Bladder cancer is the fifth most common cancer in Canada. It is the fourth most common cancer for men. Bladder cancer is less common among women (ranked eleventh). In 2021, an estimated 12,500 Canadians will have been diagnosed with bladder cancer, and 2,600 Canadians are projected to pass away from bladder cancer.
Though amenable to surgery, early bladder cancer can recur frequently. 1 The risk of recurrence is affected by factors such as size, number, T category, tumour grade, concomitant CIS, and prior recurrence. 2 Following curative surgery, adjuvant therapy to prevent recurrences is an important aspect of bladder cancer treatment. Several agents have been studied in the adjuvant setting with outcomes of progression-free survival and disease-free survival as the primary endpoints; these agents include epirubicin, doxorubicin, interferon (IFN)-2b, mitomycin C (MMC), and bacillus calmette-guerin (BCG). The purpose of this guideline is to establish best practice for the surgical management of patients with non-muscle invasive bladder cancer, as well as to describe patient selection criteria for adjuvant therapy, appropriate agents, dosing, and duration of therapy.

# Target Population
The following recommendations apply to adult patients with a diagnosis or suspicion of non-muscle invasive bladder cancer.
American Joint Committee on Cancer (AJCC) staging definitions for bladder cancer are included in Appendix A (pages 7-8).

# Management of Ta
Complete resection, including muscularis propria, is recommended.
Aside from the bladder, the urethra should be examined as well. Upper tract imaging should be performed in the initial evaluation of a patient with bladder cancer. For patients with T1HG bladder cancer on TURBT, a re-resection TURBT is recommended, particularly if muscularis propria is not sampled.

# Risk stratification:
Low risk solitary, primary, low grade Ta, 3cm), low grade Ta, or solitary primary small (3cm), recurrent, and/or multifocal. 3

# Adjuvant therapy:
Post-TURBT single-dose chemotherapy instillation should be considered for all risk categories of pTa patients, especially for low risk patients, as these patients benefit most in terms of recurrence rates at 2 years.
A. The standard of care is adjuvant-immediate chemotherapy instillation post-TUR, unless the bladder is perforated with TUR or if there is a significant risk of vesico-ureteral reflux. Chemotherapy should consist of: epirubicin (50 mg/50 mL) or mitomycin C (MMC; 40 mg/40 mL) or gemcitabine (2 g in 100 mL of saline). B. The role of single-dose postoperative chemotherapy is unclear for patients with high risk NMIBC planned for subsequent intravesical BCG.

# Induction and maintenance therapy:
Induction and maintenance therapy is recommended for intermediate and high-risk patients, including those with multifocal tumours or frequent recurrences. A. BCG: induction therapy for 6 weeks then 3-weekly injections at 3-month intervals; continue for 12-36 months, if patient is disease-free at 3 months. B. MMC: 40 mg/ mL monthly; continue for 12-24 months. C. Gemcitabine (1g in 50ml) + docetaxel (37.5mg in 50ml) induction (weekly x 6 weeks), followed by maintenance x 2 years (monthly x 12-24months). D. For intermediate risk, up to 1 year of maintenance is sufficient. For high risk, 3 years of maintenance BCG is recommended.

# Management of Recurrences
TURBT is recommended for resection and pathologic assessment of recurrences in most patients In patients with suspected TaLG recurrences, cystoscopy, biopsy +/-fulgurization under local anesthesia is an alternative.

# BCG Unresponsive Bladder Cancer
BCG unresponsive bladder cancer is defined as any of the following:
- T1HG at the first 3-month cystoscopy following induction.
- Recurrent T1HG/TaHG within 6 months of completion of adequate BCG.
- Recurrent CIS (+/-T1HG/TaHG) within 12 months of completion of adequate BCG.
Adequate BCG is defined as at least 5/6 weekly induction courses plus either at least 2/3 weekly maintenance courses or 2/6 weekly courses of a second induction cycle.

# Management of BCG unresponsive bladder cancer:
A. Radical cystectomy, pelvic lymphadenectomy, and urinary diversion is the standard of care in surgically fit patients. B. In patients ineligible or refusing cystectomy, salvage therapies include: i. Intravesical gemcitabine (1g in 50ml) + docetaxel (37.5mg in 50ml) induction (weekly x 6 weeks), followed by maintenance x 2 years (monthly x 12-24months). ii.
Intravesical mitomycin C: administer intravesically at a dose of 40 mg weekly for 4 weeks.
For management of BCG relapse not meeting definition for BCG unresponsive bladder cancer, consider rechallenge with a second induction course of BCG.

# Risk Adjusted Follow-up
Initial cystoscopy post first resection at 3 months post operatively.

# If initial cystoscopy is negative for malignancy:
- Cystoscopy annually for 5 years then in the absence of recurrence further surveillance at discretion of patient and urologist.
- If asymptomatic, routine upper tract imaging not required.
Intermediate risk: Cystoscopy q3-6 months for 2 years, then q 6-12 months for the 3rd year, then annually.

# High risk
- Cystoscopic evaluation q 3-4 months for the first 2 years, then q 6 months for 2 years then annually for 10 years. - Consider upper tract imaging q 1-2 years.
The management of Ta and T1 bladder cancer includes resection plus adjuvant-immediate chemotherapy, consisting of epirubicin or mitomycin C. 4,5 Recurrences are common in bladder cancer 3 and management consists of bacillus calmette-guerin therapy (BCG). In intermediate to high risk patients, the addition of prulifloxacin has not been shown to improve recurrence rates at six months (21.6 vs. 23.0%); 6 however, in another study, the addition of gemcitabine to BCG therapy increased the time to recurrence by 4.3 months (24.1 vs. 19.8 months; P<.05). 7 An EORTC trial (Sylvester, et al. 2010) showed that in intermediate and high risk patients (n=820), BCG significantly reduced the rate of recurrence (36.7 versus 52.7% epirubicin; P<.05) and increased the rate of overall survival (70.1 versus 62.0%; P<.05), with a median follow-up of 110 months. 8 Another smaller study (n=89 Ta/T1 patients) showed that, after a median follow-up of 102 months, BCG resulted in a significantly lower recurrence rate versus mitomycin-C (59.1 versus 80%; P<.05); disease-free survival was also higher in patients treated with BCG (90.9 versus 80.0%). 9 For Ta disease, in the event of a failure on BCG therapy, options include salvage surgery, BCG therapy plus alpha-2b interferon, or mitomycin C. 4 Gemcitabine has also demonstrated efficacy: overall survival rate was approximately 20% higher (approximately 70 versus 50%; P<.05) versus mitomycin-C at a median follow-up of 36 months; 10 recurrence rate was 35% lower (52.5 versus 87.5%; P<.05) versus BCG; 11 and recurrence free survival rate was approximately 16% higher (19 versus 3%; P<.05) versus BCG (median follow-up of 12 months). 11 However, in a smaller study of high risk patients, BCG was more efficacious than gemcitabine, in terms of recurrence rate (28.1 versus 53.1%; P<.05). 12 Larger trials with gemcitabine are required and currently BCG plus alpha-2b interferon or mitomycin-C remains the standard of care for first-line treatment of recurrent disease.
For Tis disease, in the event of a failure on BCG therapy, and for T1 high-grade disease, BCG therapy followed by repeat TURBT or discussion of immediate cystectomy is mandatory. 4 Adjuvant therapy consists of immediate instillation with epirubicin. Maintenance therapy consists of BCG with alpha-2b interferon, if the patient is disease free at first cystoscopy. In patients with stage Ta or T1 bladder cancer (n=115) given one of the following three treatments, post-TURBT: (1) maintenance therapy with BCG (81 mg, intravesically) once weekly for 6 weeks followed by three once-weekly instillations at 3, 6, 12 and 18 months; (2) BCG (81 mg, intravesically) once weekly for 6 weeks; or (3) epirubicin (40 mg, intravesically) instilled nine times, the recurrence-free survival rates after two years of follow-up were 84.6%, 65.4%, and 27.7%, respectively. 5 Maintenance therapy with BCG is an important component of care in this setting.

# Appendix A: AJCC 8th Edition
Primary Tumour (T) Tx: primary tumour cannot be assessed T0: No evidence of primary tumour Ta: Non-invasive papillary carcinoma Tis: Carcinoma in situ: "flat tumour" T1: Tumour invades subepithelial connective tissue T2: Tumour invades muscularis propria
- pT2a: Tumour invades superficial muscularis propria (inner half) This guideline was originally developed in 2013 and updated in 2022.
A formal review of the guideline will be conducted in 2023. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly.
AHS, Alberta Health Services; AJCC, American Joint Committee on Cancer; AUC, Area under the curve; BCG, Bacillus Calmette-Guerin; CBC, Complete blood count; CCA, Cancer Care Alberta; CIS Carcinoma in situ; CMV, Cisplatin, methotrexate, vinblastine; Cr, Creatinine.