so chemotherapy with MVAC or gemcitabine and cisplatin may be used (see chemotherapy for drug regimens, below) ^[1]

• While no randomized studies have been performed comparing neoadjuvant with adjuvant therapy, many centers prefer to administer chemotherapy only after cystectomy and pathologic staging (ie, adjuvant chemotherapy)

First-line chemotherapy for muscle-invasive bladder cancer ^{[1, 14, 15, 16, 13]} :

• Drugs currently used in the management of advanced bladder cancer include combinations of gemcitabine and cisplatin (GemCis): Gemcitabine 1000 mg/m² on days 1, 8, and 15 plus  cisplatin 70 mg/m² IV on day 1 or 2; repeat cycle every 28 d for a total of four cycles or

• Other drug regimens include combinations of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC): Methotrexate 30 mg/m² IV on days 1, 15, and 22 plus  vinblastine 3 mg/m² IV on days 2, 15, and 22 plus  doxorubicin 30 mg/m² IV on Day 2 plus  cisplatin 70 mg/m² IV on day 2; repeat cycle every 28d for a total of 3 cycles

• The FDA granted accelerated approval of atezolizumab, the first cancer immunotherapy that acts as a programmed cell death ligand inhibitor (PD-L1), as first-line treatment for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy. ^[17]

• Atezolizumab 1200 mg IV q3wk infused over 60 min until disease progression or unacceptable toxicity

• Pembrolizumab 200 IV q3wk infused over 30 min until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression ^[18]  

• Enfortumab vedotin 1.25 mg/kg (up to 125 mg/dose) IV on Days 1, 8, and 15 of a 28-day cycle plus pembrolizumab 200 mg IV q3Weeks (or 400 mg q6Weeks) until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression ^[19]  

• "Dose-dense" regimens for MVAC and GemCis, in which increased doses are administered along with doses of growth factor stimulants (eg, GM-CSF), have shown similar efficacy as conventional regimens.

Second-line chemotherapy for muscle invasive bladder cancer:

• There are no definitive recommendations for second-line therapy.

• Potential options for palliative therapy depends on the chemotherapy that was used for first-line treatment.

• Chemotherapy options may include drugs such as cisplatin, gemcitabine, pemetrexed, carboplatin, vinblastine, and bleomycin, which have shown some beneficial effects in various trials. ^[1]

• Atezolizumab 1200 mg IV q3wk infused over 60 min until disease progression or unacceptable toxicity ^[20]

• Nivolumab 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or  toxicity ^[21]

• Avelumab 10 mg/kg IV q2wk infused over 60 min until disease progression or unacceptable toxicity ^[22]

• Pembrolizumab 200 IV q3wk or 400 mg IV q6wk until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression ^{[23, 24]}

• Erdafitinib 8 mg PO qd initially; increase to 9 mg PO qd based on serum phosphate levels and tolerability at 14-21 days; for metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and that progressed during or following at least 1 line of prior platinum-containing chemotherapy ^[25]  

• Enfortumab vedotin 1.25 mg/kg IV on Days 1, 8, and 15 of a 28-day cycle; not to exceed 125 mg/dose for patients weighing 100 kg or greater; continue until disease progression or unacceptable toxicity ^[26]