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) [1] Non-muscle invasive bladder cancers are 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 non-muscle invasive bladder cancer 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) 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 ntravesical 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 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 [9] Radical cystectomy is the primary treatment for T2 and T3 tumors, with consideration for neoadjuvant chemotherapy Clinical evidence has demonstrated a overall survival benefit to neoadjuvant chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), compared with cystectomy alone [10] 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) First-line chemotherapy for muscle-invasive bladder cancer [1, 11, 12, 13, 10] : Drugs currently used in the management of advanced bladder cancer include combinations of gemcitabine and cisplatin: 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 In April 2016, the FDA granted accelerated approval of atezolizumab as first-line treatment for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy [14] 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 [15] "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] In May 2016, the FDA granted accelerated approval of atezolizumab, the first cancer immunotherapy that acts as a programmed cell death ligand inhibitor (PD-L1) for the treatment of urothelial carcinoma Atezolizumab 1200 mg IV q3wk infused over 60 min until disease progression or unacceptable toxicity [16] In February 2017 and April 2017, 3 other PD-L1 inhibitors, nivolumab, durvalumab and avelumab, were also granted accelerated approval for urothelial carcinoma Nivolumab 240 mg IV q2wk or 480 mg q4wk over 30 min until disease progression or unacceptable toxicity [17] Durvalumab 10 mg/kg IV q2wk infused over 60 min until disease progression or unacceptable toxicity [18] Avelumab 10 mg/kg IV q2wk infused over 60 min until disease progression or unacceptable toxicity [19] Pembrolizumab 200 IV q3wk infused over 30 min until disease progression or unacceptable toxicity, or up to 24 months in patients without disease progression