non-muscle invasive bladder urothelial carcinoma st. louis university hospital division of urology...

Non-Muscle Invasive Non-Muscle Invasive Bladder Urothelial Bladder Urothelial

CarcinomaCarcinoma

St. Louis University Hospital Division of Urology

Michael Mastromichalis, MD

OutlineOutline Diagnosis & EpidemiologyDiagnosis & Epidemiology StagingStaging Endoscopic ManagementEndoscopic Management

ComplicationsComplications Repeat TURBT and Random BiopsiesRepeat TURBT and Random Biopsies

ImmunotherapyImmunotherapy Primary Intravesical ChemotherapyPrimary Intravesical Chemotherapy RadiationRadiation Surveillance ProtocolsSurveillance Protocols Secondary Prevention StrategiesSecondary Prevention Strategies

Bladder AnatomyBladder Anatomy The urinary bladder has 3 distinct The urinary bladder has 3 distinct

histologic layershistologic layers UrotheliumUrothelium Lamina PropriaLamina Propria Detrusor (Muscularis Propria)Detrusor (Muscularis Propria)

Bladder Urothelial Bladder Urothelial CarcinomaCarcinoma

Bladder Cancer PresentationBladder Cancer Presentation Typical SymptomsTypical Symptoms Risk StratificationRisk Stratification

Grade & StageGrade & Stage CISCIS MulticentricityMulticentricity Lymphovascular InvasionLymphovascular Invasion Cytology and Molecular MarkersCytology and Molecular Markers

Asymptomatic Patients / Autopsy Asymptomatic Patients / Autopsy RatesRates

Urothelial CarcinomaUrothelial Carcinoma

UC represents over 90% of all UC represents over 90% of all bladder cancers diagnosed in the USbladder cancers diagnosed in the US

68,000 new cases are diagnosed per 68,000 new cases are diagnosed per yearyear >90% diagnosed are older than 55>90% diagnosed are older than 55 13,000 deaths annually13,000 deaths annually 500,000 survivors currently in the US500,000 survivors currently in the US

3:1 male to female, with incidence 3:1 male to female, with incidence rising in all groupsrising in all groups

Lifetime risk of 1/28Lifetime risk of 1/28

Bladder Urothelial CarcinomaBladder Urothelial Carcinoma

Smoking is the #1 risk factorSmoking is the #1 risk factorAmines, 4-aminobiphenyl & analines are the Amines, 4-aminobiphenyl & analines are the culpritsculprits

Aromatic amines in dyes, solvents, paints, Aromatic amines in dyes, solvents, paints, combustion products, rubber, and textiles combustion products, rubber, and textiles are also risk factorsare also risk factors Hairdressers, mechanics, truckersHairdressers, mechanics, truckers Phenacetin derived analgesicsPhenacetin derived analgesics Not coffee and artificial sweetenersNot coffee and artificial sweeteners

Rarely familial syndrome with DNA Rarely familial syndrome with DNA mismatch repair (Lynch II)mismatch repair (Lynch II)

Slow acetylators (40% higher) vs fast Slow acetylators (40% higher) vs fast acetylatorsacetylators

Bladder Urothelial CarcinomaBladder Urothelial Carcinoma

The vast majority of The vast majority of bladder UC are the bladder UC are the result of result of environmental environmental exposure- tobaccoexposure- tobacco Endogenous Endogenous

molecular factors molecular factors play a roleplay a role

Cyclophosphamide Cyclophosphamide & ifosfamide chemo& ifosfamide chemo

A. fangchi herbs & A. fangchi herbs & arsenicarsenic

Radiation therapyRadiation therapy Prostate, anal, Prostate, anal,

cervixcervix

Bladder Urothelial Bladder Urothelial CarcinomaCarcinoma

The entire urothelium is The entire urothelium is susceptible to susceptible to carcinogenic insult and carcinogenic insult and thus, to malignant thus, to malignant transformationtransformation A “field change A “field change

disease”disease” Tumorgenesis Tumorgenesis

separated by time and separated by time and spacespace

Cells migrate and Cells migrate and implant vs. multifocal implant vs. multifocal carcinogenesiscarcinogenesis

Urothelial CarcinomaUrothelial Carcinoma The urinary bladder is the reservoir The urinary bladder is the reservoir

of urine and therefore has a of urine and therefore has a prolonged “face-time” with renally prolonged “face-time” with renally excreted carcinogensexcreted carcinogens

UC has a long latency from exposure UC has a long latency from exposure to cancer development supporting to cancer development supporting the theory of a carcinogenic the theory of a carcinogenic cumulative effect on malignant cumulative effect on malignant transformation of the urotheliumtransformation of the urothelium

48,000 Men over 10 years- UC 48,000 Men over 10 years- UC incidence re: fluid intakeincidence re: fluid intake

1.5L of water/day << less than 240mL 1.5L of water/day << less than 240mL

Non-Muscle Invasive UCNon-Muscle Invasive UC

Historically known as ‘superficial’ Historically known as ‘superficial’ bladder cancerbladder cancer Wide range- Low-grade papillary to Wide range- Low-grade papillary to

high grade T1 with CIShigh grade T1 with CIS

70-75% are amenable to bladder 70-75% are amenable to bladder sparing treatmentssparing treatments

Grade 1,2,3 vs. Low/High Grade- Grade 1,2,3 vs. Low/High Grade- regardless of invasion or CIS presenceregardless of invasion or CIS presence

All tumors that have not invaded the All tumors that have not invaded the detrusordetrusor

Tumor GradingTumor Grading

Ta denotes a Ta denotes a papillarypapillary (LG or HG) tumor (LG or HG) tumor confined to the urotheliumconfined to the urothelium

T1 is a T1 is a papillary, sessile or nodularpapillary, sessile or nodular tumor tumor invading the lamina propria (LG or HG)invading the lamina propria (LG or HG) Anything beyond the urothelial basement Anything beyond the urothelial basement

membrane until the detrusor.membrane until the detrusor.

Examples of Cystoscopic Examples of Cystoscopic TumorTumor

CystoscopyCystoscopy

Tumor GradingTumor Grading

CIS is a CIS is a flatflat, , high-grade,high-grade, tumor confined tumor confined to the urothelium. No lamina propria to the urothelium. No lamina propria invasion. invasion. Velvety, erythematous and easily missed on Velvety, erythematous and easily missed on

cystoscopycystoscopy Severe atypia and nuclear aplasia with Severe atypia and nuclear aplasia with

disorderly architecturedisorderly architecture Can be multicentric and often occur with high-Can be multicentric and often occur with high-

grade tumorsgrade tumors OminousOminous CIS undermining of adjacent healthy CIS undermining of adjacent healthy

urotheliumurothelium

Non-Muscle Invasive Bladder Non-Muscle Invasive Bladder CancerCancer

Ta Urothelial CaTa Urothelial CaLow GradeLow Grade

Ta Urothelial CaTa Urothelial CaHigh GradeHigh Grade

Carcinoma in SituCarcinoma in Situ

Definition and Definition and EpidemiologyEpidemiology

75% of all urothelial bladder tumors 75% of all urothelial bladder tumors are NMIare NMI Ta (70%)Ta (70%) T1 (20%T1 (20% CIS (10%)CIS (10%)

Gross Hematuria- 15-35% risk of Gross Hematuria- 15-35% risk of bladder tumorbladder tumor

Microscopic Hematuria- 1-5% have Microscopic Hematuria- 1-5% have bladder tumorbladder tumor

New Irritative Symptoms- double the New Irritative Symptoms- double the risk + CIS riskrisk + CIS risk

Non-Muscle Invasive Bladder Non-Muscle Invasive Bladder CancerCancer

Who progresses% and dies% Who progresses% and dies% from NMIBC?from NMIBC?

PUNLMP PUNLMP 33 0-10-1 Papillary, LGPapillary, LG 5-105-10 1-51-5 Papillary, HGPapillary, HG 15-4015-40 10-2510-25 T1, HGT1, HG 30-5030-50 3030 CISCIS >50 >50 HG HG

precursorprecursor

Staging Non-Muscle Invasive Staging Non-Muscle Invasive Bladder CancerBladder Cancer

Papillary Urothelial Neoplasm of Papillary Urothelial Neoplasm of Low Malignant Potential- PUNLMPLow Malignant Potential- PUNLMP Orderly cellular arrangementOrderly cellular arrangement Minimal architectural abnormalitiesMinimal architectural abnormalities Minimal cellular atypiaMinimal cellular atypia

No cytologic features of malignancy, so No cytologic features of malignancy, so unlikely to progress, ergo, they are unlikely to progress, ergo, they are considered benignconsidered benign

Follow-up still recommendedFollow-up still recommended

Tumor Biology & Tumor Biology & BehaviorBehavior

Invasive vs Non-invasiveInvasive vs Non-invasive Urothelium- devoid of vessels or Urothelium- devoid of vessels or

lymphaticslymphatics

Lamina propria- rich in both providing a Lamina propria- rich in both providing a suitable scaffold for metastasis and tumor suitable scaffold for metastasis and tumor disseminationdissemination

Behavior (Progression) is primarily Behavior (Progression) is primarily grade dependentgrade dependent

HG has high recurrence and progression HG has high recurrence and progression regardless of Ta or T1 statusregardless of Ta or T1 status


Low Grade vs. High Grade Disease Low Grade vs. High Grade Disease PathwaysPathways

These are essentially different These are essentially different diseases with different diseases with different pathophysiologypathophysiology

Bladder cancer, the early years...Bladder cancer, the early years...

Tumor Biology & BehaviorTumor Biology & Behavior

First hitFirst hit- it all starts with altered cellular - it all starts with altered cellular metabolism after exposure to detoxified or metabolism after exposure to detoxified or partially detoxified carcinogenspartially detoxified carcinogens Oxidative cellular DNA damage is the resultOxidative cellular DNA damage is the result

Second hitSecond hit- genetic or acquired cellular failure - genetic or acquired cellular failure that promotes tumor, fails to inhibit tumor, or that promotes tumor, fails to inhibit tumor, or fails to repair oxidized/damaged DNA…fails to repair oxidized/damaged DNA…– Activate oncogenes (RAS gene family)Activate oncogenes (RAS gene family)– Mutated tumor suppressor genes (Rb and P53)Mutated tumor suppressor genes (Rb and P53)– Damaged APEX-1Damaged APEX-1

Tumor Biology & BehaviorTumor Biology & BehaviorOxidative DNA damage causes Oxidative DNA damage causes

chromosomal alterationschromosomal alterations

Low Grade Pathway (Ta papillary tumors)Low Grade Pathway (Ta papillary tumors) More commonMore common Much fewer chromosomal mutations & Much fewer chromosomal mutations &

abnormalitiesabnormalities Usually indolent unless convert to high grade Usually indolent unless convert to high grade

pathwaypathway Loss of part or all of Loss of part or all of Chromosome 9 (q)Chromosome 9 (q)

High Grade Pathway (CIS, T1, and muscle High Grade Pathway (CIS, T1, and muscle invasive)invasive) Numerous and variable chromosomal gains and lossesNumerous and variable chromosomal gains and losses Rb & P53 mutationsRb & P53 mutations, CH 7, 9, , CH 7, 9, 1717 (where p53 (where p53

is located)is located) Aggressivity: high p53, Ki-67, loss of E-Aggressivity: high p53, Ki-67, loss of E-

CadherinCadherin Low: No loss of E-CadherinLow: No loss of E-Cadherin


Most important risk factor in NMIUC Most important risk factor in NMIUC progression is progression is GRADEGRADE…then presence of …then presence of CISCIS

Ergo, High Grade Ta = High RiskErgo, High Grade Ta = High Risk Should be surveyed as suchShould be surveyed as such

CIS=High Grade=High Risk and is a high CIS=High Grade=High Risk and is a high grade, invasive urothelial cancer grade, invasive urothelial cancer precursorprecursor Should be treated as such because 45-80% will Should be treated as such because 45-80% will

progress to muscle invasive UC if untreated.progress to muscle invasive UC if untreated.


NMIUCNMIUC PrognosisPrognosis correlates with: correlates with: Tumor grade Tumor grade +/- CIS+/- CIS Tumor SizeTumor Size MultiplicityMultiplicity Papillary vs SessilePapillary vs Sessile +/- Lymphovascular Invasion+/- Lymphovascular Invasion

Tumor Biology & BehaviorTumor Biology & BehaviorA Gentle Word re: HGT1 LesionsA Gentle Word re: HGT1 Lesions

HGT1 tumors are usually papillary but are HGT1 tumors are usually papillary but are the most understaged tumors in bladder the most understaged tumors in bladder cancercancer 40% are understaged at time of 40% are understaged at time of

cystectomycystectomyOnly half of these are organ confined.Only half of these are organ confined.

Hydronephrosis usually indicates detrusor Hydronephrosis usually indicates detrusor invasioninvasion 85-90% association with MI urothelial 85-90% association with MI urothelial

carcinomacarcinoma


Nodular or sessile appearance usually Nodular or sessile appearance usually indicates deeper muscle invasionindicates deeper muscle invasion

Micropapillary cancer is a very aggressive Micropapillary cancer is a very aggressive variantvariant

BCG and chemo resistantBCG and chemo resistant Early cystectomy for non-muscle Early cystectomy for non-muscle

invasive diseaseinvasive disease


A Gentle Word re: HGT1 A Gentle Word re: HGT1 LesionsLesions Some investigators have suggested a new Some investigators have suggested a new

grade if grade if +deep lamina propria+deep lamina propria muscularis mucosae involvementmuscularis mucosae involvement LV invasion LV invasion

““T1b”T1b”

Due to anecdotal risk of recurrence and Due to anecdotal risk of recurrence and progression.progression.

Endoscopic ManagementEndoscopic Management Office-based cystoscopy is the mainstay of Office-based cystoscopy is the mainstay of

diagnosis and surveillance.diagnosis and surveillance. Entire urethra, prostate, bladder neck, and Entire urethra, prostate, bladder neck, and

bladderbladder Quality of efflux from each ureteral orificeQuality of efflux from each ureteral orifice

Extent, location, number, and nature of Extent, location, number, and nature of tumors as well as UO proximity, mucosal tumors as well as UO proximity, mucosal irregularities or urethral involvement irregularities or urethral involvement should be recorded and/or photographed.should be recorded and/or photographed.

Urine cytology is encouraged for baseline Urine cytology is encouraged for baseline and may encourage future random and may encourage future random biopsies if positivebiopsies if positive

Endoscopic ManagementEndoscopic Management TURBT is the initial treatment for visible TURBT is the initial treatment for visible

lesions.lesions.

Performed under regional or general Performed under regional or general anesthesiaanesthesia

Need bimanual exam before prep and Need bimanual exam before prep and drape and after case for staging.drape and after case for staging.

Cytology with cystoscopy can be helpful Cytology with cystoscopy can be helpful as a baseline marker for future as a baseline marker for future surveillance and treatment monitoringsurveillance and treatment monitoring

Endoscopic ManagementEndoscopic ManagementResectoscopeResectoscope

Examples Bladder Tumor Examples Bladder Tumor ResectionResection

Endoscopic ManagementEndoscopic Management

Retrograde pyelography if upper Retrograde pyelography if upper tract studies are insufficient or a tract studies are insufficient or a positive radiographic findingpositive radiographic finding

Ipsilateral ureteral cytology, saline Ipsilateral ureteral cytology, saline lavage, brush biopsy, or lavage, brush biopsy, or ureteroscopic resection for tissueureteroscopic resection for tissue

Some advocate transurethral biopsy Some advocate transurethral biopsy of the prostatic urethra for complete of the prostatic urethra for complete staging in men staging in men


Essential to resect all of tumor ultimately Essential to resect all of tumor ultimately to a depth of the detrusor for accurate to a depth of the detrusor for accurate stagingstaging

Separating superficial and muscle swipes Separating superficial and muscle swipes may aid the pathologist in identifying may aid the pathologist in identifying muscularis propria from muscularis muscularis propria from muscularis mucosamucosa

An increase in abdominal fullness or girth An increase in abdominal fullness or girth requires a cystogram to r/o requires a cystogram to r/o intraperitoneal perforationintraperitoneal perforation

A cystogram is required prior to post-A cystogram is required prior to post-TURBT intravesical instillationTURBT intravesical instillation


Obturator ReflexObturator Reflex Minimized with paralytic and avoiding Minimized with paralytic and avoiding

overdistentionoverdistention Bipolar in saline minimizes as wellBipolar in saline minimizes as well

Cystoscopic planning via 70 degree Cystoscopic planning via 70 degree lenslens

Resection via 30 degree lensResection via 30 degree lens Use of continuous flow with minimal Use of continuous flow with minimal

fillfill Minimal filling to minimize bladder Minimal filling to minimize bladder

movement and detrusor thinningmovement and detrusor thinning

Endoscopic ManagementEndoscopic Management Conservative treatment of diverticular Conservative treatment of diverticular

tumorstumors– Should be sampled rather than Should be sampled rather than

resectedresected– A minority advocate “purposeful A minority advocate “purposeful

perforation”perforation”– Partial cystectomyPartial cystectomy– Random biopsies would be Random biopsies would be

warranted in preop planningwarranted in preop planning

TURBT should proceed without worry of TURBT should proceed without worry of the UOthe UO

– Pure cut across UOs minimizes Pure cut across UOs minimizes scarringscarring

– Stenting to manage oedema and Stenting to manage oedema and healinghealing

Endoscopic ManagementEndoscopic Management Small, recurrent tumors- may be Small, recurrent tumors- may be

amenable to cold-cup biopsy (older amenable to cold-cup biopsy (older women) and Bugbee electrode to tumor women) and Bugbee electrode to tumor bedbed

– Laser fulguration of the tumor bed Laser fulguration of the tumor bed in high risk patients is surgeon in high risk patients is surgeon dependentdependent

Staged resections for bulky diseaseStaged resections for bulky disease

Endoscopic ManagementEndoscopic ManagementComplicationsComplications

Obturator reflex perforationObturator reflex perforation BleedingBleeding TUR SyndromeTUR Syndrome UO ObstructionUO Obstruction Unrecognized diseaseUnrecognized disease PerforationPerforation

ExtraperitonealExtraperitoneal IntraperitonealIntraperitoneal

Why Do Patients Recur?Why Do Patients Recur?(and later, what can the urologist do about it)(and later, what can the urologist do about it)

Nature of the tumor…Nature of the tumor… Poor ProtoplasmPoor Protoplasm Missed tumors at TURBTMissed tumors at TURBT Incomplete TURBT resectionIncomplete TURBT resection Implantation of shed tumor cells at Implantation of shed tumor cells at

TURBTTURBT A de novo tumor due to a tumor-A de novo tumor due to a tumor-

sensitized, “at-risk” urotheliumsensitized, “at-risk” urothelium Field change disease and the Field change disease and the

urothelium will dedifferentiate at its urothelium will dedifferentiate at its leisureleisure

Endoscopic ManagementEndoscopic Management22ndnd Look (Restage) TURBT Look (Restage) TURBT

When tumor volume, inaccessibility, When tumor volume, inaccessibility, and intraoperative medical instability and intraoperative medical instability warrant a second look for patient warrant a second look for patient safety.safety.

Recommended 2-6 weeks after all Recommended 2-6 weeks after all HGTa & T1 tumors HGTa & T1 tumors OROR if no muscle if no muscle present present

40% positivity of re-staging sites of 40% positivity of re-staging sites of HG tumors and 20-50% likelihood of HG tumors and 20-50% likelihood of T-upgrade to MI diseaseT-upgrade to MI disease

Endoscopic ManagementEndoscopic ManagementRandom BiopsiesRandom Biopsies

Is controversial. Is controversial. – Some advocate when office cytology is + or Some advocate when office cytology is + or

to f/u with CIS treatmentto f/u with CIS treatment– But denuded bladder suitable for tumor But denuded bladder suitable for tumor

implanationimplanation

Cold-cup utilized, Bugbee for Cold-cup utilized, Bugbee for hemostasishemostasis

Not indicatedNot indicated in low-risk patients and in low-risk patients and those with negative cytology.those with negative cytology.

Essential for preoperative planning in Essential for preoperative planning in partial cystectomy or neobladder partial cystectomy or neobladder (urethral sparing)(urethral sparing)

Frequently Asked…Frequently Asked…

Concurrent TURP & TURBT with a Concurrent TURP & TURBT with a hx of LG appropriatehx of LG appropriate

Concurrent TURP + TURBT with hx Concurrent TURP + TURBT with hx of HG or CIS should be staged of HG or CIS should be staged

In neobladder planning, prostate In neobladder planning, prostate TUR biopsies are necessary but must TUR biopsies are necessary but must be weighed against risk of high be weighed against risk of high grade tumor seeding and possible grade tumor seeding and possible disseminationdissemination

MMC after TURBTMMC after TURBT

Mitomycin C is the safest & most effective Mitomycin C is the safest & most effective peri-TUR intravesical chemotherapeutic peri-TUR intravesical chemotherapeutic agentagent Single dose within 6 hoursSingle dose within 6 hours Intravesical “face-time” of 1 hourIntravesical “face-time” of 1 hour Recommended in those with low and high risk Recommended in those with low and high risk

featuresfeatures Recurrence rate decreased by 30-50% and Recurrence rate decreased by 30-50% and

increased recurrence-free intervalincreased recurrence-free interval Destroys residual microscopic tumor at the Destroys residual microscopic tumor at the

TURBT siteTURBT site Used to prevent tumor implantationUsed to prevent tumor implantation

Initial tumors on the floor and side walls while Initial tumors on the floor and side walls while recurrences at the domerecurrences at the dome

MMC after TURBTMMC after TURBT If “healthy” or “academic” swipes taken, If “healthy” or “academic” swipes taken,

a cystogram can avert systemic a cystogram can avert systemic complications from extravasated complications from extravasated absorption by holding MMCabsorption by holding MMC

Local irritative symptoms are common Local irritative symptoms are common and more serious sequelae have occurred and more serious sequelae have occurred with perforation.with perforation.

Benefit seen from LGTa to HGT1, solitary Benefit seen from LGTa to HGT1, solitary papillary to multiple tumors (across the papillary to multiple tumors (across the board)board)

StagingStaging CT urograms often accompany the CT urograms often accompany the

patient after hematuria discoveredpatient after hematuria discovered Chest RoentgenogramChest Roentgenogram

Chest CT if pulmonary metastasis Chest CT if pulmonary metastasis suspected clinically or an abnormal suspected clinically or an abnormal chest x-raychest x-ray

Comprehensive metabolic panel with Comprehensive metabolic panel with hepatic components and alkaline hepatic components and alkaline phosphatase, CBC, & coagulation phosphatase, CBC, & coagulation studiesstudies Elevated alk phos or bone pain = bone Elevated alk phos or bone pain = bone

scanscan

Intravesical TherapyIntravesical Therapy Urologists should discuss treatment Urologists should discuss treatment

options and associated risks, side-effects, options and associated risks, side-effects, and benefits.and benefits.

A wide variety of agents, combinations, A wide variety of agents, combinations, durations, and outcomes are reported.durations, and outcomes are reported.

There is a true lack of uniformity There is a true lack of uniformity regarding optimal doses, number of doses, regarding optimal doses, number of doses, and timing of instillations for inductions and timing of instillations for inductions and maintenance therapiesand maintenance therapies

The optimal interval nor duration of The optimal interval nor duration of cystoscopic follow up has been defined.cystoscopic follow up has been defined.

““We’ve not done a great job with bladder We’ve not done a great job with bladder cancer”cancer”M.J. Chehval, MDM.J. Chehval, MD

Intravesical TherapyIntravesical Therapy

Goal is to treat residual or Goal is to treat residual or unresected diseaseunresected disease

Prevent future recurrences and Prevent future recurrences and progressionprogression

Delay the need for more aggressive Delay the need for more aggressive surgical surgical

interventionintervention

Prevent tumor implantation Prevent tumor implantation

Intravesical TherapyIntravesical Therapy

Takes advantage of the relatively Takes advantage of the relatively low absorptive-capacity of bladderlow absorptive-capacity of bladder

Noninvasive access to cancer siteNoninvasive access to cancer site

Relative avoidance of systemic Relative avoidance of systemic exposure to chemotherapyexposure to chemotherapy

Innovator and Pioneer of Innovator and Pioneer of Intravesical Intravesical

ImmunotherapyImmunotherapy

ImmunotherapyImmunotherapy

Goal of immunotherapy is toGoal of immunotherapy is to Augment cancer cell recognition Augment cancer cell recognition Promote tumor cell-specific cytotoxicityPromote tumor cell-specific cytotoxicity Recruit tumor cells that have evaded the Recruit tumor cells that have evaded the

immune system “onto the radar”immune system “onto the radar” If “revved” up, the BCG immune response can If “revved” up, the BCG immune response can

mimic tumor stimulated, tumor specific mimic tumor stimulated, tumor specific cytotoxicity for yearscytotoxicity for years

ImmunotherapyImmunotherapyBCGBCG

Bacillus Calmette-GuerinBacillus Calmette-Guerin Live, attenuated Mycobacterium bovisLive, attenuated Mycobacterium bovis Developed by Albert Calmette and Camille Developed by Albert Calmette and Camille

Guerin at the Pasteur InstituteGuerin at the Pasteur Institute• Used initially as a Tb vaccineUsed initially as a Tb vaccine

Massive local immune response all reflecting a Massive local immune response all reflecting a Th1 process driven by…Th1 process driven by…

Direct binding of fibronectinDirect binding of fibronectin within the within the bladder wallbladder wall


Use in CISUse in CIS CIS is often diffuse preventing complete tumor CIS is often diffuse preventing complete tumor

resectionresection 80% response rate80% response rate 50% durable at 4 yrs and 30% at 10 yrs50% durable at 4 yrs and 30% at 10 yrs Higher efficacy compared with intravesical Higher efficacy compared with intravesical

chemochemo Induction vs. induction + maintenanceInduction vs. induction + maintenance


Use in residual tumorUse in residual tumor Effectively treats Ta papillary lesions, but not Effectively treats Ta papillary lesions, but not

a surgical substitutea surgical substitute TURP + delayed BCG to prostatic urethra is TURP + delayed BCG to prostatic urethra is

effective treatment for prostatic CISeffective treatment for prostatic CIS Use as prophylaxis for 6 weeks after Use as prophylaxis for 6 weeks after

TURBTTURBT Induction* decreased Induction* decreased recurrencerecurrence by up to 40% by up to 40%

for T1 lesions compared to TUR alonefor T1 lesions compared to TUR alone Induction* + Maintenance* can reduce Induction* + Maintenance* can reduce

progressionprogression by 20-30% in HG tumors by 20-30% in HG tumors Maintenance is thought to provide long-term Maintenance is thought to provide long-term

immunostimulationimmunostimulation

BCG SchedulingBCG Scheduling

6 week induction alone is insufficient 6 week induction alone is insufficient to achieve optimal responseto achieve optimal response

Lamm and SWOG MaintenanceLamm and SWOG Maintenance – (after 6 week induction)(after 6 week induction)

@ 3 months- 3 weekly instillations@ 3 months- 3 weekly instillations @ 6 months- 3 weekly instillations@ 6 months- 3 weekly instillations then every 6 months for 3 years then every 6 months for 3 years

18 more instillations18 more instillations

BCG SchedulingBCG Scheduling

SWOG scheduling had a high SWOG scheduling had a high dropout rate due to side effectsdropout rate due to side effects

Most consider 1 year of maintenance Most consider 1 year of maintenance to be adequateto be adequate Lengthening interval and decreasing Lengthening interval and decreasing

the dose can help with bothersome the dose can help with bothersome symptomssymptoms

Multifocal, CIS & HG tumors are where Multifocal, CIS & HG tumors are where benefit seenbenefit seen

ContraindicationsContraindications AbsoluteAbsolute

Immunosuppressed and immunocompromisedImmunosuppressed and immunocompromised Immediately after TURBT/TURP, gross Immediately after TURBT/TURP, gross

hematuria or traumatic foley (disrupted hematuria or traumatic foley (disrupted urothelium)urothelium)

Hx of BCG SepsisHx of BCG Sepsis

RelativeRelative Active UTIActive UTI Total incontinenceTotal incontinence Liver diseaseLiver disease Hx of TBHx of TB Poor performance status or advanced agePoor performance status or advanced age

BCG Toxicity TreatmentsBCG Toxicity Treatments

Moderate Moderate IrritativeIrritative Symptoms, hematuria, Symptoms, hematuria, afebrile (<48hrs) afebrile (<48hrs) Get urine cultureGet urine culture Anticholinergics, pyridium, analgesics & Anticholinergics, pyridium, analgesics &

NSAIDSNSAIDS

Severe Severe IrritativeIrritative Symptoms, Fevers, or Symptoms, Fevers, or >48hrs>48hrs Urine Culture, CXR, LFT’sUrine Culture, CXR, LFT’s ID ConsultID Consult

Isoniazid and rifampin until symptoms resolveIsoniazid and rifampin until symptoms resolve Dose reduction when instillations resumeDose reduction when instillations resume

BCG Toxicity TreatmentsBCG Toxicity TreatmentsSerious ComplicationsSerious Complications

Hemodynamic changes (BCG Hemodynamic changes (BCG Sepsis), high-grade fevers, allergic Sepsis), high-grade fevers, allergic reactions, solid organ involvement reactions, solid organ involvement with fevers & rigorswith fevers & rigors– Blood and Urine Cultures, CXR, LFT’sBlood and Urine Cultures, CXR, LFT’s– Steroids, antihistamines, broad-spectrum Steroids, antihistamines, broad-spectrum

antibioticsantibiotics– ID ConsultID Consult

Isoniazid, rifampin, ethambutol, for Isoniazid, rifampin, ethambutol, for 3-6 months3-6 months

ImmunotherapyImmunotherapyInterferon-2Interferon-2/Interferon-/Interferon-αα

Mechanism is via lymphocyte activation, Mechanism is via lymphocyte activation, cytokine release cytokine release inherent antiproliferative and antiangiogenic inherent antiproliferative and antiangiogenic

propertiesproperties Less effective than BCG or intravesical Less effective than BCG or intravesical

chemochemo Not effective at eradicating residual Not effective at eradicating residual

disease, preventing recurrence, or disease, preventing recurrence, or treating CIStreating CIS Has been studied as an adjunct to BCG in an Has been studied as an adjunct to BCG in an

effort to lower BCG doseeffort to lower BCG dose Failed to demonstrate equivalence.Failed to demonstrate equivalence.

Garlic and Mistletoe extracts as Garlic and Mistletoe extracts as immunogenicsimmunogenics

University of ChicagoUniversity of ChicagoBCG Treatment and Surveillance Protocol BCG Treatment and Surveillance Protocol

for ≥HGTafor ≥HGTa Initial TURBTInitial TURBT After 4 weeks, Re-TURBT (bc HG Ta and all T1 After 4 weeks, Re-TURBT (bc HG Ta and all T1

disease)disease) *After 6 weeks, BCG x 6 weeks (induction)*After 6 weeks, BCG x 6 weeks (induction) Cystoscopy surveillance at 3 month mark*Cystoscopy surveillance at 3 month mark* 3 Weeks of BCG3 Weeks of BCG Cystoscopy surveillance at 6 month mark*Cystoscopy surveillance at 6 month mark* 3 Weeks of BCG3 Weeks of BCG Cystoscopy surveillance at 9 month mark*Cystoscopy surveillance at 9 month mark* 3 Weeks of BCG3 Weeks of BCG Cystoscopy surveillance at 12 month mark*Cystoscopy surveillance at 12 month mark*

*from 1*from 1stst dose of BCG induction dose of BCG inductionAll in all, 1 year's worth of cancer treatmentAll in all, 1 year's worth of cancer treatment induction + maintenance + 4 surveillance induction + maintenance + 4 surveillance

cystoscopiescystoscopies

Intravesical Intravesical ChemotherapyChemotherapy

Mitomycin CMitomycin C An antibiotic derivative that inhibits An antibiotic derivative that inhibits

DNA synthesis via alkylationDNA synthesis via alkylation A “larger” moleculeA “larger” molecule• systemic absorption rare unless perforationsystemic absorption rare unless perforation

Reduces recurrence and progression, Reduces recurrence and progression, although inferior to BCG induction & although inferior to BCG induction & maintenancemaintenance

Attractive due to much less toxic than Attractive due to much less toxic than BCGBCG

20-40mg/20-40mL of sterile water20-40mg/20-40mL of sterile water

Palmar Palmar DesquamationDesquamation

MMC Chemical Cystitis

Intravesical Intravesical ChemotherapyChemotherapy

MMCMMC Some advocate dehydration + oral sodium-Some advocate dehydration + oral sodium-

bicarbinate days prior to administration to bicarbinate days prior to administration to reduce urinary degradation and increase reduce urinary degradation and increase efficacyefficacy

Side effects- most common site Side effects- most common site Skin rash- palmar desquamationSkin rash- palmar desquamation Irritative symptoms and chemical cystitis Irritative symptoms and chemical cystitis

(10%)(10%) Rarely, contracted bladderRarely, contracted bladder

MMC I + M proved superior to MMC MMC I + M proved superior to MMC Induction aloneInduction alone In both recurrence and progressionIn both recurrence and progression

MMC I + M proved inferior to BCG I + M in MMC I + M proved inferior to BCG I + M in all comersall comers

Intravesical ChemotherapyIntravesical ChemotherapyDoxorubicin, Valrubicin & EpirubicinDoxorubicin, Valrubicin & Epirubicin

DoxorubicinDoxorubicinInhibits topoisomerase II and thus inhibits protein Inhibits topoisomerase II and thus inhibits protein synthesissynthesis Shown to prevent recurrence but not progressionShown to prevent recurrence but not progression

ValrubicinValrubicinApproved for treatment of BCG refractory CIS who Approved for treatment of BCG refractory CIS who refuse or are unfit for radical cystectomy refuse or are unfit for radical cystectomy 20% complete response20% complete response

EpirubicinEpirubicinDecreases recurrence when compared to TUR aloneDecreases recurrence when compared to TUR alone Not FDA approved in USNot FDA approved in US

Intravesical ChemotherapyIntravesical ChemotherapyThiotepa & Others…Thiotepa & Others…

Only agent approved for treatment of papillary Only agent approved for treatment of papillary urothelial bladder cancerurothelial bladder cancer The original and cheapest intravesical agentThe original and cheapest intravesical agent

Alkylating agent that is >50% absorbedAlkylating agent that is >50% absorbed MyelosuppressionMyelosuppression

Gemcitabine & docetaxel intravesically currently Gemcitabine & docetaxel intravesically currently being investigatedbeing investigated

Radiation TherapyRadiation Therapy

• Has not been studied extensively in Has not been studied extensively in NMI Urothelial CaNMI Urothelial Ca

• Initial very good response, short Initial very good response, short termterm

• Not effective long term for Ta or CISNot effective long term for Ta or CIS– 90% recur in 5 years90% recur in 5 years

Clinical Follow-UpClinical Follow-Up

Patient History and GU PhysicalPatient History and GU Physical U/AU/A Cystoscopy Cystoscopy

esp 1esp 1stst 3mo post-TURBT cystoscopy 3mo post-TURBT cystoscopy Urine CytologyUrine Cytology Urinary Markers?Urinary Markers? Upper tract imaging…Upper tract imaging…

Early CystectomyEarly Cystectomy

• Should be considered in patients Should be considered in patients whowho

Micropapillary Variant!Micropapillary Variant!– Do not tolerate intravesical therapyDo not tolerate intravesical therapy– Failed attempts at disease control with Failed attempts at disease control with

TURBT +IVTTURBT +IVT

– Lesions not amenable to endoscopic Lesions not amenable to endoscopic resectionresection

– Failure of TURBT and intravesical Failure of TURBT and intravesical therapytherapy• Recurrence at higher grade and Recurrence at higher grade and

multifocalitymultifocality• Progression on intravesical therapy (Grade Progression on intravesical therapy (Grade

Progression)Progression)• Invasion into detrusor (T progression)Invasion into detrusor (T progression)• Especially in HGTa or CISEspecially in HGTa or CIS

Extravesical Imaging Extravesical Imaging SurveillanceSurveillance

Most patients undergo upper tract Most patients undergo upper tract imaging for initial hematuria workupimaging for initial hematuria workup

High grade or multiple tumors warrant High grade or multiple tumors warrant upper tract annual imaging surveillance upper tract annual imaging surveillance every 1-2 yearsevery 1-2 years

Changes in cytology warrant Changes in cytology warrant investigationinvestigation

If upper tract disease is discovered, If upper tract disease is discovered, mortality rate jumps to ~50% for all-mortality rate jumps to ~50% for all-comerscomers

Must individualize based on patient’s risk of Must individualize based on patient’s risk of recurrence and progression to extravesical recurrence and progression to extravesical sites.sites.

Upper tract surveillance for low risk disease Upper tract surveillance for low risk disease not requirednot required

Upper tract recurrence <0.9% in low Upper tract recurrence <0.9% in low grade Ta diseasegrade Ta disease

Secondary Prevention Secondary Prevention StrategiesStrategies

Goal is to reduce the risk of Goal is to reduce the risk of recurrence and progressionrecurrence and progression Minimize exposure to carcinogens and Minimize exposure to carcinogens and

smokingsmoking Increased fluid intakeIncreased fluid intake

Reduces concentration and dwell time of Reduces concentration and dwell time of carcinogenscarcinogens

Low-fat, low cholesterol dietLow-fat, low cholesterol diet Vitamin A and B6 have been Vitamin A and B6 have been

disappointingdisappointing High Dose MTV- advantage seen at 5 High Dose MTV- advantage seen at 5

yearsyears Oncovite championed by Don Lamm, MDOncovite championed by Don Lamm, MD Suppresses partially transformed cellsSuppresses partially transformed cells Hepatotoxic >40K IU per dayHepatotoxic >40K IU per day

Urine CytologyUrine Cytology Voided/Cystoscopically attained Voided/Cystoscopically attained

urine specimen is examined for urine specimen is examined for exfoliated cancer cellsexfoliated cancer cells

Less effective for LG tumors (30% Less effective for LG tumors (30% sensitivity)sensitivity) Well differentiated and normal cells Well differentiated and normal cells

retain their cohesive properties and are retain their cohesive properties and are less commonly shedless commonly shed

Sensitivity and specificity are quite Sensitivity and specificity are quite high for HG and CIS, although high for HG and CIS, although subjective (pathologist)subjective (pathologist)

Positive test is not an indication for Positive test is not an indication for treatment but does warrant upper treatment but does warrant upper and lower tract workup + TUR and lower tract workup + TUR prostate stripprostate strip

Urine CytologyUrine Cytology

Can be used to screen, evaluate, & Can be used to screen, evaluate, & follow-up high risk patientsfollow-up high risk patients

Can be used to monitor recurrence, Can be used to monitor recurrence, progression and response to progression and response to intravesical therapiesintravesical therapies

Gravity vs. barbotage specimensGravity vs. barbotage specimens Inform cytopathologist if specimen Inform cytopathologist if specimen

from bowelfrom bowel

Urine MarkersUrine Markers

May aid in diagnosis and May aid in diagnosis and surveillance of patients with NMIUCsurveillance of patients with NMIUC

Many commercially availableMany commercially available NMP-22NMP-22 BTA TRAKBTA TRAK ImmunoCytImmunoCyt Urovysion FISHUrovysion FISH

Under InvestigationUnder Investigation

Although radical cystectomy is beyond the Although radical cystectomy is beyond the scope of this talk…. There is data re: early scope of this talk…. There is data re: early cystectomy in…cystectomy in… high-risk, recurring and progressing patientshigh-risk, recurring and progressing patients those recurring at 3month post-TURBT those recurring at 3month post-TURBT

cystoscopycystoscopy Intravesical failuresIntravesical failures

HGT1 tumors are usually papillary but are HGT1 tumors are usually papillary but are the most understaged tumors in bladder the most understaged tumors in bladder cancercancer 40% are understaged at time of cystectomy40% are understaged at time of cystectomy

Only half of these are organ confined at time of Only half of these are organ confined at time of cystectomycystectomy

Long-Term InvestigationLong-Term Investigation Laser ablation therapy for known Laser ablation therapy for known

low-grade papillary tumorslow-grade papillary tumors Argon, KTP, Holmium, & Neodynium-YAGArgon, KTP, Holmium, & Neodynium-YAG In select lower and upper tract tumors with In select lower and upper tract tumors with

close surveillanceclose surveillance No obturator nerve stimulationNo obturator nerve stimulation Not appropriate for new lesions or initial Not appropriate for new lesions or initial

TURBTTURBT Collateral damageCollateral damage

Office FulgurationOffice Fulguration In low risk and recurrent LGTa papillary In low risk and recurrent LGTa papillary

tumors or papillomastumors or papillomas

FutureFutureFluorescent CystoscopyFluorescent Cystoscopy

5-aminolevulinic acid (5-ALA) 5-aminolevulinic acid (5-ALA) A precursor to heme biosynthesis is A precursor to heme biosynthesis is

instilled into the bladderinstilled into the bladder Taken up by neoplasmsTaken up by neoplasms Blue light excites the agent and can Blue light excites the agent and can

detect otherwise unseen CIS on detect otherwise unseen CIS on white lightwhite light

Many false + due to inflammatory Many false + due to inflammatory lesionslesions

Fluorescent CystoscopyFluorescent Cystoscopy

FutureFuture

Photodynamic TherapyPhotodynamic Therapy Reactive oxygen species have an Reactive oxygen species have an

antitumor effectantitumor effect Activates a photosensitizing agent in Activates a photosensitizing agent in

the urothelium delivered systemically or the urothelium delivered systemically or intravesicallyintravesically

Porfimer sodiumPorfimer sodium 5-ALA5-ALA

In addition to irritative symptoms, In addition to irritative symptoms, tissue sloughing, bladder tissue sloughing, bladder contracture, and VUR are well contracture, and VUR are well known side effectsknown side effects

FutureFuture

Molecular markers are being studied Molecular markers are being studied to predict recurrence, progression, to predict recurrence, progression, and response to therapyand response to therapy Flow cytometryFlow cytometry p53 and Rb in serum & urinep53 and Rb in serum & urine Proliferative indicesProliferative indices Urinary growth factorsUrinary growth factors Matrix metalloproteins (MMPs)Matrix metalloproteins (MMPs) Urinary Plasminogen ActivatorUrinary Plasminogen Activator

El FinEl Fin

References available upon request.References available upon request. Questions?Questions?

non-muscle invasive bladder urothelial carcinoma st. louis university hospital division of urology...

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