Most bladder cancer is urothelial carcinoma and presents with painless gross hematuria. The central management split is non-muscle-invasive (NMIBC) versus muscle-invasive (MIBC) disease — they are effectively different diseases with different…
34 pathway steps5 pathways2 local-policy steps
Your learning progress0 of 31 chapters complete
Saved privately in this browser and shared across state tabs.
Didactics
Shared across all locations
Most bladder
cancer is urothelial carcinoma and presents with painless gross
hematuria. The central management split is non-muscle-invasive
(NMIBC) versus muscle-invasive (MIBC) disease — they are
effectively different diseases with different natural histories, and
the whole game is not missing the transition.
9.1 Presentation, risk factors, and diagnosis
Painless
gross hematuria is the classic presentation. Irritative symptoms
(urgency, frequency, dysuria) with a sterile culture should raise
the specter of carcinoma in situ (CIS) — a flat, high-grade lesion
that is easy to miss and behaves aggressively.
Dominant
risk factor: tobacco (3–4x risk; accounts for roughly half of
cases). Also occupational aromatic amines (dyes, rubber, leather,
printing, painting), chronic irritation (long-term catheters,
stones), prior pelvic radiation, cyclophosphamide, and — worldwide
— Schistosoma haematobium (squamous cell carcinoma).
Work-up:
cystoscopy (direct visualization — nothing replaces it), CT
urography (to evaluate the upper tracts — 2–5% have synchronous
upper-tract disease), and urine cytology (sensitive for high-grade
disease and CIS; poor for low-grade).
Diagnosis
and initial staging is by TURBT (transurethral resection of
bladder tumor). The specimen MUST include detrusor muscle in order
to assess for invasion — a TURBT without muscle in the specimen is
an inadequate staging procedure and often needs to be repeated.
Enhanced
cystoscopy (blue-light/fluorescence or narrow-band imaging)
improves detection of CIS and small papillary tumors.
9.2 Non-muscle-invasive bladder cancer (NMIBC)
Confined to the
mucosa and submucosa: Ta (papillary, mucosa only), T1 (invades the
lamina propria — a genuinely dangerous stage that can progress),
and CIS (flat, high-grade, confined to the urothelium). NMIBC is
characterized by a high recurrence rate (~50–70%) and a variable
progression rate, which is why surveillance is lifelong.
Risk group
Typical features
Management
Low risk
Solitary, small (< 3 cm), low-grade Ta, primary
TURBT + a single immediate post-operative instillation of
intravesical chemotherapy (mitomycin or gemcitabine) — this
alone meaningfully reduces recurrence. Surveillance
Intermediate risk
Multifocal, recurrent, larger, or low-grade with other features
TURBT + induction intravesical chemotherapy (or BCG), then
maintenance; surveillance
High risk
Any high-grade, any T1, any CIS, or large/multifocal high-grade
Ta
Consider a REPEAT (restaging) TURBT at 4–6 weeks, then
intravesical BCG induction + maintenance (typically 1–3 years).
Consider early cystectomy for very-high-risk disease
Intravesical
BCG: live attenuated Mycobacterium bovis instilled into the
bladder — an immunotherapy that provokes a local immune response.
Standard is a 6-week induction course followed by maintenance. It
remains the most effective agent for high-risk NMIBC and CIS. Expect
irritative voiding symptoms and low-grade flu-like symptoms after
instillation. Note that BCG supply constraints have been an ongoing
national problem and may affect scheduling.
BCG
safety — know this: do NOT instill BCG if there is a traumatic
catheterization, gross hematuria, active UTI, or within ~2 weeks of
a TURBT — bacteremia and disseminated BCG (BCGosis) can result. A
patient with a high fever (> 38.5°C), rigors, or systemic
illness after BCG needs urgent evaluation and anti-tuberculous
therapy, not reassurance.
Surveillance:
cystoscopy with cytology at 3 months, then at intervals
determined by risk (often every 3 months for the first 2 years, then
lengthening). This is largely APP-run at our practice.
9.3 The intravesical and bladder-sparing drug
menu — know the indication for each
This is one of
the fastest-moving areas in urology, and the agents are NOT
interchangeable — each has a specific, narrow indication. The two
questions that determine which drug a patient gets: (1) is this
LOW-grade intermediate-risk disease, or HIGH-risk/BCG-unresponsive
disease? and (2) has the patient already failed BCG?
Agent
Indication
Practical notes
Mitomycin or gemcitabine (standard intravesical chemo)
A single immediate post-TURBT instillation (low/intermediate
risk); induction ± maintenance for intermediate risk
Cheap, well tolerated, reduces recurrence. Not adequate for
high-risk disease
RECURRENT LOW-GRADE INTERMEDIATE-RISK NMIBC (LG-IR-NMIBC) in
adults — the first and only drug approved for this specific
group (FDA, June 2025)
A reverse-thermal HYDROGEL that becomes a gel at body
temperature, holding mitomycin against the urothelium for
sustained exposure. This is CHEMOABLATION — it can treat the
tumor WITHOUT a TURBT, sparing repeat trips to the OR. 75 mg
instilled weekly x 6. In ENVISION: ~78% complete response at 3
months, with ~79% of responders durable at 12 months. Expect
dysuria and urinary frequency
BCG-UNRESPONSIVE high-risk NMIBC WITH CIS (± papillary tumors)
in adults (FDA, September 2025)
Not an instillation — an intravesical drug-RELEASING SYSTEM: a
small pretzel-shaped silicone device placed in the bladder that
osmotically releases gemcitabine continuously over the indwelling
period. Placed and removed in the office WITHOUT general
anesthesia. In SunRISe-1: ~82% complete response, with ~51% still
in CR at 1 year. A genuine bladder-preserving option for the
patient who is unfit for, or refusing, cystectomy
Nadofaragene firadenovec-vncg (Adstiladrin)
BCG-unresponsive NMIBC with CIS ± papillary tumors
A gene therapy — an adenoviral vector delivering interferon
alfa-2b to the urothelium. Give 75 mL intravesically once every
3 months after anticholinergic premedication; retain in the bladder
for 1 hour. Avoid in immunocompromised or immunodeficient patients.
If there is no complete response at 3 months, or if CIS recurs,
consider cystectomy
Nogapendekin alfa inbakicept (Anktiva) + BCG
BCG-unresponsive NMIBC with CIS ± papillary tumors
An IL-15 agonist given WITH BCG to re-sensitize the immune
response
Pembrolizumab (Keytruda)
BCG-unresponsive CIS ± papillary tumors in patients ineligible
for or declining cystectomy
Systemic IV immunotherapy — watch for immune-related adverse
events (Chapter 20). Infused in-house at our practice
Gemcitabine + docetaxel (sequential intravesical)
BCG-unresponsive or BCG-intolerant disease; also used when BCG is
unavailable
Off-label but widely used, well tolerated, and effective — a
workhorse in the BCG-shortage era
Mitomycin gel (Jelmyto, UGN-101)
LOW-GRADE UPPER-TRACT urothelial carcinoma (renal pelvis/calyces)
— not bladder
Delivered via ureteral catheter or nephrostomy; a kidney-sparing
alternative to nephroureterectomy (Section 9.5)
Three bladder-preserving drugs, in one line each
ZUSDURI = the LOW-grade
drug. Recurrent low-grade INTERMEDIATE-risk NMIBC. It lets you
chemoablate the tumor instead of resecting it — think “treat
it without another TURBT.”
INLEXZO = the BCG-FAILURE
drug. BCG-unresponsive HIGH-risk NMIBC with CIS. An indwelling
gemcitabine-releasing device placed in the office — think
“bladder preservation for the patient facing cystectomy.”
ADSTILADRIN = the quarterly GENE-THERAPY option for adults with
BCG-unresponsive HIGH-risk NMIBC with CIS ± papillary tumors. Give
75 mL intravesically every 3 months and retain for 1 hour.
Do not mix them up: ZUSDURI is for recurrent low-grade
intermediate-risk disease; INLEXZO and ADSTILADRIN are
bladder-preserving options for BCG-unresponsive high-risk disease
with CIS.
BCG-unresponsive
disease — the decision that matters: radical cystectomy
remains the gold standard and the only reliably curative option. The
bladder-sparing agents above (Inlexzo, Adstiladrin, Anktiva + BCG,
pembrolizumab, gem/doce) are for patients who are unfit for, or who
decline, cystectomy — and they require rigorous surveillance. Do
NOT let a patient churn through one failed bladder-sparing therapy
after another while a curable cancer progresses to muscle invasion.
Set a clear plan and a clear off-ramp up front.
APP roles in NMIBC
You will perform
intravesical instillations, place and remove intravesical
systems, run surveillance cystoscopy clinics, and counsel on the
every-3-month rhythm early on.
Reinforce smoking cessation at EVERY visit — it lowers
both recurrence and progression, and it is the single most
valuable thing you can tell these patients.
9.4 Muscle-invasive bladder cancer (MIBC)
Invasion
into the detrusor muscle (≥ T2) is aggressive, with
substantial metastatic potential, and requires prompt definitive
treatment. Staging: CT chest/abdomen/pelvis; consider FDG PET/CT
(Chapter 21).
Standard
of care: neoadjuvant cisplatin-based chemotherapy (which confers
a survival benefit — this is not optional if the patient is
cisplatin-eligible) followed by radical cystectomy with bilateral
pelvic lymph node dissection and urinary diversion (ileal conduit,
or continent diversion/orthotopic neobladder).
Bladder
preservation (trimodal therapy): maximal TURBT + concurrent
chemoradiation, for selected patients with solitary tumors, no CIS,
no hydronephrosis, and good bladder function. Requires rigorous
surveillance and a willingness to proceed to salvage cystectomy.
Metastatic
disease: platinum-based chemotherapy, immune checkpoint
inhibitors (pembrolizumab, avelumab maintenance), antibody-drug
conjugates (enfortumab vedotin, sacituzumab govitecan), and targeted
agents (erdafitinib for FGFR alterations). Enfortumab vedotin plus
pembrolizumab has become a front-line standard — a fast-moving
area. our practice infuses immunotherapy in-house (Chapter 20).
Do not delay
Muscle-invasive disease is
time-sensitive. Every month of delay to cystectomy worsens
survival. Avoid prolonged intravesical trials when muscle
invasion is present — get the patient to definitive treatment.
Any new visible hematuria in
a patient with a bladder-cancer history warrants prompt
evaluation — assume recurrence until proven otherwise.
Hydronephrosis in a bladder-cancer patient is an ominous
sign — it usually means locally advanced disease.
9.5 Upper-tract urothelial carcinoma (UTUC) —
do not forget the kidneys and ureters
The same
urothelium lines the renal pelvis and ureters. UTUC accounts for
~5–10% of urothelial cancers, presents with hematuria or flank
pain, and is diagnosed with CT urography, ureteroscopy with biopsy,
and selective cytology.
Risk factors
mirror bladder cancer, plus aristolochic acid, analgesic abuse, and
Lynch syndrome (screen for it in young patients or those with a
suggestive family history).
Standard
treatment for high-risk disease is radical nephroureterectomy with
excision of the bladder cuff.
Kidney-sparing
options for LOW-GRADE, low-volume disease (or a solitary kidney):
endoscopic ablation, or instillation of mitomycin gel (Jelmyto,
UGN-101) — a reverse-thermal gel delivered via ureteral catheter
or nephrostomy that coats the upper tract and lets us chemoablate
low-grade UTUC without removing the kidney. Think of it as the
upper-tract cousin of Zusduri (Section 9.3).
Patients
with UTUC need bladder surveillance (~50% develop bladder tumors);
patients with bladder cancer need periodic upper-tract imaging. The
field is the whole urothelium.
Clinical Pathway
Click any node to expand
Most bladder cancer is urothelial carcinoma presenting with painless gross hematuria. The central split is non-muscle-invasive (NMIBC) versus muscle-invasive (MIBC) — effectively different diseases with different natural histories, and the whole game is not missing the transition.
Painless gross hematuria until proven otherwise — and a TURBT that is only a staging procedure if it contains muscle.
Select a box to open its teaching details.
The other presentation not to miss
Irritative symptoms (urgency, frequency, dysuria) with a sterile culture should raise the specter of carcinoma in situ (CIS) — a flat, high-grade lesion that is easy to miss and behaves aggressively.
Ch 9.1
Ask about
Tobacco — 3–4x risk; accounts for roughly half of cases
Cystoscopy — direct visualization; nothing replaces it
CT urography — evaluate the upper tracts; 2–5% have synchronous upper-tract disease
Urine cytology — sensitive for high-grade disease and CIS; poor for low-grade
Enhanced cystoscopy
Blue-light/fluorescence or narrow-band imaging improves detection of CIS and small papillary tumors
Ch 9.1 — work-up
The requirement
The specimen MUST include detrusor muscle in order to assess for invasion — a TURBT without muscle in the specimen is an inadequate staging procedure and often needs to be repeated.
Ch 9.1 — TURBT
The central management split
The stages
Ta — papillary, mucosa only
T1 — invades the lamina propria; a genuinely dangerous stage that can progress
CIS — flat, high-grade, confined to the urothelium
Consequence
Recurrence is ~50–70%, which is why surveillance is lifelong.
Ch 9.2
Staging
CT chest/abdomen/pelvis
Consider FDG PET/CT (Chapter 21)
Ch 9.4
Local policy
Why
It lowers both recurrence and progression.
Ch 9.3 — APP roles in NMIBC
Risk-stratify, then match the instillation to the risk group — and run the surveillance that makes it work.
Select a box to open its teaching details.
The groups
Low risk — solitary, small (< 3 cm), low-grade Ta, primary
Intermediate risk — multifocal, recurrent, larger, or low-grade with other features
High risk — any high-grade, any T1, any CIS, or large/multifocal high-grade Ta
Ch 9.2
Management by risk group
Regimen
A single immediate post-operative instillation of intravesical chemotherapy — mitomycin or gemcitabine
Then surveillance
Ch 9.2
Regimen
TURBT + induction intravesical chemotherapy (or BCG), then maintenance
Surveillance
Ch 9.2
Sequence
Consider a REPEAT (restaging) TURBT at 4–6 weeks
Then intravesical BCG induction + maintenance — typically 1–3 years
Consider early cystectomy for very-high-risk disease
Ch 9.2
What to expect
Irritative voiding symptoms after instillation
Low-grade flu-like symptoms after instillation
Why it stays first
It remains the most effective agent for high-risk NMIBC and CIS.
Scheduling reality
BCG supply constraints have been an ongoing national problem and may affect scheduling
Ch 9.2 — intravesical BCG
Time-critical
Hold the instillation for
Traumatic catheterization
Gross hematuria
Active UTI
Within ~2 weeks of a TURBT
After BCG — urgent
High fever > 38.5°C, rigors, or systemic illness needs urgent evaluation and anti-tuberculous therapy, not reassurance
Ch 9.2 — BCG safety
Local policy
The schedule
Cystoscopy with cytology at 3 months
Then intervals determined by risk — often every 3 months for the first 2 years, then lengthening
APP roles
Perform intravesical instillations
Place and remove intravesical systems
Run surveillance cystoscopy clinics
Counsel on the every-3-month rhythm early on
Ch 9.2 — surveillance
The agents are NOT interchangeable — each has a specific, narrow indication. Two questions decide which drug a patient gets.
Select a box to open its teaching details.
The questions
1. Is this LOW-grade intermediate-risk disease, or HIGH-risk / BCG-unresponsive disease?
2. Has the patient already failed BCG?
Ch 9.3
Indication
A single immediate post-TURBT instillation — low/intermediate risk
Induction ± maintenance for intermediate risk
Limit
Not adequate for high-risk disease
Ch 9.3
The two new drugs — do not mix them up
Why it is different
A reverse-thermal HYDROGEL that becomes a gel at body temperature, holding mitomycin against the urothelium for sustained exposure. This is CHEMOABLATION — it can treat the tumor WITHOUT a TURBT, sparing repeat trips to the OR.
Dosing
75 mg instilled weekly x 6
Data and side effects
ENVISION: ~78% complete response at 3 months, with ~79% of responders durable at 12 months
Expect dysuria and urinary frequency
One line
ZUSDURI = the LOW-grade drug — "treat it without another TURBT"
Ch 9.3
Why it is different
Not an instillation — an intravesical drug-RELEASING SYSTEM: a small pretzel-shaped silicone device placed in the bladder that osmotically releases gemcitabine continuously over the indwelling period. Placed and removed in the office WITHOUT general anesthesia.
Data
SunRISe-1: ~82% complete response, with ~51% still in CR at 1 year
Who it is for
A genuine bladder-preserving option for the patient who is unfit for, or refusing, cystectomy
One line
INLEXZO = the BCG-FAILURE drug — "bladder preservation for the patient facing cystectomy"
Ch 9.3
What it is
Nadofaragene firadenovec-vncg (Adstiladrin)
A non-replicating adenoviral vector-based gene therapy that delivers the gene for interferon alfa-2b to the bladder urothelium
Administration
Premedicate with an anticholinergic before each instillation
Instill 75 mL intravesically once every 3 months
Retain in the bladder for 1 hour
Safety gate
Avoid in patients who are immunocompromised or immunodeficient because of the risk of disseminated adenovirus infection
If there is no complete response at 3 months, or if CIS recurs, consider cystectomy — do not let bladder preservation delay curative surgery
One line
ADSTILADRIN = the quarterly GENE-THERAPY option for BCG-unresponsive high-risk NMIBC with CIS ± papillary tumors
Ch 9.3
The agents
Nogapendekin alfa inbakicept (Anktiva) + BCG — an IL-15 agonist given WITH BCG to re-sensitize the immune response
Pembrolizumab (Keytruda) — systemic IV immunotherapy for BCG-unresponsive CIS ± papillary tumors in patients ineligible for or declining cystectomy; watch for immune-related adverse events (Chapter 20)
Gemcitabine + docetaxel (sequential intravesical) — for BCG-unresponsive or BCG-intolerant disease, and when BCG is unavailable; off-label but widely used, well tolerated, effective — a workhorse in the BCG-shortage era
Our practice
Pembrolizumab is infused in-house at our practice
Ch 9.3
How it is given
Delivered via ureteral catheter or nephrostomy
A kidney-sparing alternative to nephroureterectomy (Section 9.5)
Ch 9.3
Time-critical
The rule
Do NOT let a patient churn through one failed bladder-sparing therapy after another while a curable cancer progresses to muscle invasion. Set a clear plan and a clear off-ramp up front.
Who the bladder-sparing agents are for
Patients who are unfit for, or who decline, cystectomy
They require rigorous surveillance
Do not mix them up
ZUSDURI is for recurrent low-grade intermediate-risk disease; INLEXZO and ADSTILADRIN are bladder-preserving options for BCG-unresponsive high-risk disease with CIS
Ch 9.3 — BCG-unresponsive disease
Time-sensitive. Every month of delay to cystectomy worsens survival.
Select a box to open its teaching details.
Staging
CT chest/abdomen/pelvis
Consider FDG PET/CT (Chapter 21)
Ch 9.4
Why
Neoadjuvant cisplatin-based chemotherapy confers a survival benefit.
Ch 9.4 — standard of care
Diversion options
Ileal conduit
Continent diversion / orthotopic neobladder
Ch 9.4 — standard of care
Selection criteria
Solitary tumors
No CIS
No hydronephrosis
Good bladder function
The commitment
Requires rigorous surveillance and a willingness to proceed to salvage cystectomy
Targeted agents — erdafitinib for FGFR alterations
Our practice
our practice infuses immunotherapy in-house (Chapter 20)
Ch 9.4 — metastatic disease
Time-critical
Three cautions
Avoid prolonged intravesical trials when muscle invasion is present
Any new visible hematuria in a patient with a bladder-cancer history warrants prompt evaluation — assume recurrence until proven otherwise
Hydronephrosis in a bladder-cancer patient is an ominous sign — it usually means locally advanced disease
Ch 9.4 — do not delay
The same urothelium lines the renal pelvis and ureters. The field is the whole urothelium.
Select a box to open its teaching details.
Presentation
Hematuria
Flank pain
Ch 9.5
Orders
CT urography
Ureteroscopy with biopsy
Selective cytology
Ch 9.5
UTUC-specific
Aristolochic acid
Analgesic abuse
Lynch syndrome — screen for it in young patients or those with a suggestive family history
Ch 9.5
Treatment by grade and volume
The operation
Radical nephroureterectomy with excision of the bladder cuff.
Ch 9.5
Options
Endoscopic ablation
Instillation of mitomycin gel (Jelmyto, UGN-101) — a reverse-thermal gel delivered via ureteral catheter or nephrostomy that coats the upper tract and lets us chemoablate low-grade UTUC without removing the kidney
Mental model
Think of it as the upper-tract cousin of Zusduri (Section 9.3)
Ch 9.5
Both ways
Patients with UTUC need bladder surveillance — ~50% develop bladder tumors
Patients with bladder cancer need periodic upper-tract imaging