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NMIBC risk classification, from AUA NMIBC Guidelines

NMIBC risk of recurrence and progression, from Campbell's

EORTC risk tables, from Sylvester et al

Management of positive cytology, from Campbell's

Non-Muscle Invasive Bladder Cancer (AUA management algorithm)

Risks of Recurrence and Progression

• Progression: any upstaging or upgrading
• Low grade: may be a separate disease and may not progress to high grade
• TaLG: 50-70% recurrence, < 5% progression
• T1HG: > 80% recurrence, 50% progression
• CiS: 40-83% progression if untreated, up to 20% have invasive disease on cystectomy, increases upstaging in cystectomy for T1 disease (55% vs 6%), node-positive disease in 3%
• Grade is a greater predictor of progression as opposed to stage
• Upstaging occurs in 34-62% T1 disease

Persistent disease and Recurrences (intermediate/high risk)

• Positive cytology: consider prostatic urethral biopsies and upper tract evaluation, prostatic urethra affected in 24-39% recurrences, 20% with positive cytology have urethral disease, and 25% with recurrence have upper tract disease
• After induction therapy: repeat induction BCG/MMC, up to 50% response after 2nd course but 20-50% progression
• Within 6mo of iBCG x2 or iBCG + mBCG: do not give further BCG, consider up-front cystectomy instead of giving more BCG (80% failure rate)
• Within 12mo of iBCG x2 or iBCG + mBCG but unwilling/unfit for cystectomy: consider intravesical chemotherapy, pembrolizumab (CiS within 12mo completing BCG), or clinical trials (if available)

Up-Front Cystectomy for NMIBC

• Indications: T1 recurrence after iBCG x1, T1 persistence on reTURBT, T1 plus CiS/LVI/variant histology
• Benefits: worse mortality when NMIBC progresses to MIBC as opposed to an initial MIBC diagnosis
• Upstaging: up to 50% NMIBC upstaged at cystectomy, 15% already have micrometastases
• 10yr survival: 67-92%
• Low/Intermediate disease: not indicated unless all other options have failed

Prostatic urethral cancer

• Prevalence: 90% have associated bladder cancer, but only seen in 3% bladder cancer patients, usually CiS
• Mucosal disease: TURP increases BCG penetration
• Ductal disease: TURP + BCG or cystectomy + urethrectomy
• Stromal invasion: considered T4 disease, 25% 5yr overall survival, NAC then cystectomy/urethrectomy

BCG

Types

• Live-attenuated strain (8 types) of TB, reconstituted in 50mL saline
• No evidence for preferred strain, strength, or combining with other agents

Administration and success

• Instructions: hold in bladder for 1-2hrs, avoid if recent traumatic catheterization, minimize fluid intake prior
• 30% remain disease free at 10yrs
• Only intravesical therapy with proven decreased progression rates (15% vs 37%)
• T1 disease: 16-40% recurrence and 4-40% progression rates
• Less efficacious than TURBT for residual tumors
• 50% success for prostatic urethral tumors
• PPD: patients that develop positive PPD have a higher chance of responding to BCG
• SWOG 8507 (Lamm 2000): give maintenance BCG x3 at 3, 6, 12, 18, 24, 30, and 36mo - recurrence-free survival at 5yrs increased 41% -> 60%
• EORTC 30692: increased recurrence-free survival (HR 1.61) at 5yrs if 3yrs BCG instead of only 1yr
• Vs intravesical chemo: BCG shown to decrease recurrence AND progression, MMC only decreases recurrence

Risks/side effects

• Contraindications: immunocompromised patients, prior BCG sepsis, gross hematuria, traumatic catheterization, incontinence
• Side effects: dysuria, hematuria, fever (5%), BCG sepsis (0.5%), granulomatous infection, bladder contraction, myelosuppression
• Prevalence:70% report some side effects, 8% need to stop therapy
• BCG Grade 1 toxicity: obtain UCx, manage symptoms
• BCG Grade 2 toxicity (symptoms > 48hrs): obtain UCx + CXR + LFTs, treat with rifampin + isoniazid (up to 3mo), consider dose reduction and pretreating with isoniazid prior to BCG administration
• BCG Grade 3 toxicity (allergy or solid organ involvement): isoniazid + rifampin, stop BCG (do not restart), consider ID consult
• Granulomatous prostatitis/epididymitis/orchitis: isoniazid + rifampin x3-6mo

Definition of BCG failures

• BCG refractory: persistent disease after 6mo or progression after 3mo
• BCG relapse: recurrence after BCG treatment, early (within 12mo) or late (> 24mo)
• BCG intolerance: disease persistence due to inability to tolerate BCG due to side effects
• BCG unresponsive: BCG refractory or relapse within 6mo treatment, recommend up front cystectomy (best survival), intravesical therapies, or immunotherapy

Other NMIBC Therapies

Mitomycin (MMC)

• Benefits: recurrence RR=0.71, no effect on progression
• Tips: no fluids 8hrs prior, alkalinize urine with NaBicarb 1.3g night before + morning of + 30min prior to instillation, give high concentration (40mg/20mL water)
• Side effects: bladder contraction (5%), allergy (5%), cystitis (30-40%), skin reaction (if touches skin)

Doxorubicin/Epirubicin

• Benefits: recurrence - RR=0.80 for doxorubicin, RR=0.63 for epirubicin
• No effect on progression
• Side effects: bladder contraction (5%) with doxorubicin, cystitis (10-40%)

Gemcitabine

• Can give immediately post-TURBT, give with doxorubicin for BCG refractory disease (T1 or CiS)
• Combined gemcitabine + docetaxel: no difference in combo therapy vs BCG for 2yr recurrence free survival, after failing induction BCG x1
• Side effects: LUTS (10-20%), hematuria (5%), cystitis (1-3%), myelosuppression (rare), pulmonary fibrosis (rare)

Thiotepa

• Higher risk of systemic absorption due to low molecular weight
• Side effects: myelosuppression (10%), dysuria

Pembrolizumab

• Approved for BCG-unresponsive, high-risk NMIBC with CiS (and not interested in cystectomy)
• Side effects: dermatitis (20%), pneumonitis (8%), colitis (2%), hepatitis (1%), nephritis (0.5%)

Other immunotherapies

• IFN-2a: stimulates immune response, given with BCG, flu symptoms (15-20%), fever (10%)
• Nadoferagene firadenovec: gene therapy with adenovirus, induces IFN-2a production, causes LUTS (60%)