Bladder Cancer

Risk Factors

• Smoking → 50–60% of cases (most common RF)
• Occupational → aromatic amines (β-naphthylamine), benzene; dye/rubber/plastic/dry-cleaning
• Chemoradiotherapy — cyclophosphamide only proven chemo agent
• Chronic infection/irritation — Schistosomiasis → SCC; Foley catheter → ~1% incidence; surveillance after 8 years
• Family history — 1st-degree relative → 2× risk
• Arsenic exposure
• Lynch syndrome
• Obesity

Risk factors for adenocarcinoma specifically

• Cystitis glandularis
• Cystitis cystica
• Bladder exstrophy
• Urachal cyst
• Augmented bladder
• CIS
• Chronic irritation
• Uretero-sigmoidostomy
• Bilharziasis

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Genetics

• Carcinogen-handling polymorphisms raise risk — N-acetyltransferase 2 (NAT2) and deletion of glutathione S-transferase μ (GSTM1)

Pathway	Alterations
Low grade	FGFR-3 + TERT, PI3K or Ras — chromosome 9; FGFR3 mutated in 80% of Ta LG
High grade	TP53 — chromosome 17 · PTEN — chromosome 10 · RB — chromosome 13
MIBC / metastatic	p53 inactivation in up to 76% of MIBCs; dual deletion of p53 and PTEN drives metastatic disease

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Pathology

Histology

• UC 90% | SCC 2–5% | Adenocarcinoma 2% | Small cell <1%
• 75% present as NMIBC; 25% as MIBC/metastatic

Grading (WHO/ISUP 2004/2016)

• PUNLMP — recurrence 12–35%; progression 4%
• Low grade — recurrence 50–70%; progression ~5% (Ta)
• High grade — recurrence ~80% (T1); progression ~50% (T1)

CIS

• Flat, non-invasive, HG by definition; field disease
• Progression if TURBT only: ~54%
• Even with full BCG response → progression in 30–40% long-term

Aggressive Variants (→ upfront cystectomy)

• Micropapillary — not sensitive to chemotherapy; immediate cystectomy preferred
• Plasmacytoid — chemo-resistant
• Sarcomatoid - upfront cystectomy

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Microscopic Hematuria (2025 AUA Guidelines)

Definition: ≥3 RBCs/HPF on single properly collected specimen (CUA: ≥2 RBCs/HPF on 2 samples)

Risk of urinary tract malignancy in hematuria: 10% overall (gross 13%; microscopic 1–3%)

AUA Risk Stratification

	Low	Intermediate	High
Age	F <60 / M <40	F>60 / M 40–59	M ≥60
Smoking	Never or <10 pack-yr	10–30 pack-yr	>30 pack-yr
UA	3–10 RBC/HPF	11–25 RBC/HPF (or low-risk + repeat 3–10)	>25 RBC/HPF
Gross hematuria	—	—	Yes
UC risk factors	None	Present	—

Investigations by risk:

• Low: repeat UA within 6 months (cystoscopy/imaging optional)

• Intermediate: renal US + cystoscopy; serum Cr/GFR

• High: CT urography + cystoscopy; serum Cr/GFR

• Low-risk who elect no workup and have persistent MH on repeat → reclassify as intermediate/high

• Anticoagulants: same evaluation regardless of anticoagulation level

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TNM Staging (AJCC 8th)

T Stage

Stage	Description
Ta	Non-invasive papillary
Tis	CIS (flat)
T1	Invades lamina propria
T2a / T2b	Superficial / deep muscularis propria
T3a / T3b	Perivesical fat microscopically / macroscopically
T4a	Prostate stroma, SV, uterus, vagina
T4b	Pelvic/abdominal wall

N Stage

• N1: single node in true pelvis (perivesical, obturator, internal/external iliac, presacral)
• N2: multiple nodes in true pelvis
• N3: common iliac nodes

M Stage

• M0 | M1a: non-regional LN (beyond common iliac) | M1b: visceral

Stage Grouping

Stage	TNM
I	T1 N0 M0
II	T2 N0 M0
IIIA	T3–T4a N0–N1
IIIB	T1–T4a N2–N3
IVA	T4b any N M0 OR any T any N M1a
IVB	Any T any N M1b

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Diagnosis

Presentation

• Painless gross hematuria — most common symptom (85%)
• Storage LUTS (urgency/frequency/dysuria) → think CIS in absence of UTI
• Risk of malignancy: gross hematuria 13%; microscopic hematuria 1–3%

Workup of Suspected Bladder Cancer

• CBC
• Renal profile
• Hepatic profile
• Urinalysis
• PSA
• Urine culture
• Urine cytology
• CT urography ± chest imaging (chest imaging guided by the pathology)
• Cystoscopy

Urine Cytology

• Sensitivity ~50% (HG 84%; LG 16%); Specificity ~85%
• Strength = specificity (not sensitivity — use tumour markers for that)
• NOT indicated for microscopic hematuria workup (AUA)

Enhanced Cystoscopy

• White light cystoscopy remains the standard of care
• Blue light (HAL): photosensitizer instilled 1–4h pre-op; improves CIS detection; reduces residual tumour 20% vs. white light
  • Detects 14.7% more Ta tumours and 40.8% more CIS lesions than white light
• NBI: no instillation; improves detection; prognostic impact unknown

Imaging

• Upper tract imaging (CT urography preferred) for all suspected bladder cancer
• Hydronephrosis → suspicious for muscle invasion
• Delay imaging ≥7 days post-TURBT to avoid T3 artifact

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NMIBC

Risk Stratification

Risk	Definition
Low	PUNLMP; solitary LG Ta ≤3 cm
Intermediate	LG Ta recurring within 1 yr; solitary LG Ta >3 cm; multifocal LG Ta; LG T1; solitary HG Ta ≤3 cm
High	HG T1; recurrent HG Ta; HG Ta >3 cm or multifocal; any CIS; BCG failure in HG disease; LVI; variant histology; HG prostatic urethral involvement

A solitary HG Ta ≤3 cm is intermediate-risk — high grade alone does not make it high-risk; recurrence, size >3 cm or multifocality does.

Tumour characteristics that raise the risk

Characteristic	Drives
Multifocality	Recurrence
Size > 3 cm	Recurrence
Higher grade	Progression
Higher stage	Progression
Recurrence within one year	Both

Prognosis (by stage)

• Ta: recurrence 50–70%; progression ~5% (LG) | LG progression 3–10%
• T1: recurrence ~80%; progression ~50%
• CIS: progression ~54%
• Understaging in HG T1: 30–50%
• Grade > stage for predicting progression (unique to bladder cancer)

TURBT Pearls

• Lenses: 30° for preliminary inspection and therapeutic use; 70° for bladder neck, dome, anterior wall
• Bipolar advantages vs. monopolar: reduced obturator reflex risk; uses 0.9% NS (no electrolyte risk); monopolar uses 1.5% glycine or sterile water
• Diverticular tumours: no detrusor → accurate staging difficult; invasion beyond lamina propria = T3a; low-grade → resection + fulguration; high-grade → partial or RC strongly considered
• Obturator reflex (lateral wall tumours): adduction of ipsilateral leg → risk perforation
  • Prevention: minimize bladder distention, use bipolar, muscle relaxant, obturator nerve block (20–30mL lidocaine), tap pedal intermittently
  • Spinal with a regional block, or GA with a muscle relaxant
  • Decrease the cutting current
• Bladder perforation (<5% of cases): extraperitoneal (most common) → Foley + observation; intraperitoneal (posterior/dome) → abdominal exploration + repair
• Random biopsies: indicated in HG disease and when neobladder planned (prostatic urethral biopsy); not in LG with negative cytology
• Combined TURBT + TURP: acceptable for LG tumour; avoid for HG tumour (risk seeding/intravasation)
• Use cutting current over the mass near ureter,
• Placing a ureteral stent should be avoided , 1- does not reduce risk of stricture and 2- increase the risk of upper UC of 3 folds
• Taking deeper cut or after removing it to take a biopsy from the base to ensure muscle present
• In the bladder, use the Nd:YAG laser at 35 W

Complications of TURBT

• Bleeding
• Perforation (can be managed laparoscopically)
• Inability to void
• Infection
• Urethral stricture
• Nerve injury from positioning — posterior tibial and common peroneal nerves

Random Bladder Biopsy — Indications

• Positive cytology with no gross tumour
• Tumour is low grade but cytology is high grade
• Partial cystectomy consideration
• Post-BCG for CIS — to evaluate for complete response
• Suspected CIS | Multifocal tumours

Prostatic Urethral Biopsy — Indications

• Tumour at bladder neck
• Suspected/known CIS
• Multifocal disease
• Positive cytology with no gross tumour
• Lesion in the prostatic urethra

Re-TURBT — Indications

• Perform at 2–6 weeks after the initial resection
• All high-risk disease
• All Ta high grade — even if < 3 cm
• All T1 — even if low grade
• Incomplete initial resection
• Large or multifocal tumours
• Large anterior wall tumours
• TaHG → upstaged in ~15%
• T1 (all) → upstaged in ~30%
• No muscle in specimen → ~50% are muscle-invasive
  • This figure is T1-specific — a low-risk solitary LG Ta with no muscle in the specimen does not need a re-TURBT

Surveillance by Risk

Low Risk:

• Single post-op intravesical chemotherapy
• Cystoscopy at 3 months → then annually × 5 years

Intermediate Risk:

• Intravesical chemo induction ± maintenance If LG Ta
• If HG Ta → BCG induction + maintenance (1 year)
• Cystoscopy: 3, 6, 9, 12 months → q6 months (year 2) → annually × 5 years
• Urine cytology

High Risk:

• BCG induction + maintenance × 3 years
• Cystoscopy: q3 months × 2 years → q6 months × 3 years → annually for life
• Urine cytology
• CTU at 1 year, then every 1–2 years

AUA/SUO surveillance schedule

Risk	Tumour status	Cystoscopy schedule	Upper tract imaging
Low	Solitary Ta low grade	3 months after initial resection; annually beginning at 9 months if no recurrence; consider cessation at 5+ years; consider cytology or tumour markers	Not necessary unless hematuria present
Intermediate	Multiple Ta low grade · large tumour · recurrence at 3 months	Every 3–6 months for 1–2 years; every 6–12 months for the next 2 years; annually thereafter; consider cytology or tumour markers	Consider imaging at 1–2 year intervals, especially for recurrence
High	Any high grade, including CIS	Every 3–4 months for 2 years; then every 6 months for 3 years; annually for life; cytology on the same schedule	Annually for 2 years, then consider lengthening the interval

• Restart the clock with each recurrence — applies to intermediate and high risk

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Intravesical Chemotherapy

Agents:

• Mitomycin C (MMC) — DNA synthesis inhibitor; 40 mg in 40 cc NS, instilled within 6 hours of TURBT
  • Rationale: prevents floating tumour cells implanting in the bladder wall
  • AE: chemical cystitis + rash, calcification, irritative LUTS, dermatitis, decreased bladder capacity
  • Gemcitabine and doxorubicin have a similar effect but cause less calcification and irritation
• Gemcitabine (SWOG 0337 — ARR ≈10–15% at 4 years; better tolerated than MMC)
• Thiotepa — AE: bone marrow suppression (low MW → systemic absorption)
• Doxorubicin
• Valrubicin — BCG-refractory CIS only; response rate ~20%; only for those unfit for cystectomy

Efficacy:

• Reduces recurrence ~35% at 5 years, ~15% at 1 year
• Does NOT significantly reduce progression
• Immediate post-TURBT instillation (within 6h)
• Contraindicated if: extensive resection, suspected perforation, gross hematuria, allergy, immunocompromise (relative)

Comparison of intravesical agents

Agent	Perioperative use	Risk group	Cystitis	Other toxicity	Dropout	Concentration / dose
Doxorubicin	Yes	Low–intermediate	20–40%	Fever, allergy, contracted bladder 5%	2–16%	50 mg / 50 mL
Epirubicin	Yes	Low–intermediate	10–30%	Contracted bladder rare	3–6%	50 mg / 50 mL
Thiotepa	Yes	Low–intermediate	10–30%	Myelosuppression 8–19%	2–11%	30 mg / 30 mL
Mitomycin	Yes	Low–intermediate	30–40%	Rash 8–19%, contracted bladder 5%	2–14%	40 mg / 20–40 mL
BCG	No	Intermediate–high	60–80%	Serious infection 5%	5–10%	1 vial / 50 mL
Interferon	No	Salvage	< 5%	Flu-like symptoms 20%	Rare	50–100 MU / 50 mL
Gemcitabine	Yes	Salvage	Mild	Occasional nausea	< 10%	1–2 g / 50–100 mL
Valrubicin	No	Salvage	Mild	UTI, abdominal pain, asthenia	< 10%	800 mg / 55 mL

• Thiotepa is the only chemotherapeutic agent FDA-approved specifically for intravesical treatment of papillary bladder cancer — it causes myelosuppression, so avoid it in immunocompromised patients

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BCG

• Dose: 50mg in 50mL NS; dwell 2 hours
• Mechanism: activates macrophages → T-cell–mediated destruction of abnormal urothelium; initial contact via macrophages
• Schedule: induction weekly × 6 weeks (start 2–4 weeks post-TURBT) → maintenance at 3, 6, 12, 18, 24, 30, 36 months

Timepoint	Course
Month 0	Induction BCG — 6 doses
Month 3	1st maintenance — 3 doses
Month 6	2nd maintenance
Month 12	3rd maintenance
Month 18	4th maintenance*
Month 24	5th maintenance*
Month 30	6th maintenance*
Month 36	7th maintenance*

* High risk only — the pattern is 0, 3, 6, then every 6 months.

• Intermediate risk → maintenance to month 12 ONLY
• For any intermediate-risk patient, offer either induction BCG or induction intravesical chemotherapy; give maintenance only if they responded to induction
• Cystoscopy before every maintenance cycle — if negative, give the dose; if positive, do a TURBT, restage and re-stratify

Outcomes:

• Recurrence reduction: 40%
• Progression reduction: 35%
• CIS response rate: ~80%
• 2nd induction response: 30–50%
• BCG + interferon — several trials suggest the combination allows a reduced BCG dose, which may reduce side effects

Absolute contraindications (SHIT-IT):

• Sepsis / personal history of BCG sepsis
• Hematuria (gross)
• Immunosuppressed
• TURBT, immediately after (risk intravasation)
• Incontinence (total)
• Traumatic catheterization

Relative CI: UTI, liver disease (precludes isoniazid), personal history of tuberculosis (risk theorized but unknown), poor performance status, advanced age

No or insufficient data — not established contraindications

• Prosthetic materials — no increased risk of infectious or other complications shown in the limited literature
• Ureteric reflux
• Anti-TNF medications — theoretically predispose to BCG sepsis

BCG Toxicity Management:

Grade 1 — moderate symptoms, < 48 hours

• Mild-to-moderate irritative voiding symptoms, mild hematuria, fever < 38.5 °C
• Urine culture to rule out bacterial UTI
• Anticholinergics, topical antispasmodics (phenazopyridine), analgesics, NSAIDs

Grade 2 — severe symptoms and/or > 48 hours

• All grade 1 measures, plus urine culture, chest radiograph, liver function tests
• Consider reducing the dose to one-half to one-third when instillations resume
• Consider pre-treating with a single dose of isoniazid before each subsequent instillation
• Isoniazid and rifampin orally until symptoms resolve — do not use monotherapy
• Add vitamin B6 / pyridoxine
• Watch for rifampin drug interactions (e.g. warfarin); monitor LFTs

Grade 3 — serious complications (haemodynamic changes, persistent high fever)

• Allergic reactions (joint pain, rash): all grade 1 and 2 measures, plus isoniazid and rifampin depending on response, with B6

• Solid organ involvement (liver, lung, kidney): stop BCG instillations; start isoniazid and rifampin; if symptoms persist, involve an infectious-disease specialist with anti-tuberculous expertise; ethambutol may be added

• Cycloserine often causes severe psychiatric symptoms — strongly discouraged

• BCG is almost uniformly resistant to pyrazinamide — that drug has no role

• Consider prednisone when the response is inadequate or for septic shock — never give it without effective antibacterial therapy

• Adjuncts: pyridoxine (B6) with INH; INH toxicity → liver/nerves; ethambutol toxicity → eyes

• Granulomatous prostatitis: common post-BCG; usually asymptomatic; can mimic prostate Ca on MRI → continue BCG if asymptomatic; avoid quinolones during treatment

Adequate BCG = 1 inductions + ≥1 maintenance cycle or a second induction

BCG Failure Terminology:

Term	Definition
BCG-refractory	Persistent disease despite 2 induction courses, or induction plus maintenance (usually within 6 months), or intolerance of BCG
BCG-relapsing	Recurrence after initial response (>12 months)

• Declaring failure may take up to 6 months — the response rate in high-grade bladder cancer treated with BCG rises from 57% to 80% between 3 and 6 months after therapy, so calling failure too early misclassifies responders

High-risk patterns of failure:

• T1 HG after 3 months
• TaHG or CIS after induction + maintenance

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Indications for Early Cystectomy in NMIBC

• T1 high grade — including on repeat resection
• T1 with LVI or variant histology
• Micropapillary or sarcomatoid
• HG tumour in diverticulum
• Distal ureteric or prostatic urethral involvement
• Multifocal CIS
• BCG-refractory superficial disease — CIS, T1, or high-grade Ta
• Crippled bladder from mitomycin or BCG
• Access issues — severe urethral stricture, bladder too large, tumour too large
• Patient preference

Management of BCG-unresponsive disease:

• Standard of care: RC + PLND ( no muscle no chemo )

BCG-unresponsive unfit for cystectomy:

• Pembrolizumab (KEYNOTE-057: CR 41% at 3 months)
• Gemcitabine + docetaxel
• Valrubicin ( for CIS )

If BCG is unavailable

• AUA recommends intravesical mitomycin-C as the preferable alternative — a six-week induction with monthly maintenance
• Gemcitabine + docetaxel — induction only
• Heated mitomycin may be given alone
• IV pembrolizumab for BCG-refractory disease
• Valrubicin — a semisynthetic analogue of doxorubicin, FDA-approved for BCG-refractory CIS in patients who cannot tolerate cystectomy

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Benign Bladder Pathologies

Entity	Key Feature	Management
Nephrogenic adenoma	Hobnail cells; chronic inflammation	Resection ± long-term antibiotics; high recurrence
Cystitis cystica/glandularis	Associated with adenocarcinoma	TURBT + annual cystoscopy
Hemangioma	—	—
Malakoplakia	Associated with infection	Antibiotics ± anti-TB therapy
Inverted papilloma	~18% risk of associated malignancy	TUR
Pseudo-squamous trigonitis / squamous metaplasia	Present in 40% of women and 5% of men; associated with UTI, trauma, previous surgery	Usually incidental

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MIBC — Management Overview

Stage	Primary Treatment
Stage II & IIIA	NAC → radical cystectomy + PLND
Stage IIIB	Systemic chemo → reassess resectability
Stage IV	Chemo → reassess / palliation

Initial treatment of non-metastatic disease, by histology

Histology	Usual initial treatment
Urothelial — usual type	Varies by tumour stage
Urothelial — mixed histology	Treated the same as usual type
Urothelial — micropapillary, plasmacytoid, sarcomatoid	Radical cystectomy *
Squamous cell carcinoma	Radical cystectomy *
Adenocarcinoma	Radical cystectomy *
Urachal carcinoma	Partial or radical cystectomy *
Small cell carcinoma	Systemic chemotherapy †
Pheochromocytoma	Partial cystectomy

* Radiation and systemic chemotherapy are generally ineffective. † In patients who respond to chemotherapy, consolidation with radical cystectomy and/or pelvic radiation may be given.

• Partial cystectomy is contraindicated if the tumour is large, even in a favourable location

Neoadjuvant Chemotherapy (NAC)

• SWOG 8710: MVAC + RC vs. RC alone → pT0 rate 38% vs. 15%; 5-yr OS 57% vs. 43%
• Meta-analysis (n=3005): +5% 5-yr OS; +9% 5-yr DFS; pCR 30–40% vs. 15%
• Preferred regimen: GC (gemcitabine + cisplatin)
• NAC should start within 8 weeks of diagnosis; RC within 12 weeks of completing NAC
• Downstaging achieved in ~50%; improves 5-yr survival ~5%
• The 5–9% survival benefit holds under three conditions — no nodal disease, T2–T3 only, and a cisplatin-based regimen
• Carboplatin should NOT substitute cisplatin in resectable disease
• KEYNOTE-905 (cisplatin-ineligible, n=344): neoadjuvant EV + pembrolizumab + RC + PLND vs. RC + PLND → 2-yr EFS 75% vs. 39%; 2-yr OS 80% vs. 63%; pCR 57% vs. 8.6% (Presented ESMO 2025)

NAC histological notes:

• Pure non-urothelial histologies → perioperative chemotherapy not routinely recommended
• Exception: pure small cell/neuroendocrine → NAC is mainstay
• Mixed tumours (squamous/glandular differentiation) derive greater benefit from MVAC than pure UC (secondary analysis SWOG 8710)
• NAC is active in mixed tumours containing adenocarcinoma or squamous cell cancer, but not against altered growth patterns such as micropapillary and nested urothelial cancer
• Small cell carcinoma of the bladder is treated as metastatic disease — chemotherapy first, then either radiotherapy or surgery to clear local disease
• Any small cell / neuroendocrine component → cisplatin, etoposide and radiotherapy

Cisplatin eligibility:

• GFR ≥ 60 | NYHA ≤ Class III | No ≥Grade 2 neuropathy or hearing loss | Good PS
• If ineligible → proceed directly to cystectomy

Adjuvant Chemotherapy

• Indications: pT3b/T4 | positive LN | LVI
• CheckMate 274 (adjuvant nivolumab): DFS +10 months; no OS benefit
• AMBASSADOR (adjuvant pembrolizumab): DFS +5 months; no OS benefit
• NIAGARA (periop durvalumab): pCR +8%; 2-yr EFS +8%

Radical Cystectomy

• Standard: bilateral PLND + RC
• Males: bladder + prostate + seminal vesicles
• Females: bladder + ovaries + tubes + uterus/cervix + anterior vagina (organ sparing based on disease characteristics)
• Min PLND template: obturator + internal iliac + external iliac; ≥12 nodes
• Extended PLND: no benefit over standard (SWOG S1011, LEA AUO AB 25/02)
• 25% have pathologic LN metastases at cystectomy → most important prognostic factor
• Prognostic factors post-RC: pT stage and LN status (strongest) | margin status | LVI | hydronephrosis | variant histology
• Node-positive: 70–80% will recur; survival ~15% at 15 months
• Sending ureteric margins is controversial and not standard of care. When frank tumour is found in the ureter, resect to a negative margin. When only CIS is found, maximal resection without compromising ureteric length for the diversion is advocated

Operative sequence

1. Antibiotics, ± bowel prep, positioning, Foley catheter + orogastric tube
2. Midline incision; mobilize the bladder and ureters
3. Divide the ureters at their insertion into the bladder
4. Take down the lateral pedicles of the bladder and prostate
5. Ligate the dorsal venous complex and divide the prostatic urethra
6. Deliver the specimen
7. Lymph node dissection
8. Urinary diversion
9. Drain and Foley catheter

When to abort the cystectomy

• Extensive peri-ureteric disease
• T4b
• Invasion into the sigmoid
• Unresectable nodal mass

Boundaries — standard lymph node dissection

Direction	Boundary
Laterally	Genitofemoral nerve
Medially	Internal iliac artery
Caudally	Cooper's ligament
Cranially	Crossing of the ureter at the common iliac artery

Boundaries — extended lymph node dissection

Direction	Boundary
Proximal	Aortic bifurcation
Distal	Internal inguinal ring
Posterior	Obturator nerve
Medial	Bladder
Lateral	Genitofemoral nerve

Lymph node density

• LND = number of positive nodes ÷ total nodes removed
• > 20% → poor prognosis — give adjuvant therapy
• < 20% → better prognosis

Urethrectomy — Indications

Men:

• Gross urethral tumour | Diffuse CIS | Positive urethral margin | Positive prostatic biopsy | Urethral recurrence

Women:

• Gross tumour at bladder neck | Anterior vaginal wall involvement | Positive urethral margin

• Risk factors for urethral recurrence in men: diffuse CIS, prostatic stromal involvement — prostatic stromal invasion carries a 30% risk of urethral recurrence

• Risk factors for urethral recurrence in women: bladder neck involvement, anterior vaginal wall

Bladder Preservation (Trimodal Therapy)

• Indication: refuses RC or unfit for surgery
• Criteria: no hydronephrosis | solitary/localized | Stage T2 | no CIS | good bladder function | complete TURBT resectability
• Components: maximal TURBT + chemoradiotherapy (cisplatin preferred) + EBRT (~64 Gy)
• RT alone should not be offered as curative
• Can offer RT for symptom control ( refractory hematuria ) [ Hemostatic dose ]

Follow-up after RC

• CT chest + abdomen/pelvis q6–12 months × 2–3 years, then annually
• Labs (electrolytes, renal, ±B12) q3–6 months × 2–3 years, then annually
• Vitamin B12: if >60 cm ileum resected or terminal ileum used

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Urinary Diversion

Metabolic Complications by Segment

Segment	Electrolyte Disturbance
Stomach	Hypochloraemia, hypokalaemia, metabolic alkalosis
Jejunum	Hypochloraemia, hyperkalaemia, metabolic acidosis
Ileum	Hyperchloraemia, hypokalaemia, metabolic acidosis

• Stomach augmentation: treat metabolic alkalosis with arginine hydrochloride infusion
• Never extend stomach augmentation to the pylorus

Ileal Conduit

• Length: 10–15 cm; located 10–15 cm from ileocecal valve
• Contraindications: short bowel syndrome, IBD
• Stones in conduit → most pass spontaneously

General Contraindications to Continent Diversion

• GFR < 40 mL/min | Cr > 180 µmol/L | Significant proteinuria
• Poor dexterity | Liver failure
• Positive urethral margin / known urethral TCC (for neobladder)
• IBD | Extensive prior pelvic radiotherapy

Orthotopic Neobladder (Studer — Most Common)

• 60 cm ileum (25 cm proximal to ileocecal valve)
• Distal ileum → detubularized reservoir; proximal 20 cm → afferent limb
• Ureters implanted in Bricker fashion
• Use buttonhole enterotomy with cold scissors → avoids stricture at uretereoileal anastomosis
• Absorbable staples best for large bowel pouch (no risk of bowel ischaemia)
• Stones: if small → transurethral; if large → percutaneous or open

Diversion Comparisons

Diversion	Stone Risk	Retention Risk
Kock pouch	Highest (nipple valve)	Yes (nipple valve)
Stomach	Lowest	—

# Ileocecal valve preserved by T or Kock pouch

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Metastatic / Locally Advanced Disease

First-Line

• Cisplatin-eligible: GC × 4–6 cycles (preferred); or MVAC / DD-MVAC
• Cisplatin-ineligible: gemcitabine + carboplatin
• Unfit for combination: single-agent gemcitabine, paclitaxel, or docetaxel
• Immunotherapy: not routinely recommended 1st-line in cisplatin-eligible patients
• KEYNOTE-361: pembro ± chemo vs. chemo alone — no significant difference

Second-Line

• Pembrolizumab (KEYNOTE-045) — the standard second-line option after platinum. In a phase III RCT of 542 patients randomised to pembrolizumab monotherapy vs chemotherapy (paclitaxel, docetaxel or vinflunine), median OS was 10.3 vs 7.4 months (HR 0.73), independent of PD-L1 expression. Led to EMA and FDA approval. [EAU]
• Atezolizumab — the first checkpoint inhibitor FDA-approved for metastatic urothelial carcinoma, but the indication was subsequently withdrawn: the phase III IMvigor211 trial (n=931) did not meet its primary endpoint, with OS 11.1 vs 10.6 months vs chemotherapy. [EAU]

Later Lines

• On progression, or if not eligible for chemotherapy → checkpoint inhibitors (pembrolizumab, ipilimumab, nivolumab)

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