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OncologyStandardLast updated 29 May 2026

Bladder Cancer

Based on the 2024 AUA / 2021 CUA NMIBC guidelines. These notes apply to urothelial carcinoma, not other histologies (pure squamous cell, adenocarcinoma, small cell, or other pure non-urothelial carcinomas).

Epidemiology

  • ~75–80% of bladder-cancer patients present with NMIBC; ~20–25% with MIBC and/or metastatic disease.
  • Of NMIBC: 70% Ta, 20% T1, 10% CIS. Most Ta tumours are low-grade; T1 tumours are almost always high-grade (only ~2% are low-grade). Adjusted incidence of stage Ta has risen, while Tis and T1 have slightly decreased.

Genetics

  • Tumour-suppressor genes are mainly activated by allelic deletion of one allele followed by point mutation of the other (microsatellite analysis amplifies DNA repeats in the genome).
  • Low-malignant-potential NMIBC: chromosome 9, FGFR-3. High-malignant-potential NMIBC: deletion of RB and TP53. Alterations of p53, RB, and PTEN are associated with CIS and carry a very poor prognosis.
  • p53 is the most common mutation in invasive (≥T2) tumours; high-risk p53 lesions have a 75% progression rate vs 25% in p53-negative lesions (requires prospective validation).

Prognosis

Recurrence — rate ~60–70%. Two theories: a genetic field defect (multiple new tumours arising spontaneously) and local reimplantation of tumour cells after resection (implantation may explain early recurrences; initial tumours are most common on the floor and lower sidewalls, recurrences near the dome from "flotation"). Risk factors (3): prior recurrence rate (<1 year), number of tumours, tumour size (>3 cm).

Progression (to higher grade or stage) — rate ~20–30%. Risk factors (3):

  • Grade (most important) — more important than stage, unlike most cancers. HG tumours progress with similar frequency whether invasive (T1) or non-invasive (Ta); ~7% of Ta disease is HG.
  • Stage (second) — TaLG: recurrence ~55%, stage progression ~6%; T1HG: recurrence ~45%, progression ~17%.
  • CIS — if treated with TURBT only, recurrence is as high as 90% and progression to MIBC >50%; even complete responders to BCG progress in 30–40% on long-term follow-up. Concomitant CIS significantly increases progression and disease-specific mortality.

Other risk factors (2021 CUA, 5): age >70; extensive lamina-propria invasion (T1 substaging by micrometric extent or microanatomic level [T1a/b/c]; none universally adopted); lymphovascular invasion (independent factor for progression in high-risk disease — needs prospective validation); aggressive histologic variants (micropapillary, plasmacytoid, sarcomatoid — associated with under-staging and early progression); and persistent disease at the first surveillance cystoscopy after induction. Campbell's adds tumour architecture (papillary vs sessile) and the status of the remaining urothelium.

Cancer-specific survival is 70–85% in HG NMIBC, higher in LG disease.

EORTC risk tables give an individualized probability of recurrence and progression (developed from 2,596 Ta/T1 patients in 7 EORTC trials), based on (6): number of tumours, tumour size, prior recurrence rate, T category, concomitant CIS, and grade. The calculator likely overestimates risk, as very few patients received BCG.

Repeat (Re-)Resection

Benefits (3):

  • More accurate staging — re-TURBT upstaging rates: pTa 0.4%, pT1 8%.
  • Improves patient selection and response to BCG therapy.
  • Improves outcomes — pTa: lower recurrence (not progression); pT1: lower progression and overall mortality, with a trend to lower cancer-specific mortality. (Divrik 2010 RCT, n=210 newly diagnosed T1: second TUR within 2–6 weeks significantly reduced recurrence and progression at 66-month median follow-up.)

Indications (AUA):

  • Recommended — incomplete initial TUR (when repeat is technically feasible); and all T1 (upstaging to MIBC reported in ~30%; risk relates to muscularis propria on the initial specimen — 40–50% upstaging if no muscle present vs 15–20% if present, so repeat is recommended even when muscle is present). Residual T1 disease at repeat resection carries ~80% progression risk — counsel regarding early cystectomy. May be omitted when it won't change management (e.g. immediate radical cystectomy planned).
  • Consider — high-risk disease (larger/multifocal tumours at increased risk of incomplete initial resection); and high-grade disease (guidelines specify TaHG; residual tumour found in up to 50% of HG Ta, up to 15% upstaged).

Intravesical Therapy

Either chemotherapy or immunotherapy, used therapeutically (CIS or residual non-visible tumour), prophylactically (prevent recurrence/progression), or as adjuvant in the immediate postoperative setting.

Intravesical chemotherapy

Immediate instillation after TURBT — MOA: reduces tumour-cell implantation and has an ablative effect on small occult/residual tumour at the resection site.

  • Indications: 2024 AUA — consider in low- and intermediate-risk NMIBC. 2021 CUA — recommended for intermediate-risk and for patients with ≤1 recurrence/year and an EORTC recurrence score <5; should be offered to all presumed low-risk patients at TURBT.
  • Contraindications: after extensive resection, suspected perforation, or significant bleeding requiring irrigation. (Saline irrigation may be considered for low-/intermediate-risk patients when chemotherapy is contraindicated or unavailable — 2021 CUA.)
  • Efficacy: no benefit on progression or survival (only BCG delays or reduces HG progression); reduces recurrence (NNT 8, ARR ~12%). Meta-analysis (Perlis 2013, 13 studies, 2,548 patients): recurrence-free interval prolonged 38% (HR 0.62), early recurrences 12% less likely, NNT 8 — though 12 of 13 studies had high risk of bias. SWOG 0337 (Messing 2018, ~400 suspected LG NMIBC, gemcitabine vs saline within 3 h): ARR 10–15% at 4 years for recurrence, no difference in muscle invasion or death. Most effective for an initial solitary, low-grade, papillary tumour; limited benefit with recurrent/multiple tumours; no benefit in HG disease.

Commonly used agents (5): gemcitabine (inhibits DNA synthesis; 2 g in 100 mL), mitomycin C (alkylating agent; 40 mg in 20–40 mL), epirubicin, doxorubicin, pirarubicin — all equal efficacy per CUA. (Campbell's: MMC appears the most effective perioperative agent, though epirubicin is used in Europe and direct comparisons are lacking.) Thiotepa and combination epirubicin + MMC have also been evaluated.

MMC administration can be optimized (4): higher concentration (40 mg in 20 mL), urinary alkalinization with sodium bicarbonate (reduces drug degradation), pre-treatment dehydration, and complete bladder drainage beforehand. Efficacy of post-operative instillation falls significantly if given beyond 24 hours.

Adverse events: MMC — local irritative symptoms/chemical cystitis (most common), rash/contact dermatitis (second most common), UTI, hematuria, fever/chills, hand/foot desquamation, decreased bladder capacity from contractures, calcified eschars, and added difficulty of subsequent cystectomy; rare serious sequelae and deaths, especially with perforation (withhold chemotherapy with extensive resection or suspected perforation; consider better-tolerated gemcitabine). Thiotepa — local irritative symptoms and myelosuppression (low molecular weight predisposes to systemic absorption).

Induction + maintenance chemotherapy: benefit over induction alone is unclear (unlike BCG, where maintenance efficacy is established). Chemotherapy is less toxic than BCG (favoured by many in Europe); if recurrence develops during induction/maintenance chemotherapy, consider induction + maintenance BCG (superior in this setting).

Intravesical immunotherapy

MOA: a massive local immune response activating cell-mediated cytotoxic mechanisms; response may be limited by immunosuppressive disease or advanced age.

Bacillus Calmette-Guérin (BCG) — a live attenuated strain of Mycobacterium bovis (closely related to M. tuberculosis) with anti-tumour activity; originally developed as a TB vaccine (Morales 1976 published the first successful trial).

  • Efficacy: superior to chemotherapy for recurrence (ARR 25% vs 12%) and the only agent shown to reduce progression (ARR 4%). Cochrane (6 RCTs, 585 patients): 12-month recurrence 26% (BCG + TUR) vs 51% (TUR alone). Superior to doxorubicin/epirubicin and similar to mitomycin for recurrence. Progression — SWOG-8216/38 (262 patients): 15% (BCG) vs 37% (doxorubicin); meta-analysis (24 trials, 4,863 patients): progression 10% vs 14% control (ARR 4%; only maintenance BCG benefited; no OS or bladder-cancer-death difference). Cochrane BCG vs MMC (6 trials, 1,527 patients): recurrence reduced only in the high-risk subgroup, no progression/survival difference — choose based on adverse events and cost.
  • More adverse events than chemotherapy — use cautiously in low-risk disease. AUA: preferred initial treatment for CIS. BCG can treat residual papillary lesions but is not a substitute for surgical resection.
  • Maintenance: optimal dose and schedule are undetermined, but results are better with maintenance if tolerated. SWOG 8507 (550 patients): 5-year recurrence-free survival 41% (induction only) vs 60% (induction + maintenance), ARR 19%; only 16% tolerated the full schedule, and two-thirds who stopped did so within the first 6 months.
  • Dose reduction: small series show reduced toxicity with no efficacy difference. CUA — European studies show the dose can be cut to 1/3–1/4 with comparable efficacy, but Morales showed reduced efficacy in North American patients; EORTC 30962 (1,355 patients): 3-year full-dose gave superior recurrence-free rates without added toxicity, no progression/OS difference. AUA — a meta-analysis favoured standard-dose recurrence-free survival (no PFS difference); in high-risk (HG T1) patients, 3-year full-dose beat 1-year 1/3 dose, so full dose is recommended in this subgroup.

Contraindications:

  • Absolute (mnemonic "SHIT-IT", 6): Sepsis or history of BCG sepsis; Hematuria (gross; intravasation risk); Immunosuppressed/immunocompromised (small series suggest this may not be absolute); TURBT (immediately after, due to intravasation and septic-death risk); Incontinence (total); Traumatic catheterization (intravasation risk).
  • Relative (4): UTI (intravasation risk), liver disease (precludes isoniazid if sepsis occurs), poor performance status, advanced age.
  • Insufficient data: prosthetic materials, ureteral reflux, anti-TNF medications (theoretical sepsis risk).
  • Not contraindications: previous BCG vaccine (one cohort: positive PPD → better recurrence-free survival) and personal history of tuberculosis (Taiwan cohort, 3,915 patients: no efficacy/safety difference). Note: BCG in patients with an ileal conduit carries up to a 10% sepsis risk from absorption.

Dose, strain, schedule: full dose 120 mg in 50 cc normal saline, 2-hour dwell; avoid quinolones (affect BCG viability). Most-used US strains: Tice and Connaught (insufficient evidence to prefer one). Induction — 2-hour instillation weekly × 6, begun 2–4 weeks after resection to allow re-epithelialization. Maintenance — 2-hour instillation weekly × 3 at 3, 6, 12, 18, 24, 30, and 36 months from the start of induction. Perform urinalysis before each instillation; delay after traumatic catheterization; restrict fluid/diuretic/caffeine intake; clean the toilet with bleach.

Adverse events: most occur in the first year; serious toxicity in ~5%. Mechanisms — bacterial-mediated (responds to antituberculous therapy) vs non-bacterial sterile hypersensitivity (more delayed, responds to corticosteroids). Classified as local vs systemic:

  • Local (~2/3 of patients, from BCG-contaminated urine): most common is cystitis-like symptoms — hematuria, urgency, dysuria, frequency (up to 71%; expected post-administration, no infection on UA/culture, must be distinguished from bacterial cystitis; usually lasts 1–2 days and worsens with subsequent instillations). Others: bladder contracture; granulomatous prostatitis (common; can mimic prostate cancer on MRI, cause abnormal DRE/PSA; mostly asymptomatic → no intervention and maintenance can continue) and prostate abscess; granulomatous epididymo-orchitis/testicular abscess; upper-tract pyelonephritis, abscess, granuloma, or ureteral stricture; balanitis.
  • Systemic (~1/3, from bloodstream dissemination): most common is fever (indicates immune activation and a more favourable anti-tumour response; usually mild <38.5°C, <48 h — persistent or high fever warrants an infection work-up). Most serious is sepsis (1:15,000, potentially fatal). Others: malaise, spondylodiscitis/intramuscular abscess, mycotic pseudoaneurysm, pneumonitis, granulomatous hepatitis/lymphadenitis, peritonitis, choroiditis, parotitis, hypercalcemia.
  • Management: isoniazid, rifampin, and cycloserine for systemic toxicity; reduce BCG dose and/or dwell time to improve tolerability.

Interferon (IFN) — multiple anti-tumour properties, but more expensive and less effective than BCG or chemotherapy as a solitary agent; can occasionally be effective after BCG failure.

Combination therapy — combination chemotherapy, or BCG + chemotherapy: no major benefit over BCG monotherapy. BCG + IFN-α: some activity in BCG failures (may not exceed BCG alone); 2017 Cochrane (5 RCTs, 1,231 NMIBC patients, not BCG-failure): no difference in recurrence, progression, or cancer-specific survival, with a more favourable side-effect profile (reduced BCG dose) but higher cost.

Other treatments

  • Device-assisted therapy — electromotive drug administration (EMDA) with intravesical MMC (electric current increases drug uptake) and chemohyperthermia with intravesical MMC (radiofrequency heats the urothelium to 41–44°C); both promising but need validation.
  • Photodynamic therapy — a photosensitizer (porfimer sodium [Photofrin] systemically or HAL intravesically) is activated by red laser light (630 nm) for 12–20 minutes, generating cytotoxic free radicals and singlet oxygen; CIS response rate ~66%.
  • Radiation therapy — typically restricted to patients who refuse cystectomy after intravesical failure or are unfit for major surgery.

BCG Failure

2016 International Bladder Cancer Group definitions (4):

  • BCG-intolerant — disease persistence from inability to receive adequate BCG because of toxicity. (Adequate BCG = ≥5–6 weekly induction instillations plus ≥1 maintenance cycle [≥2 of 3 weekly treatments] or a second induction cycle [≥2 of 6].)
  • BCG-relapsing — recurrence of HG disease after a disease-free state at 6 months following adequate BCG; sub-stratified early (<12 months), intermediate (12–24), late (>24); prognosis improves with a longer disease-free interval.
  • BCG-refractory — persistent HG disease at 6 months despite adequate BCG, or any stage/grade progression by 3 months after the first cycle; increased progression risk and worse 5-year survival.
  • BCG-unresponsive — includes all BCG-refractory tumours, BCG-relapse within 6 months of last exposure, and CIS within 12 months of completing adequate BCG; denotes the highest-risk subgroup for whom additional BCG is not feasible.

(BCG-resistant [2015 CUA]: recurrence/persistence at 3 months of lesser stage or grade that resolves by 6 months. Low-grade recurrences during or after BCG are not considered BCG failure. Prognosis: intolerance > relapsing > refractory [worst].)

Management of BCG-unresponsive disease:

  • Standard of care: radical cystectomy + lymph-node dissection.
  • BCG-unresponsive with CIS or HG Ta: a second-line intravesical therapy may be considered before cystectomy.
  • For CIS who are unfit for or refuse cystectomy (4): IV pembrolizumab, intravesical oportuzumab monatox, intravesical nadofaragene firadenovec, or BCG + N-803; also valrubicin. (Chemoradiation is not recommended for BCG-unresponsive CIS.)
  • For those unfit for/refusing cystectomy: a clinical trial; sequential intravesical gemcitabine/docetaxel induction + maintenance (Steinberg 2020, 276 patients: recurrence-free survival 60% at 12 months, 46% at 24 months); other combinations (sequential gemcitabine/MMC, BCG + IFN); or single-agent intravesical therapy (MMC, epirubicin, docetaxel, gemcitabine, valrubicin) — sequential combinations are favoured over single agents.
  • Repeat induction BCG: after induction-only therapy with later relapse, a second induction course achieves 30–50% response; more than 2 induction courses are not recommended (high failure rate).

Agents for BCG-unresponsive disease:

  • Pembrolizumab — PD-1 checkpoint inhibitor; 200 mg IV q3 weeks for up to 24 months. KEYNOTE-057 (96 patients, BCG-unresponsive CIS): complete response 41% at 3 months, median duration 16.2 months; FDA-approved January 2020.
  • Nadofaragene firadenovec (Adstiladrin) — a non-replicating adenovirus vector with IFN-α2b; transduced into bladder cells to produce antitumour IFN-α2b. Single-arm trial (157 patients): 53% complete response within 3 months, maintained in 46% at 12 months; FDA-approved December 2022; instilled every 3 months.
  • Oportuzumab monatox (Vicineum) — an anti-EpCAM antibody fused to a Pseudomonas toxin that binds bladder-cancer cells.
  • BCG + N-803 — N-803 is an IL-15 superagonist antibody–cytokine fusion protein co-administered intravesically with BCG to activate NK and CD8+ T-cells without inducing a T-reg response.

Timely Cystectomy

Despite local therapy, many HG NMIBC cases progress to invasion and risk of cancer death. "Early" cystectomy is performed before the traditional indication of documented muscle invasion; a reasonable goal is "timely" cystectomy for at-risk patients. Cystectomy for CIS or persistent HG papillary disease after 2 courses of intravesical therapy is standard of care and not considered "early." Campbell's indications: HG deeply invading the lamina propria; lymphovascular invasion; diffuse CIS; disease in diverticula; substantial involvement of the distal ureters or prostatic urethra; refractory to initial therapy; too large or anatomically inaccessible for complete endoscopic removal; or a patient who understands the trade-offs and requests definitive therapy.

Surveillance and Prevention

At 10 years, only ~30% of patients remain free of progression or recurrence, so close follow-up is mandatory. Most protocols use cystoscopy and urinary cytology every 3 months for 18–24 months, then every 6 months for 2 years, then annually — resetting with each newly identified tumour. Local anaesthetic at cystoscopy shows no benefit (may worsen pain and cloud visualization); a video monitor reduces pain by ~50% in men. Cytology is useful in surveillance given its high sensitivity and positive predictive value for HG tumours and CIS.

Extravesical surveillance — incidence of UTUC after bladder cancer is 3% (1.6% low-risk to 4.1% high-risk); modality is CT and intravenous urography.

Prostatic urethral UC — secondary involvement of the prostatic urethra and ducts occurs in 10–15% of high-risk non-muscle-invasive disease within 5 years and 20–40% within 10 years. Low-grade ductal involvement is usually managed by complete TURP (for eradication and to allow intravesical therapy contact); high-grade ductal involvement is best managed by radical cystoprostatectomy ± urethrectomy.

Secondary prevention — smoking cessation, increased fluid intake, and a low-fat diet may all reduce recurrence risk.