Risk-adapted management of recurrent non-muscle invasive bladder cancer*

Risk stratification at time of disease recurrence^[1-3]	Prior management	Treatment of recurrent disease	Later-line therapy
Intermediate-risk disease: LG Ta with recurrence within one year Solitary LG Ta >3 cm Multifocal LG Ta Solitary HG Ta ≤3 cm LG T1	TUR only	Surveillance, office tumor fulguration, or TURBT	Continue surveillance, office tumor fulguration, or TURBT; or intravesical therapy.
		Intravesical chemotherapy	Intravesical BCG.
		Intravesical BCG	Intravesical chemotherapy.
	Prior intravesical chemotherapy	Intravesical BCG	Other intravesical chemotherapy. Evaluate for radical cystectomy if unable to control disease.
	Prior intravesical BCG	Intravesical chemotherapy
High-risk disease: HG Ta >3 cm Multifocal or recurrent HG Ta HG T1 CIS	TUR only	Intravesical BCG	Refer to treatment approach for high-risk disease, prior BCG therapy.
	Prior intravesical chemotherapy	Intravesical BCG	If recurrence is more than 6 months (Ta/T1) or 12 months (CIS) after the last BCG dose, retreat as a late relapse with a second cycle of intravesical BCG. If disease does not respond, radical cystectomy is preferred over a third cycle of intravesical BCG. Otherwise, refer to treatment approach for high-risk disease, prior BCG therapy: BCG-unresponsive disease.
	Prior BCG therapy: BCG-exposed disease^¶	Intravesical BCG
	Prior BCG therapy: BCG-unresponsive disease^Δ	Radical cystectomy^◊
	Prior BCG therapy: BCG-unresponsive disease^Δ	For patients who are ineligible for or decline radical cystectomy, options include intravesical therapy^§ or systemic pembrolizumab (for CIS with or without Ta/T1 disease)	Radical cystectomy.
Very high-risk disease: HG T1 with any of the following: Multiple and ≥3 cm tumors Presence of concurrent CIS (in the bladder or prostatic urethra) Presence of LVI Variant histology (eg, micropapillary, plasmacytoid, sarcomatoid, neuroendocrine)	Radical cystectomy (regardless of prior therapy)
	Patient is not eligible for or declined radical cystectomy	Refer to treatment approach for high-risk disease.

LG: low grade; TUR: transurethral resection; TURBT: transurethral resection of bladder tumor; BCG: Bacillus Calmette-Guerin; HG: high grade; CIS: carcinoma in situ; LVI: lymphovascular invasion.

* Non-muscle invasive bladder cancer is a heterogeneous group of tumors that can be papillary tumors (Ta [non-invasive] or T1 [lamina propria invasive]) and/or CIS. Ta tumors can be LG or HG. T1 tumors are almost always HG. Clinical trial enrollment is encouraged, where available.

¶ BCG-exposed is defined as high-risk non-muscle invasive bladder cancer treated with a single round of induction BCG without maintenance therapy, and those who receive maintenance BCG but relapse with high-grade disease more than 12 months and less than 24 months after the last dose of BCG.

Δ BCG-unresponsive is defined as one of the following, in the absence of urothelial carcinoma of the prostatic urethra or upper tract:

Persistent or recurrent high-grade Ta/Tis urothelial carcinoma of the bladder after completion of at least induction (≥5 doses) and one round of maintenance (or second induction; ≥2 doses) intravesical BCG.
Persistent or recurrent high-grade T1 bladder cancer after induction BCG (≥5 doses) without further maintenance therapy.
Initial complete response (no disease six months after diagnosis) followed by subsequent high-grade recurrence within 6 (Ta/T1) or 12 months (CIS with or without Ta/T1) after the last BCG dose.

◊ For BCG-unresponsive disease, radical cystectomy is the most definitive therapy with the lowest risk of progression, but there is risk of overtreatment.

§ Preferred options for intravesical therapy for BCG-unresponsive disease include sequential gemcitabine and docetaxel, and nadofaragene firadenovec (for CIS with or without Ta/T1 disease). Single-agent intravesical gemcitabine, docetaxel, or mitomycin are alternatives for those who are unable to receive the preferred agents.

References:

Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol 2016; 196:1021.
Kim SH, Lerner SP. Risk Stratification of Nonmuscle Invasive Bladder Cancer and Innovative Approaches to Management of Ta Low-Grade Tumors. J Clin Oncol 2023; 41:163.
Bhindi B, Kool R, Kulkarni GS, et al. Canadian Urological Association guideline on the management of non-muscle-invasive bladder cancer. Can Urol Assoc J 2021; 15:E424.

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Risk-adapted management of recurrent non-muscle invasive bladder cancer*