“Intravesical Therapy in Bladder Cancer: Comprehensive Guide on Treatment, BCG, and Chemotherapy”

Intravesical Therapy for Bladder Cancer

Definition:
Intravesical therapy refers to the direct instillation of therapeutic agents into the urinary bladder via a catheter, after complete transurethral resection of visible bladder tumors (TURBT).

Rationale:
• Targets the bladder lining directly → achieves high local drug concentration with minimal systemic toxicity.
• Reduces risk of tumor recurrence and progression.
• Effective in eradicating residual microscopic disease.

Types of Agents Used:
1. Chemotherapy agents: Mitomycin C, Epirubicin, Doxorubicin, Gemcitabine.
2. Immunotherapy: Bacillus Calmette–Guérin (BCG).

Protocols:
• Induction therapy: Weekly instillations for 6–8 weeks.
• Maintenance therapy: Periodic instillations for 1–3 years (especially for BCG).
• Immediate single instillation: Within 24 hours of TURBT to reduce tumor cell re-implantation.

Administration Technique:
• Drug instilled into bladder via catheter.
• Retained for ~1–2 hours (“dwell time”).
• Patient repositioned intermittently for uniform bladder exposure.

Adverse Effects:
• Chemotherapy: Chemical cystitis, dysuria, bladder irritation, rare systemic toxicity.
• Immunotherapy (BCG): Cystitis, fever, hematuria, granulomatous prostatitis, rarely sepsis.

Clinical Impact:
• Standard of care for non–muscle invasive bladder cancer (NMIBC).
• Decreases recurrence rate by up to 50%.
• Improves disease-free survival in intermediate and high-risk patients.

Intravesical therapy is a cornerstone in the management of non–muscle invasive bladder cancer (NMIBC). By delivering chemotherapy or immunotherapy agents directly into the bladder, it maximizes local tumor control while minimizing systemic side effects. This presentation highlights the rationale, techniques, agents, protocols, clinical benefits, and adverse effects of intravesical therapy, with emphasis on BCG and intravesical chemotherapy. It also summarizes guideline-based approaches (EAU, AUA, NCCN), making it a comprehensive resource for students, urologists, and oncologists.

1. INTRAVESICAL THERAPY
by Dr. Naseer Hussain
MCh,Surgical Oncology
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2. Epidemiology of bladder cancer
•Stands at 9
th position , among all cancers
•Incidence – 614298 new cases annually
•Mortality – 220596 deaths / year
•Gender – 3 to 4 x more common in men
•Age – peak incidence in 60-70yrs
…GLOBOCON 2022
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3. BLADDER CANCER
NMIBC MIBC
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4. •Non-muscle invasive bladder cancer (NMIBC) is a cancer originating in
the inner lining of the bladder (urothelium) or the superficial layer
beneath it (lamina propria), without invading the muscle layer.
•Pathological Classification:
Ta tumors: Appear as papillary, finger-like growths on the bladder
surface. 
T1 tumors: Have begun to invade the lamina propria, a layer of
connective tissue just below the urothelium. 
Tis (Carcinoma in situ): A high-grade, flat-appearing tumor that is
confined to the urothelium but is considered a precursor to muscle-
invasive cancer. 
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6. TURBT
INTRAVESICAL
CHEMOTHERAPY
SURVEILLANCE
NMIBC
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7. RISK STRATIFICATION
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8. CORE INDICATIONS
•Post-TURBT (low risk)
•Intermediate-risk disease
•High-risk disease (T1, high-grade, CIS)
•Recurrent NMIBC
•BCG-refractory cases (if cystectomy not possible)
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9. FLOTATION
DIRECT DRUG DELIVERY
PREVENTION OF RECURRENCE
MODULATION OF TUMOR BIOLOGY
ORGAN PRESERVATION
RATIONALE FOR INTRAVESICAL THERAPY
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10. ERADICATE RESIDUAL MICROSCOPIC DISEASEPREVENT TUMOR CELL IMPLANTATION
REDUCE RECURRENCE RATES OF NMIBC DELAY or PREVENT PROGRESSION TO MIBC
ACHIEVE LOCAL HIGH DRUG CONCENTRATION PRESERVE BLADDER AND ITS FUNCTION
ENHANCE LOCAL IMMUNE RESPONSE IMPROVE OVERALL SURVIVAL AND QUALITY OF LIFE
GOALS
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11. CLASSIFICATION
IMMUNOTHERAPY
CHEMOTHERAPY
NOVEL AGENTS
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12. CHEMOTHERAPEUTIC AGENTS
AKYLATING AGENTS
MITOMYCIN
THIOTEPA
ANTHRACYCLINS
DOXORUBICIN
EPIRUBICIN
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13. IMMUNOTHERAPEUTIC AGENTS
LIVE ATTENUATED BACTERIA
•BCG
INTERFERONS
•INTERFERON - alpha
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14. •PEMBROLIZUMAB
•ATEZOLIZUMAB
CHECKPOINT
INHIBITORS
•NADOFARAGENE
FIRADENOVEC (Adstiladrin)
•OPORTUZUMAB MONATOX
GENE THERAPY
VECTORS
NOVEL AGENTS
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15. TIME LINE
PERIOD DRUGS INTRODUCED
1950s THIOTEPA INTRODUCED
1970s BCG DISCOVERED (Morales, 1976)
1980s MITOMYCIN C
1990s BCG = goldstandard , VALRUBICIN
2000s Maintenance BCG, GEMCITABINE, TAXANES
2010s Salvage regimens, device assisted delivery
2020s Gene therapy ( NADOFARAGENE ), Immunotherapy era
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16. SWOG trial
15%
progression
rate in patients
receiving BCG
37%
progression
rate in patients
receiving
chemotherapy
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17. THIOTEPA
In controlled clinical trials (n = 950 patients),
it has been shown to significantly decrease tumor recurrence in 6
of 11 studies by up to 41% (mean decrease, 16%).
SIDEEFFECTS - MYELOSUPPRESSION
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18. DOXORUBICIN
doxorubicin demonstrated a 13%
to 17% improvement over TUR in preventing recurrence but no
advantage in preventing tumor progression (15.2% vs. 12.6%)
The principal side effect of intravesical doxorubicin
is chemical cystitis, which can occur in up to half of the
patients. Reduced bladder capacity has been reported in several series
The doxorubicin derivative epirubicin decreases recurrence
compared with TUR alone by 12% to 15%
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19. •VALRUBICIN
Valrubicin is a semisynthetic analogue of doxorubicin that was
approved by the FDA for treatment of BCG-refractory CIS in patients
who cannot tolerate cystectomy; the drug became available in 2009
in the United States
In a cohort of 90 patients with BCG-refractory
CIS, only 21% demonstrated a complete response (Steinberg et al.,
2000), so its use is not widespread.
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20. MITOMYCIN C
MMC is an alkylating agent instilled weekly (20–60 mg) for 6–8 weeks; effective mainly in reducing
recurrence, less so progression compared to BCG.
Meta-analyses show BCG superior in progression control, but MMC has fewer side effects and remains a viable
option for recurrence reduction.
Optimized delivery (empty bladder, alkalinization, higher concentration, fasting) improves efficacy.
Electromotive drug administration (EMDA) and hyperthermia (chemohyperthermia) enhance MMC
penetration and reduce recurrence rates.
Combination of BCG with electromotive MMC shows better recurrence, progression, and survival outcomes in
some studies.
HIVEC (heated MMC recirculation system) shows promising results but needs more randomized trial evidence.
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22. GEMCITABINE
Intravesical gemcitabine is safe, well-tolerated, and shows 39–70% recurrence
reduction, including modest efficacy in BCG-refractory patients.
It appears most useful after BCG failure, with some trials showing improved disease-
free survival though no clear benefit in progression or cystectomy rates.
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23. BCG administration protocol
BCG is given intravesically (50 mL saline, via catheter) usually 2–4 weeks post-
TURBT, after bladder re-epithelialization.
Delay treatment if traumatic catheterization or active UTI; asymptomatic
bacteriuria may not require delay.
Patients should retain BCG for 1–2 hours, with fluid/diuretic restriction beforehand
to improve efficacy.
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24. BCG MECHANISM
BCG binds to fibronectin in the bladder wall, inducing a strong local immune
response with cytokine release (TNF-α, GM-CSF, IFN-γ, ILs).
The key effect is a Th1-dominant immune response (↑ IFN-γ, IL-2, IL-12), activating
cell-mediated cytotoxicity responsible for antitumor action.
Efficacy may be reduced in immunosuppressed or elderly patients, but BCG can still
be used safely without significantly higher risk of sepsis.
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25. BCG vs CHEMOTHERAPY
BCG is the most effective intravesical therapy, superior to chemotherapy in
reducing both recurrence and progression, especially with induction +
maintenance.
Chemotherapy agents (MMC, doxorubicin, epirubicin, thiotepa) reduce recurrence
but do not reduce progression, unlike BCG.
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26. Intravesical BCG can treat residual papillary bladder tumors and superficial
prostatic duct carcinoma, but it should not replace surgical resection. BCG after
TURBT reduces recurrence by ~40% on average, with maintenance therapy
proving superior to induction alone.
In high-risk T1 disease, BCG lowers recurrence (16–40%) and progression (4–40%)
compared with TURBT alone.
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27. BCG reduces progression risk in high-risk NMIBC and CIS, with meta-analyses
showing a 23–35% reduction compared to chemotherapy or TUR alone.
The benefit is most evident with maintenance BCG, while chemotherapy has not
shown significant impact on progression.
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28. Induction BCG alone is insufficient; maintenance therapy (SWOG regimen: 3 years) gives superior
recurrence-free and overall survival.
Second induction course adds 25–30% response, but further courses carry 20–50% risk of
progression; 6-month nonresponse predicts poor prognosis.
Oddens et al. trial: intermediate-risk benefits from 1 year full-dose BCG, high-risk from 3 years;
reduced doses show mixed efficacy.
Quinolones post-instillation reduce cystitis-related side effects without affecting oncologic
outcomes; INH has inconsistent benefit.
Predictive biomarkers (CyPRIT cytokine panel) show promise in forecasting recurrence and guiding
BCG response.
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29. ABSOLUTE RELATIVE
Immunosuppressed & immunocompromised UTI
Immediately after TUR LIVER DISEASE
Personal h/o BCG sepsis Personal h/o TB
Gross hematuria Poor overall PS
Traumatic catheterization Advanced age
Total incontinence
CONTRAINDICATIONS TO BCG THERAPY
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30. BCG toxicity management
G1
Symptoms – Mild irritative voiding, mild hematuria, fever <38.5°C.
Assessment – Do urine culture to exclude bacterial UTI
Management- anti cholinergics, topical antispasmodics, analgesics
G2
•Severe irritative voiding, hematuria, or symptoms > 48hrs. Urine culture, CXR, LFTs done
•Continue grade 1 measures, consider dose reduction, use INH + RIF with vit B6
G3
•Shock, persistent fever, allergy, or organ involvement
•Stop BCG, start INH + RIF + VIT B6: add ETHAMBUTOL if poor response
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31. Interferons (IFNs) in intravesical therapy
MECHANISM IFNs (esp. IFN-α) have antitumor effects: inhibit nucleotide synthesis, upregulate
tumor antigens, antiangiogenic, and enhance immune cell activity.
Efficacy as monotherapyIFN alone is less effective and more expensive than BCG/chemotherapy, with CIS
complete response rates only 20–43% and poor long-term efficacy (<15%).
Dose dependency Higher doses (100 million units) are more effective than low doses (10 million
units).
Role in BCG failureIFN can work in 15–20% of patients after BCG failure, though activity against T1
tumors is limited.
Combination therapyIFN + BCG shows additive effects, allows reduced BCG dosing with similar efficacy,
but large trials show no clear superiority over BCG alone.
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32. Comparisions among intravesical agents
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33. Nadofaragene firadenovec (Adstiladrin therapy)
MECHANISM Uses a virus to deliver the interferon alfa-2b gene into bladder lining cells, which
then produce interferon to stimulate the immune system against cancer.
INDICATION For high-risk NMIBC not responding to BCG; given once every 3 months.
SIDE EFFECTS Fatigue, bladder spasms, frequent urination, hematuria.
CAUTION Safe in most, but as it’s a live virus, it’s not recommended for patients with
weakened immune systems.
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34. Timing of IVT (Immediate Post-TURBT vs Delayed)
IMMEDIATE POST TURBT (Single Instillation within 24
hours)
Delayed/Induction Therapy (2–4 weeks post-TURBT)
Rationale: Kills floating tumor cells, prevents
implantation at resection sites.
Rationale: Allows bladder mucosa to re-epithelialize
and heal before repeated instillations.
Evidence: Reduces early recurrence by ~35–40%
(especially in low/intermediate-risk Ta/T1 tumors).
Timing: Typically starts 2–4 weeks after TURBT
Agents Used: Commonly MMC, epirubicin,
gemcitabine.
Agents Used: BCG or chemotherapy (MMC,
gemcitabine, etc.) in weekly courses.
Contraindications: Bladder perforation, extensive
resection, significant bleeding.
Indication: For intermediate- and high-risk NMIBC
(recurrence prevention, CIS management).
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35. Instillation Techniques & Dwell Time
PREPARATION Bladder should be completely emptied before instillation; restrict fluids for 2–4 hours
prior.
INSTILLATIONDrug is introduced via urethral catheter into the bladder in a sterile manner.
DWELL TIME Retain drug for about 1.5–2 hours (minimum 1 hour, maximum 2 hours). Patients may
be asked to rotate position (supine, prone, lateral) to ensure uniform contact.
POST CARE After voiding, advise increased fluid intake; urine should be handled with precautions
(especially with BCG, bleach disinfection recommended).
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36. comparison of Induction vs. Maintenance Intravesical Therapy
INDUCTION THERAPYInitial intensive course, usually weekly instillations for 6
weeks; goal is to eradicate residual disease and trigger
immune/chemo response.
Maintenance TherapyAdditional periodic instillations after induction (e.g., SWOG
schedule: 3 weekly doses at 3, 6 months, then every 6
months up to 3 years); goal is to prevent recurrence and
progression.
Efficacy Induction alone often insufficient for high-risk disease;
maintenance significantly lowers recurrence and
progression rates (especially with BCG).
Risk StratificationIntermediate-risk patients may benefit from 1 year, while
high-risk patients need up to 3 years of maintenance for
best outcomes.
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37. comparison of adverse effects
LOCAL IRRITATION SYSTEMIC EFFECTS
Chemotherapy: Causes chemical cystitis,
dysuria, frequency, urgency, and
hematuria from urothelial irritation.
Chemotherapy: Rare systemic absorption
→ myelosuppression, alopecia, nausea,
hepatotoxicity (depends on drug e.g.,
mitomycin, doxorubicin).
Immunotherapy (BCG): Causes
granulomatous cystitis/prostatitis,
irritative voiding, and sterile pyuria.
Immunotherapy: Risk of systemic BCG
infection/sepsis (fever, malaise,
pneumonitis, hepatitis, disseminated
infection).
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38. Landmark Clinical Trials in Intravesical Therapy
Morales et al., 1976First clinical use of BCG intravesical therapy
Lamm et al., SWOG 8507
Trial (2000)
Defined role of maintenance BCG vs induction alone.
EORTC/GU Group Meta-
Analysis (Sylvester et al.,
2002)
BCG superior to intravesical chemotherapy in recurrence & progression prevention.
Bohle & Bock, 2004 Meta-
analysis
Confirmed BCG reduces progression risk significantly compared to MMC.
Herr et al., 1988
(Randomized Trial) –
Showed delayed progression and reduced cystectomy rates with BCG vs TUR alone
in high-risk patients.
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39. Oddens et al., EORTC 30962 Trial (2013) Compared different doses and durations of BCG
maintenance.
Sylvester et al., 2005 Meta-analysis (24 Trials, >4800
pts)
Demonstrated maintenance BCG reduces recurrence
risk by 32% vs chemotherapy
Chou et al., 2017 Systematic Review (AUA guidelines
basis)
Confirmed BCG reduces recurrence & progression
compared to intravesical chemotherapy, but with
higher toxicity.
Nepple et al., 2010 (BCG + IFN Trial, 670 pts) Tested BCG + Interferon-α2b vs BCG alone.
Adstiladrin (Nadofaragene Firadenovec) Phase III Trial,
2020 (Boorjian et al.)
Gene therapy (adenovirus-mediated IFN-α2b) for BCG-
unresponsive NMIBC
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40. TURBT is the first step; intravesical therapy reduces recurrence and progression risk
Risk stratification (low, intermediate, high) guides therapy choice (chemo vs BCG).
Single immediate post-TURBT instillation of chemotherapy lowers recurrence in low-risk disease.
BCG is the gold standard for high-risk NMIBC; requires induction + maintenance (up to 3 years).
Maintenance is key – improves recurrence and progression outcomes compared to induction alone.
Adverse effects differ: chemo → chemical cystitis/systemic toxicity; BCG → granulomatous prostatitis, rare
sepsis.
BCG-unresponsive disease → cystectomy preferred; alternatives include gemcitabine, docetaxel, or gene
therapy (Adstiladrin).
Close follow-up is mandatory – most recurrences occur within the first 5 years.
Future directions include novel agents, gene therapy, and combination regimens to overcome BCG failure.
TAKE HOME MESSAGE
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41. THANK YOU…
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