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Non-Muscle Invasive Bladder Cancer BCG Failures:
“University of Iowa Hospitals and Clinics Experience”
Paul Gellhaus
Assistant Clinical Professor
Iowa???
Disclosures
• none
Caveats
• Dr. Michael O’Donnell research / clinical experience
• NOT recommendations / guidelines / FDA approved
• Single university, small numbers
• Share experience & “hypothesis generating” discussion
University of Iowa Experience
1. “Enhanced” Bladder Surveillance (detection)
2. Clinic-based upper tract CIS treatment
3. Novel intravesical immune and sequential chemotherapy agent treatments
Bladder cancer recurrence:is a Problem
~70% of bladder tumors will recur after TURBT alone
Highest local recurrence rate of any solid malignancy
Highest cost cancer from diagnosis to death
15-20% will progress to muscle invasion.
Bladder cancer recurrence:is a Problem
Risk factors
Stage & Grade
Size & Multiplicity
Prior Recurrence
Presence of CIS
UTUC is possible source of bladder seeding CIS: 11-36% prior bladder high-grade disease
Bladder cancer recurrence:is a Problem
How can we improve??
Better detection of occult disease
Multiple effective treatment options
1. “Enhanced” Bladder Surveillance
• “Restaging” bladder and upper tracts evaluation• High grade/risk NMIBC
• After initial treatment (TURBT & intravesicalinduction)
UIHC “Enhanced” Surveillance
Test StandardSurveillance EnhancedSurveillance
WhitelightCystoscopy ✅ ✅
UrineCytology ✅ ✅
BlueLightCystoscopy ✅
BilateralRetrogradePyelograms ✅
BilateralUreteralWashCytology ✅
RandomBladderBiopsies ✅
*no gross bladder tumor seen
** Prostatic urethral biopsy in men
UIHC: “Enhanced” Surveillance
Outcomes n %
Procedures 439 100.0
Recurrences 207 47.1
SSPositive 148 33.7
SSNegativeESPositive 59 13.4
• Blue light: 7%• Other methods each added ~1-2%
Surveillance Area Difference p-value
Standard 0.7536 (Ref)
“Enhanced” 0.8451 0.0915 <0.01
UIHC “Enhanced” Surveillance
• Number needed to screen to detect one additional recurrence over the standard of care
– 4.6 restaging procedures
UIHC “Enhanced” Surveillance
• Enhancement only recurrence:– 4.4% Upper tract
– CIS 69%
– Ta 16%
– T1 8.8
– T2 1.5%
UIHC “Enhanced” Surveillance
Only 16% progressed to cystectomy
T1HG 93%
Oberle, AUA 2017
UIHC “Enhanced” Surveillance
• Rational: – Detecting occult disease (primary CIS)
– Reduce “seeding” as a source of recurrence• Upper tract
• Prostatic urethra
• T1HG CSS: Durable 93% ~ 4 years median follow up
2. Upper Tract CIS Treatment
• Positive selective cytology, negative RPG / URS
• Induction topical agent
– Ureteral catheter (>90%)
– Nephrostomy tube (<10%)
Technique for Retrograde
Instillation• clinic fluoroscopy suite, topical lidocaine, flexible cystoscopy,
• 4 Fr whistle tip catheter, 0.018 angled glide wire
> 100 patients; safe and effective
Topical Therapy for CIS UTUC
• Induction (x 6 weeks) treatments
–Maintenance
•BCG: 1x 3-weekly @ 3 months
•Chemo: 6x monthly maintenance
Topical Therapy for CIS UTUC
• After induction
–“Enhanced” surveillance
• CT every 6 months for 2-3 years
Localizing POSITIVE HG Upper Tract Cytology
• 1 year RFS: BCG: 65% (n=43)• Gemcitabine/Docetaxel: 90% (n=11) Unpublished
3. Intravesical Treatment
• BCG (with maintenance)
– Recommended for high-grade or high risk cases
– 30-40% absolute reduction papillary recurrence
– 60-70% CIS complete response
– ~ 27% progression reduction
BCG failure x 1 are a problem
• BCG failures X1 – ~35% response 2nd course of BCG
• How can we improve this response?
BCG failure x 2 are another problem
• BCG failures x 2:– <20% response another course of BCG
– offered cystectomy before progression
• unwilling or unfit for cystectomy• Clinical trial
• Intravesical chemotherapy
BCG failures are a problem
• How can we improve this response?
1.BCG with immune stimulating agents
2.Sequential chemotherapy
BCG + immunostimulation
1. INF (50 million units)– Stimulate a synergistic immune
response
– Increase efficacy of bladder cancer suppression
BCG + Interferon for BCG Failures
• BCG Naïve Age >= 80: 2 yr DFS 40% DFS (vs 60%)– HR~1.6
HR~1.8
HR~1.6
HR~1.6
Failure x 1 = 3 years DFS
~50%
BCG + immunostimulation
• “Quad” BCG: – INF: 50 million units
– IL-2: 22 million units–GM-CSF [sargramostim]: 250 mcg SQ
“Quad BCG”:Intravesical BCG +Interferon + IL-2 plus subq GM-CSF
• No apparent disadvantage to age >80• N = 8, 2 yr DFS ~70%
HR~1.8
HR~1.6
HR~1.0
55% 53%
• ~50% failed within 6 months
• 1&2 year DFS ~50%
Steinberg RL, Urol Oncol 2017
Intravesical Chemotherapy• Mitomycin: alkylating agent
• Doxorubicin(Adriamycin): topoisomerase
inhibitor & DNA intercalator
– Valrubicin
• Gemcitabine: Pyrimidine (Cytosine) analog
• Docetaxel: Microtubular stabilizing agent
Intravesical Chemotherapy
• Single agent chemotherapy (MMC, Adriamycin) +/- maintenance
– low to intermediate risk (low-grade) to reduce recurrence
– No effect on reducing progression
– Vesicants
Intravesical Chemotherapy• Vesicant
– Causes vesicles (blisters)
– Contact irritant
– Dystrophic calcification (MMC)
– Mild to severe bladder irritation and symptoms
• Rarely permanent, severe dysfunction
– bladder cripple
Intravesical Chemotherapy
• “Newer” agents (gemcitabine, docetaxel)
– Gemcitabine more effective than MMC
• 72% vs 61% (Addeo JCO 2010)
• Single post op dose (Messing, JAMA 2018)
• Non-vesicants
– Well tolerated
Intravesical Chemotherapy• Vesicant
– Mitomycin
– Doxorubicin (Adriamycin)
– Valrubicin
• Non-vesicant: “newer” agents
– Gemcitabine
– Docetaxel
Sequential Chemotherapy
• Combined vesicant agent
–Promising results
–Poorly tolerated
–High discontinuation rate
Sequential Chemotherapy
• Gemcitabine & Docetaxel:
–Non-vesicant:
–Very well tolerated
–Nearly no side effects
Sequential Chemotherapy
1.Gemcitabine: 1g 50ml NS &
Docetaxel: 37mg in 50ml NS
Sequential Chemotherapy
• Single drug instilled via catheter
– Clamped for 90 minutes and drained
• Second drug instilled
– Catheter removed, patient can leave clinic
– Voids 2 hours later
BCG Failures: Gemcitabine-Docetaxel
> 24 months: “Durable responders”
Unpublished
Sequential Chemotherapy
2. “Quad” Chemo:
– One vesicant + one non-vesicant agent
– Adriamycin 50mg in 50ml NS & Gemcitabineone week
– Docetaxel + Mitomycin 40mg 20ml water next week
– 4x 2-week 4-drug cycles
= 8 total weeks
Quad Chemo: AG-DM X 8
N=12
BCG Failure and/or Gem-Doce Failure
>12 months durable response
Gemcitabine-Docetaxel BCG-Naïve
Unpublished n = 30
• RFS @ 2 years• 7/7 (100%) intermediate risk• 10/11 (92%) CIS• 8/12 (67%) Ta/T1 HG• >80 yo: Equivalent response
Intravesical Chemotherapy
• Increase effectiveness• Reduce oral intake 4 hours prior
• Avoid caffeine or diuretic that day
• Minimum 1.5 hours dwell time
• Mitomycin & Gemcitabine• alkalinize urine with oral NaCO3 pm before & am
• NSAID (naproxen) 1 hour prior• reduce side effects
• potentially increase efficacy
Take Home Messages
1. Improve detection by “Enhanced” Surveillance
– Cysview (Blue light)
– Assessing for occult CIS
• Upper tract and prostatic urethra
Take Home Messages
2. Reduce recurrence by treating upper tract CIS
– Topical immune or chemotherapy agents
– Consider clinic placed ureteral catheter via flexible cystoscopy
Take Home Messages
3. Improve efficacy of topical bladder agents
–BCG immunostimulation
• IFN
• “Quad”
IFN + IL2 and subq GM-CSF
Take Home Messages
3. Improve efficacy of topical bladder agents
–Sequential chemotherapy
• Gemcitabine/Docetaxel
• Quad Chemo: – Adriamycin + Gemcitabine then
– Docetaxel + Mitomycin
– x 8 cycles
Take Home Messages
3. Improve efficacy of topical bladder agents
• >80 years old BCG Failures – “Quad BCG” IFN + IL2 and subq GM-CSF
– Gemcitabine/docetaxel
• Gemcitabine/docetaxel BCG naïve:– Promising alternative first line intermediate/high risk
• BCG ineligible, intolerant, or unavailable
• > 80 years old
