Non-Muscle Invasive Bladder Cancer BCG Failures: University of Iowa Hospitals and Clinics Experience Paul Gellhaus Assistant Clinical Professor
Iowa???
none Disclosures
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 treatment options
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: Risk factors Stage & Grade Size & Multiplicity Prior Recurrence Presence of CIS is a Problem UTUC is possible source of bladder seeding
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 & intravesical induction)
UIHC Enhanced Surveillance Test Standard Surveillance Enhanced Surveillance White light Cystoscopy Urine Cytology Blue Light Cystoscopy Bilateral Retrograde Pyelograms* Bilateral Ureteral Wash Cytology Random Bladder Biopsies Prostatic urethral biopsy in men *no gross bladder tumor seen
UIHC: Enhanced Surveillance Outcomes n % Procedures 439 100.0 Recurrences 207 47.1 SS Positive 148 33.7 SS Negative ES Positive 59 13.4 Blue light: 7% Other methods each added ~1-2%
UIHC Enhanced Surveillance Enhanced only detection: 4.4% Upper tract CIS 69% Ta 16% T1 8.8% T2 1.5%
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
Oberle, AUA 2017 UIHC Enhanced Surveillance T1HG 93% Only 16% progressed to cystectomy
UIHC Enhanced Surveillance Rational: Detecting occult disease (primary CIS) Reduce seeding as a source of recurrence Upper tract Prostatic urethra
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 30-40% 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. IFN (50 million units) Stimulate a synergistic immune response Increase efficacy of bladder cancer suppression
BCG + Interferon for BCG Failures HR~1.6 BCG Failure HR~1.6 x 1 HR~1.8 = 3 years DFS ~50% BCG Naïve Age 80yo: 2 yr DFS 40% DFS (vs 60%) HR~1.6
BCG + immunostimulation Quad BCG: IFN: 50 million units IL-2: 22 million units GM-CSF [sargramostim]: 250 mcg SQ
Steinberg RL, Urol Oncol 2017 Quad BCG : Intravesical BCG + Interferon + IL-2 plus subq GM-CSF ~50% failed within 6 months HR~1.0 HR~1.6 HR~1.8 1&2 year DFS ~50% 55% 53% No apparent disadvantage to age >80
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 Mild to severe bladder irritation and symptoms Rarely permanent dysfunction Dystrophic calcification (MMC)
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
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 Unpublished > 24 months: Durable responders
Sequential Chemotherapy 2. Quad Chemo: One vesicant + one non-vesicant agent Adriamycin 50mg in 50ml NS & Gemcitabine one week Docetaxel + Mitomycin 40mg 20ml water next week 4x 2-week cycles = 8 total weeks
BCG Failure and/or Gem-Doce Failure Quad Chemo: AG-DM X 8 >12 months durable response N=12
Gemcitabine-Docetaxel BCG-Naïve RFS @ 2 years 7/7 (100%) intermediate risk 10/11 (92%) CIS 8/12 (67%) Ta/T1 HG >80 yo: Equivalent response n = 30 Unpublished
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 cysto placed ureteral catheters
Take Home Messages 3. Improve efficacy of topical bladder agents BCG with 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 4 cycles (8 weeks total)
Take Home Messages 3. Improve efficacy of topical bladder agents >80 years old: immunosenescence Quad BCG IFN + IL2 and subq GM-CSF Gemcitabine/docetaxel
Take Home Messages 3. Improve efficacy of topical bladder agents BCG ineligible, intolerant, or unavailable Gemcitabine/docetaxel Promising alternative first line intermediate/high risk
If I were to be invited back