Canadian Urological Association guideline on the management of non-muscle invasive bladder cancer

Abstract

Risk factors 1. Former or current tobacco smoking is the most common risk factor associated with bladder cancer and smoking cessation should be encouraged in all patients (Level of Evidence [LE] 3; strong recommendation). Symptoms and diagnosis 2. White-light cystoscopy (WLC) is recommended in the initial evaluation of patients suspected to have bladder cancer. Cystoscopy should be performed with a flexible cystoscope whenever available (LE 1; strong recommendation). 3. Urine cytology (voided or collected by bladder washing) is recommended as an adjunct to cystoscopy in patients suspected to have bladder cancer (LE 2; strong recommendation). 4. Upper urinary tract imaging is recommended in the initial workup of patients suspected to have bladder cancer (LE 3; strong recommendation). Prognostic factors for recurrence and progression 5. The most important prognostic factors for recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) are stage and grade (LE 2). All patients with bladder cancer should be properly staged and, specifically for NMIBC, reporting grade is paramount for further management decisions (LE 2; strong recommendation). 6. Other prognostic factors are age >70yr, large tumour size (≥3cm), multiple tumours, the presence of concomitant carcinoma in situ (CIS), extensive invasion of the lamina propria, prior recurrence rates > 1 per year and status at first assessment after transurethral resection of the bladder tumour (TURBT) (LE 2), as well as lymphovascular invasion (LVI) (LE 3). 7. Aggressive histological variants such as micropapillary, plasmacytoid and sarcomatoid are associated with increased risk of under-staging and progression (LE 3). Pathological review, preferably by a dedicated uro-pathologist, should be considered in settings where variant histology is suspected or atypical tumours are seen during TURBT (e.g., sessile mass) (LE 3; weak recommendation). Risk stratification 8. All patients with NMIBC should be stratified according to the risk of both recurrence and progression for adequate patient counselling and treatment planning (LE 2; strong recommendation). The modified CUA risk stratification system is a suitable tool for this purpose. Transurethral resection 9. Patients presenting with a bladder tumour should undergo initial TURBT for diagnostic confirmation and pathological evaluation (LE 2; strong recommendation). 10. Initial TURBT aims for complete tumour resection with sampling of the underlying detrusor muscle as the first step of curative-intent treatment of NMIBC (LE 2; strong recommendation). Patients with presumed low grade (LG) Ta or CIS might be spared from muscle sampling at initial TURBT (LE 3; weak recommendation). 11. When available, blue light cystoscopy (BLC) (LE 1; weak recommendation) or narrow band imaging (LE 2; weak recommendation) can increase tumour detection at first TURBT and reduce recurrence risk. 12. A restaging TURBT should be performed in patients with T1 NMIBC, or when a complete resection was not achieved with the first TURBT (LE 2; strong recommendation). Restaging TURBT is not required in patients who will proceed to radical cystectomy (RC) based on the findings of the first TURBT. 13. In select cases of high grade (HG) Ta tumours (e.g., large and/or multiple tumours), a restaging TURBT can be considered (LE 3; weak recommendation). 14. The suggested window for a restaging TURBT is within 6 weeks of the first resection (LE 3; weak recommendation). 15. Patients presenting with a positive urine cytology, but normal appearing bladder at WLC and normal upper urinary tract imaging are at higher risk of harbouring occult CIS and should undergo random bladder biopsies (or use of BLC with directed biopsies) (LE 2; strong recommendation). 16. Biopsies or transurethral resection of the prostatic urethra should be included with random bladder biopsies in the presence of a positive bladder urine cytology, but normal appearing bladder at WLC and normal upper tract imaging (LE 3; strong recommendation). 17. Prostatic urethral biopsy (or transurethral resection) can also be considered in the presence of extensive bladder CIS or tumour at the bladder neck or trigone (LE 3; weak recommendation). 18. Patients with prostatic urethral involvement (PUI) with CIS restricted to the urethral mucosa can be managed conservatively with transurethral resection of the prostate (TURP) plus intravesical BCG (LE 3; weak recommendation). Repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). RC can be discussed as an alternative option (LE 4; weak recommendation). 19. In patients with HG T1 or CIS extending into the prostatic ducts, RC should be considered (LE 3; weak recommendation). TURP followed by intravesical BCG is an alternative option. In this instance, close followup with repeat prostatic urethral biopsies after induction BCG should be considered (LE 3; weak recommendation). 20. In patients with prostatic stromal invasion, neoadjuvant cisplatin-based chemotherapy followed by RC is recommended (LE 3; strong recommendation – refer to MIBC CUA guideline). Single instillation of chemotherapy (SIC) post-TURBT 21. SIC (with mitomycin-C, epirubicin, doxorubicin, pirarubicin or gemcitabine) should be offered to all patients with presumed low-risk NMIBC at TURBT and should be administered within 24 hours after endoscopic resection (LE 1; strong recommendation). 22. SIC is recommended for intermediate-risk NMIBC and for patients with ≤ 1 recurrence/year and EORTC recurrence score < 5 (LE 1; strong recommendation). SIC should be discussed even when further adjuvant intravesical chemotherapy is planned (LE 2; weak recommendation). 23. The benefit of SIC in patients with high-risk NMIBC is unclear when intravesical Bacillus Calmette-Guérin (BCG) is planned as adjuvant treatment (LE 3). 24. SIC should not be administered after extensive resection or when bladder perforation is suspected (LE 3; strong recommendation). Adjuvant intravesical chemotherapy 25. Patients with intermediate-risk NMIBC should be considered for adjuvant induction intravesical chemotherapy (LE 1; strong recommendation) with subsequent maintenance for up to 1 year (LE 3; weak recommendation), or induction BCG with maintenance therapy (refer to statement #30). 26. Substratification of intermediate-risk patients with recurrent LG Ta NMIBC can be used to guide adjuvant treatment decisions (LE 3; weak recommendation). For this purpose, 4 factors should be considered: number of tumours, size (≥ 3cm), time to recurrence (< 1 year) and frequency of recurrence (> 1/year). - Patients with low-intermediate-risk NMIBC (0 factors) may be treated similarly to low-risk patients, with SIC alone (LE 3; weak recommendation). - Patients with high-intermediate-risk NMIBC (≥3 factors) may be treated as high-risk patients with induction and maintenance BCG (LE 3; weak recommendation). 27. Patients who develop recurrence during intravesical chemotherapy may be offered induction followed by maintenance BCG (LE 3; weak recommendation). 28. Although intravesical chemotherapy through device-assisted therapy has shown promising results in small randomized controlled trials, further studies are needed to validate its routine clinical use. Adjuvant intravesical BCG 29. In patients with high-risk NMIBC, BCG therapy with induction (weekly instillations for 6 weeks) followed by 3-year maintenance (weekly instillations for 3 weeks at 3, 6, 12, 18, 24, 30 and 36 months) is the standard of care for reducing disease recurrence and progression rates (LE 1; strong recommendation). 30. When BCG is administered for intermediate-risk NMIBC, induction (weekly instillations for 6 weeks) followed by 1-year maintenance (weekly instillations for 3 weeks at 3, 6 and 12 months) is recommended (LE 1; strong recommendation). 31. RC with pelvic lymph node dissection is the standard of care for BCG-unresponsive bladder cancer in surgically fit patients (LE 3; strong recommendation). For patients with BCG-unresponsive CIS or HG Ta, a second-line bladder-preserving therapy can be considered before RC (LE 3; weak recommendation). 32. Promising efficacy has been reported with intravenous pembrolizumab, intravesical oportuzumab monatox, nadofaragene firadenovec, and BCG plus N-803. These should be considered as potential options in patients with BCG-unresponsive CIS who are unfit for or refuse to undergo RC (LE 2; weak recommendation). 33. Alternative options such as sequential intravesical gemcitabine/docetaxel (induction plus maintenance) may be considered for patients with BCG-unresponsive disease who are unfit for or refuse to undergo RC (LE 3; weak recommendation). Additional alternatives may also include other combination intravesical therapy (e.g., sequential gemcitabine/mitomycin-C, BCG + interferon if available) or single-agent intravesical therapy (mitomycin-C, epirubicin, docetaxel, gemcitabine) (LE 3; weak recommendation). 34. Clinical trials may be considered for BCG-unresponsive patients who are unfit for or refuse to undergo RC. Treatment adjustments only if BCG shortage 35. For patients with intermediate-risk NMIBC during BCG shortage, intravesical chemotherapy is recommended as the first-line option. If BCG is planned as a second-line therapy for this population, induction might be administered with reduced dosing (1/2 or 1/3 dose) and maintenance can be omitted (LE 3; weak recommendation). 36. For patients with high-risk NMIBC, full BCG schedule (induction followed by maintenance) is recommended (LE 1; strong recommendation). Only during BCG shortage, when full dose is not possible due to limited supply, dose reduction to 1/2 or 1/3 might be considered, while maintenance can be reduced to one year (LE 3; weak recommendation). 37. When BCG is unavailable, single agent chemotherapy (e.g., mitomycin-C, gemcitabine) or sequential combination of intravesical chemotherapy (e.g., gemcitabine/docetaxel) is recommended with induction followed by monthly maintenance for up to one year (LE 3; weak recommendation). Timely cystectomy 38. Upfront RC should be considered for patients with large volume, diffuse, endoscopically unresectable NMIBC (LE 3; strong recommendation) 39. Upfront RC should be offered to patients with HG T1 disease with additional adverse tumour pathological features including: variant histology (e.g., micropapillary, plasmacytoid, sarcomatoid), extensive invasion of the lamina propria or invasion into or beyond the muscularis mucosa (T1b/c), presence of LVI, concomitant CIS in the bladder or prostatic urethra, multiple and large (≥3cm) tumours, or persistent HG T1 upon restaging TURBT (LE 3; strong recommendation). Followup 40. The first surveillance cystoscopy is recommended for all patients at 3 months after TURBT (LE 2; strong recommendation). 41. A risk-based surveillance strategy should be used in patients with no evidence of recurrence at the 3-month cystoscopy: - Low-risk patients might be followed with cystoscopy at 1 year and then yearly for 5 years (LE 3; weak recommendation). Urine cytology is not necessary in the followup of low-risk patients (LE 4; weak recommendation). - Intermediate-risk patients should be followed with cystoscopies and urine cytology every 3-6 months in the first 2 years, every 6-12 months in the 3rd year, and annually thereafter (LE 3; weak recommendation). - High-risk patients should be followed with cystoscopies and urine cytology every 3-4 months during the first 2 years, every 6 months during years 3 and 4, and annually thereafter (LE 3; weak recommendation). 42. Upper tract imaging is recommended with random bladder/prostatic urethral biopsies (or use of BLC with directed biopsies) if positive urine cytology with normal WLC is found during surveillance (LE 3; weak recommendation). 43. Upper tract imaging is recommended in the first year and every 2 years thereafter for high-risk patients (LE 3; weak recommendation). 44. Fulguration under local anesthesia might be considered for small (<5mm) papillary tumours and negative cytology in patients with a prior history of papillary urothelial neoplasm of low malignant potential or LG Ta NMIBC (LE 3; weak recommendation).