Non–Muscle-Invasive Non–Muscle-Invasive Bladder Cancer (Ta, Bladder Cancer (Ta,

T1, and CIS)T1, and CIS)

By By

Dr. Mohammed S Al-ShehriDr. Mohammed S Al-Shehri

► superficial bladder cancer, malignant urothelial superficial bladder cancer, malignant urothelial tumors that have not invaded the detrusor tumors that have not invaded the detrusor

► Patients with macroscopic (gross) hematuria Patients with macroscopic (gross) hematuria have reported rates of bladder cancer of 13% have reported rates of bladder cancer of 13% to 34.5%to 34.5%

► Microscopic hematuria is associated with a Microscopic hematuria is associated with a 0.5% to 10.5% rate of bladder cancer0.5% to 10.5% rate of bladder cancer

► cystoscopy and upper tract imaging are cystoscopy and upper tract imaging are indicated in patients with hematuria and/or indicated in patients with hematuria and/or unexplained irritative symptomsunexplained irritative symptoms

► Approximately 70% of bladder tumors are non–Approximately 70% of bladder tumors are non–muscle invasive at presentation. Of these, 70% muscle invasive at presentation. Of these, 70% present as stage Ta, 20% as T1, and 10% as CISpresent as stage Ta, 20% as T1, and 10% as CIS

► sessile morphology and/or the presence of necrosis sessile morphology and/or the presence of necrosis suggest high-grade disease likely to be invasive suggest high-grade disease likely to be invasive

STAGINGSTAGING

► Pathologic GradingPathologic Grading► A papilloma (grade 0)A papilloma (grade 0) is a papillary lesion with is a papillary lesion with

a fine fibrovascular core covered by normal a fine fibrovascular core covered by normal bladder mucosabladder mucosa

► Well-differentiated tumors( grade 1)Well-differentiated tumors( grade 1) papillary papillary urothelial tumors of low malignant potentialurothelial tumors of low malignant potential

► Moderately differentiated (low grade—old Moderately differentiated (low grade—old grade 2)grade 2) tumors tumors low-grade urothelial low-grade urothelial carcinomascarcinomas

► Poorly differentiated tumors ( grade 3 ),Poorly differentiated tumors ( grade 3 ), named named high-grade urothelial carcinomahigh-grade urothelial carcinoma

STAGINGSTAGING

► Pathologic StagingPathologic Staging

► The most important risk factor for The most important risk factor for progression is grade, not stageprogression is grade, not stage

► CIS was the second most important CIS was the second most important prognostic factor after gradeprognostic factor after grade

► Prognosis also correlates with tumor size, Prognosis also correlates with tumor size, multiplicity, papillary versus sessile multiplicity, papillary versus sessile configuration, presence or absence of configuration, presence or absence of lymphovascular invasion, and status of the lymphovascular invasion, and status of the remaining urotheliumremaining urothelium

► Low-grade Ta lesions recur at a rate of 50% to 70% Low-grade Ta lesions recur at a rate of 50% to 70% and progress in approximately 5% of cases and progress in approximately 5% of cases

► In contrast, high-grade T1 lesions recur in more In contrast, high-grade T1 lesions recur in more than 80% of cases and progress in 50% of patients than 80% of cases and progress in 50% of patients within 3 yearswithin 3 years

► CIS is occasionally mischaracterized as CIS is occasionally mischaracterized as “premalignant” but it is actually a flat, noninvasive “premalignant” but it is actually a flat, noninvasive UC that is high grade by definitionUC that is high grade by definition

► Between 40% and 83% of patients with CIS will Between 40% and 83% of patients with CIS will develop muscle invasion if untreated, especially if develop muscle invasion if untreated, especially if associated with papillary tumorsassociated with papillary tumors

ENDOSCOPIC SURGICAL ENDOSCOPIC SURGICAL MANAGEMENTMANAGEMENT

► Bimanual examination of the bladder should be Bimanual examination of the bladder should be performed under anesthesia before prepping and performed under anesthesia before prepping and drapingdraping

► Urinary cytology is obtained as a baseline and to Urinary cytology is obtained as a baseline and to establish the likelihood of high-grade diseaseestablish the likelihood of high-grade disease

► location, number, and nature of tumors is recordedlocation, number, and nature of tumors is recorded► Expert consensus is that patients with solitary or Expert consensus is that patients with solitary or

limited low-grade Ta lesions do not need imaging, limited low-grade Ta lesions do not need imaging, owing to the very low risk of extravesical diseaseowing to the very low risk of extravesical disease

► TUR of bladder tumor (TURBT) under regional or TUR of bladder tumor (TURBT) under regional or general anesthesia is the initial treatment for visible general anesthesia is the initial treatment for visible lesions and is performed both to remove all visible lesions and is performed both to remove all visible tumors and to provide specimens for pathologic tumors and to provide specimens for pathologic examination to determine stage and gradeexamination to determine stage and grade

► Resection is performed using a 30-degree lens Resection is performed using a 30-degree lens placed through a resectoscope sheath, because this placed through a resectoscope sheath, because this deflection allows visualization of the loop placed at deflection allows visualization of the loop placed at this locationthis location

► Continuous irrigation with the bladder filled only Continuous irrigation with the bladder filled only

enough to visualize its contents minimizes bladder enough to visualize its contents minimizes bladder wall movement and lessens thinning of the detrusor wall movement and lessens thinning of the detrusor through overdistention through overdistention

► Lifting the tumor edge away from detrusor lessens Lifting the tumor edge away from detrusor lessens the chance of perforation the chance of perforation

► Separately, send the tumor base to determine the Separately, send the tumor base to determine the presence of muscle invasionpresence of muscle invasion

► TUR has been performed in sterile water, because TUR has been performed in sterile water, because saline solutions conduct electricity and disperse saline solutions conduct electricity and disperse energy from the monopolar cautery cutting loopenergy from the monopolar cautery cutting loop

► bipolar electroresection is reported to allow bipolar electroresection is reported to allow transurethral resection in saline (TURIS) and to transurethral resection in saline (TURIS) and to minimize the risk of the obturator reflex that can minimize the risk of the obturator reflex that can predispose to bladder perforation predispose to bladder perforation

► The use of general anesthesia with muscleThe use of general anesthesia with muscle--paralyzing paralyzing agents also prevents obturator reflexagents also prevents obturator reflex

► Anterior wall tumors and tumors at the dome in Anterior wall tumors and tumors at the dome in patients with large bladders can be difficult to reach. patients with large bladders can be difficult to reach. Minimal bladder filling combined with manual Minimal bladder filling combined with manual compression of the lower abdominal wall to bring the compression of the lower abdominal wall to bring the tumor toward the resectoscope facilitates removal tumor toward the resectoscope facilitates removal

► Care must be taken during resection near the ureteral Care must be taken during resection near the ureteral orifice orifice

► Pure cutting current causes minimal scarring and may Pure cutting current causes minimal scarring and may be safely performed, including direct resection of the be safely performed, including direct resection of the orifice if necessary orifice if necessary

► hemostasis hemostasis ► If a tumor appears to be muscle invasive, biopsies If a tumor appears to be muscle invasive, biopsies

of the borders and base in order to establish of the borders and base in order to establish invasion may be performed in lieu of complete invasion may be performed in lieu of complete resectionresection

Complications of TURBTComplications of TURBT

►uncontrolled hematuria and clinical uncontrolled hematuria and clinical bladder perforation occur in less than 5% bladder perforation occur in less than 5% of cases of cases

►avoiding overdistention of the bladder, avoiding overdistention of the bladder, and using anesthetic paralysis during the and using anesthetic paralysis during the resection of significant lateral wall lesions resection of significant lateral wall lesions to lessen an obturator reflex response to lessen an obturator reflex response

► large, bulky tumors and those that appear to be large, bulky tumors and those that appear to be muscle invasive are often best resected in a muscle invasive are often best resected in a staged manner staged manner

►risk of tumor seeding appears to be risk of tumor seeding appears to be low low

►TUR syndrome from fluid absorption is TUR syndrome from fluid absorption is uncommon uncommon

►resection of the ureteral orifice may resection of the ureteral orifice may lead to obstructionlead to obstruction

Repeat TURBTRepeat TURBT

► Complete tumor removal is not always possible, Complete tumor removal is not always possible, whether due to excessive tumor volume, anatomic whether due to excessive tumor volume, anatomic inaccessibility, medical instability requiring premature inaccessibility, medical instability requiring premature cessation, or risk of perforation cessation, or risk of perforation

► Repeat TURBT is usually appropriate in the evaluation Repeat TURBT is usually appropriate in the evaluation of T1 tumors, because a repeat TUR can demonstrate of T1 tumors, because a repeat TUR can demonstrate worse prognostic findings in up to 25% of specimens worse prognostic findings in up to 25% of specimens

► This is especially likely if no muscle is identified on This is especially likely if no muscle is identified on initial pathology, which can occur in almost half of initial pathology, which can occur in almost half of casescases

► There is no consensus on timing of repeat TURBT, but There is no consensus on timing of repeat TURBT, but most authors recommend 1 to 4 weeks after the most authors recommend 1 to 4 weeks after the initial resection initial resection

The Role of “Random” or The Role of “Random” or Additional BiopsiesAdditional Biopsies

► Biopsies of any suspicious areas are an important Biopsies of any suspicious areas are an important part of a complete evaluatiopart of a complete evaluatio

► random biopsies to identify CIS in otherwise random biopsies to identify CIS in otherwise

normalnormal--appearing mucosa with positive cytology appearing mucosa with positive cytology

► indicated in the setting of multiple tumorsindicated in the setting of multiple tumors ► Prostatic urethral biopsy using the cutting loop may Prostatic urethral biopsy using the cutting loop may

be performed, especially if neobladder creation is be performed, especially if neobladder creation is anticipated for high-risk disease anticipated for high-risk disease

Perioperative Intravesical Perioperative Intravesical Therapy to Prevent Tumor Therapy to Prevent Tumor

ImplantationImplantation ► Mitomycin C Mitomycin C ((MMCMMC) ) appears to be the most appears to be the most

effective adjuvant intravesical chemotherapeutic effective adjuvant intravesical chemotherapeutic agent perioperatively agent perioperatively

► single dose administered within 6 hours lessens single dose administered within 6 hours lessens recurrence rates (50%)recurrence rates (50%)

► BCG can never be safely administered immediately BCG can never be safely administered immediately after, because the risk of bacterial sepsis and death after, because the risk of bacterial sepsis and death

is highis high ► Chemotherapy should be withheld in patients with Chemotherapy should be withheld in patients with

extensive resection or when there is concern about extensive resection or when there is concern about perforation perforation

►OfficeOffice--Based Endoscopic Based Endoscopic ManagementManagement

► Many patients with small Many patients with small ((<0.5 mL<0.5 mL) ) lowlow--grade grade

recurrences can be managed safely in the office recurrences can be managed safely in the office setting using diathermy or laser ablation under setting using diathermy or laser ablation under intravesical local anesthetic intravesical local anesthetic

► many small, lowmany small, low--grade tumors can be safely grade tumors can be safely observed until they exhibit significant growth observed until they exhibit significant growth due to the minimal risk of progression due to the minimal risk of progression

►Fluorescent CystoscopyFluorescent Cystoscopy ► Fluorescent cystoscopy with 5-ALA (5-Fluorescent cystoscopy with 5-ALA (5-

aminolevulinic acid ) derivatives improves the aminolevulinic acid ) derivatives improves the ability to visualize inconspicuous tumorsability to visualize inconspicuous tumors..

► When using this technology, both small papillary When using this technology, both small papillary tumors and almost one third more cases of CIS tumors and almost one third more cases of CIS overlooked by cystoscopy are identified overlooked by cystoscopy are identified

IMMUNOTHERAPYIMMUNOTHERAPY

► Intravesical immunotherapy results in a massive Intravesical immunotherapy results in a massive local immune response characterized by induced local immune response characterized by induced expression of cytokines in the urine and bladder expression of cytokines in the urine and bladder wall and by an influx of granulocytes and wall and by an influx of granulocytes and mononuclear cellsmononuclear cells

► The initial step appears to be direct binding to The initial step appears to be direct binding to

fibronectin within the bladder wall fibronectin within the bladder wall

► leading to direct stimulation of cellleading to direct stimulation of cell--based based immunologic response immunologic response

Bacillus CalmetteBacillus Calmette--GuérinGuérinBCGBCG

► BCG is an attenuated mycobacterium developed as BCG is an attenuated mycobacterium developed as a vaccine for tuberculosis that has demonstrated a vaccine for tuberculosis that has demonstrated antitumor activity in several different cancers antitumor activity in several different cancers

► The vaccine is reconstituted with 50 mL of saline The vaccine is reconstituted with 50 mL of saline and should be administered through a urethral and should be administered through a urethral catheter under gravity drainage catheter under gravity drainage

► Treatments are generally begun 2 to 4 weeks after Treatments are generally begun 2 to 4 weeks after tumor resection tumor resection

► After instillation, the patient should retain the After instillation, the patient should retain the solution for 2 hours solution for 2 hours

BCG Treatment of Carcinoma BCG Treatment of Carcinoma in Situ in Situ ((CISCIS))

► The American Urological Association (AUA) Guidelines The American Urological Association (AUA) Guidelines Panel supported BCG as the preferred initial treatment Panel supported BCG as the preferred initial treatment

option for CISoption for CIS ► The initial tumorThe initial tumor--free response rate is as high as 80% free response rate is as high as 80% ► Approximately 50% of patients experience a durable Approximately 50% of patients experience a durable

response for a median period of 4 years response for a median period of 4 years ► approximately 30% of patients remain free of tumor approximately 30% of patients remain free of tumor

progression or recurrence over a 10-year periodprogression or recurrence over a 10-year period► there was a 68% complete response rate to BCG and there was a 68% complete response rate to BCG and

a 49% complete response rate to chemotherapy a 49% complete response rate to chemotherapy

BCG Treatment of Residual BCG Treatment of Residual TumorTumor

► Intravesical BCG can effectively treat residual Intravesical BCG can effectively treat residual papillary lesions but should not be used as a papillary lesions but should not be used as a substitute for surgical resection substitute for surgical resection

► Carcinoma of the mucosa or the superficial ducts of Carcinoma of the mucosa or the superficial ducts of the prostate can be adequately treated by BCG with the prostate can be adequately treated by BCG with

a 50% tumora 50% tumor--free ratefree rate

BCG Prophylaxis to Prevent BCG Prophylaxis to Prevent RecurrenceRecurrence

► The efficacy of BCG after TURBT for highThe efficacy of BCG after TURBT for high--risk risk papillary disease has been demonstrated in several papillary disease has been demonstrated in several series of T1 lesions, with recurrence rates of 16% to series of T1 lesions, with recurrence rates of 16% to 40% and progression rates of 4.4% to 40%, a 40% and progression rates of 4.4% to 40%, a substantial improvement compared with TUR alone substantial improvement compared with TUR alone

Impact of BCG on Impact of BCG on ProgressionProgression

► Two separate metaTwo separate meta--analyses have reached the analyses have reached the conclusion that BCG reduces the risk of progression conclusion that BCG reduces the risk of progression by 27% by 27%

Determining Optimum BCG Determining Optimum BCG Treatment ScheduleTreatment Schedule

► several studies suggest that a 6-week several studies suggest that a 6-week induction course alone is insufficient to induction course alone is insufficient to obtain an optimal response in many patients obtain an optimal response in many patients

► The average additional response to a The average additional response to a second induction course is 25% in those second induction course is 25% in those patients treated for prophylaxis and 30% in patients treated for prophylaxis and 30% in CIS patients CIS patients

► additional courses of BCG to treat refractory additional courses of BCG to treat refractory patients after a second 6-week course are patients after a second 6-week course are accompanied by a significant risk of tumor accompanied by a significant risk of tumor progression in 20% to 50% of patients progression in 20% to 50% of patients

► 6-week induction course 6-week induction course ► followed by three weekly instillations at 3 and followed by three weekly instillations at 3 and

6 months and every 6 months there after for 3 6 months and every 6 months there after for 3 yearsyears

► Estimated median recurrence-free survival Estimated median recurrence-free survival was 76.8 months in the maintenance arm and was 76.8 months in the maintenance arm and 35.7 months in the control arm 35.7 months in the control arm

► 16% of patients tolerated the full dose16% of patients tolerated the full dose--schedule regimen schedule regimen

► Two thirds of the patients who stopped BCG Two thirds of the patients who stopped BCG due to side effects did so in the first 6 months due to side effects did so in the first 6 months

► Several investigators have evaluated the potential Several investigators have evaluated the potential for BCG dose reduction for BCG dose reduction

► In general, a decrease in toxicity with no statistical In general, a decrease in toxicity with no statistical difference in efficacy has been noted in small seriesdifference in efficacy has been noted in small series

► highhigh--grade tumors may respond better to full grade tumors may respond better to full

dosingdosing

Cleveland Clinic Approach to Cleveland Clinic Approach to Management of BCG ToxicityManagement of BCG Toxicity

► Grade 1Grade 1: : Moderate symptomsModerate symptoms < < 48 hr48 hr ► MildMild//moderate irritative voiding symptoms, mild moderate irritative voiding symptoms, mild

hematuria, fever < 38.5° Chematuria, fever < 38.5° C

AssessmentAssessment Possible urine culture to rule out bacterial urinary Possible urine culture to rule out bacterial urinary tract infection tract infection

Symptom ManagementSymptom Management

Anticholinergics, topical antispasmodics Anticholinergics, topical antispasmodics ((phenazopyridinephenazopyridine)), analgesics, nonsteroidal anti, analgesics, nonsteroidal anti--inflammatory drugs inflammatory drugs

► Grade 2Grade 2: : Severe symptoms andSevere symptoms and//oror > > 48 hr48 hr► Severe irritative voiding symptoms, hematuria, or symptoms Severe irritative voiding symptoms, hematuria, or symptoms

lasting > 48 hr lasting > 48 hr AssessmentAssessment All maneuvers for grade 1All maneuvers for grade 1 Urine culture, chest radiograph, liver function tests Urine culture, chest radiograph, liver function tests ManagementManagement ► I.D consultation with physician experienced in I.D consultation with physician experienced in

management of mycobacterial infectionsmanagement of mycobacterial infections//complicationscomplications► Consider dose reduction to one half to one third of dose Consider dose reduction to one half to one third of dose

when instillations resume when instillations resume ► Antimicrobial AgentsAntimicrobial Agents ► Isoniazid and rifampins, 300 mgIsoniazid and rifampins, 300 mg//day and 600 mgday and 600 mg//day, day,

orally until symptom resolution orally until symptom resolution

► Grade 3Grade 3: : Serious complications Serious complications ((hemodynamic changes, persistent highhemodynamic changes, persistent high--grade fever , grade fever ,

Allergic Reactions (joint pain, rash)Allergic Reactions (joint pain, rash) Perform all maneuvers described for grades 1 and 2, plus:Perform all maneuvers described for grades 1 and 2, plus:

Isoniazid, 300 mg/day, and rifampin, 600 mg/day, for 3 to 6 Isoniazid, 300 mg/day, and rifampin, 600 mg/day, for 3 to 6 months depending on response months depending on response

Solid Organ Involvement (epididymitis, liver, lung, kidney, Solid Organ Involvement (epididymitis, liver, lung, kidney, osteomyelitis, prostate)osteomyelitis, prostate)

Isoniazid, 300 mg/day, rifampin, 600 mg/day, ethambutol, Isoniazid, 300 mg/day, rifampin, 600 mg/day, ethambutol, 15 mg/kg/day single daily dose for 3 to 6 months15 mg/kg/day single daily dose for 3 to 6 months

BCG is almost uniformly resistant to pyrazinamide, so this BCG is almost uniformly resistant to pyrazinamide, so this drug has no role.drug has no role.

ConsiderConsider prednisone, 40 mg/day, when response is prednisone, 40 mg/day, when response is inadequate or for septic shock (inadequate or for septic shock (nevernever given without given without effective antibacterial therapy). effective antibacterial therapy).

Contraindications to BCG Contraindications to BCG TherapyTherapy

Absolute ContraindicationsAbsolute Contraindications

► Immunosuppressed and immunocompromised Immunosuppressed and immunocompromised patients patients

► Immediately after transurethral resection based on Immediately after transurethral resection based on the risk of intravasation and septic death the risk of intravasation and septic death

► Personal history of bacillus CalmettePersonal history of bacillus Calmette--Guérin Guérin ((BCGBCG) ) sepsis sepsis

► Gross hematuria Gross hematuria ((intravasation riskintravasation risk))► Traumatic catheterization Traumatic catheterization ((intravasation riskintravasation risk)) ► Total incontinence Total incontinence ((patient will not retain agentpatient will not retain agent))

Relative ContraindicationsRelative Contraindications ► Urinary tract infection Urinary tract infection ((intravasation riskintravasation risk))► Liver disease Liver disease ((precludes treatment with isoniazid if precludes treatment with isoniazid if

sepsis occurssepsis occurs))► Personal history of tuberculosisPersonal history of tuberculosis► Poor overall performance status Poor overall performance status ► Advanced age Advanced age

No or Insufficient Data on Potential Need for No or Insufficient Data on Potential Need for ContraindicationsContraindications

► Patients with prosthetic materials Patients with prosthetic materials ► Ureteral reflux Ureteral reflux ► Anti–tumor necrosis factor medications Anti–tumor necrosis factor medications

((theoretically predispose to BCG sepsistheoretically predispose to BCG sepsis))

InterferonInterferon

► Interferon as a solitary agent is more expensive and Interferon as a solitary agent is more expensive and less effective than BCG or intravesical chemotherapy less effective than BCG or intravesical chemotherapy in eradicating residual disease, preventing recurrence in eradicating residual disease, preventing recurrence of papillary disease, and treating CISof papillary disease, and treating CIS

► CIS responses from 5% at low doses CIS responses from 5% at low doses ((10 million units10 million units) ) to as high as 43% at high doses to as high as 43% at high doses ((100 million units100 million units))

► longlong--term efficacy for CIS is less than 15% term efficacy for CIS is less than 15% ► Several trials investigated the combination of BCG Several trials investigated the combination of BCG

and interferon and suggested the potential and interferon and suggested the potential superiority of the combination or the possibility of superiority of the combination or the possibility of decreasing the dosage of BCG, which may reduce decreasing the dosage of BCG, which may reduce side effects side effects

INTRAVESICAL INTRAVESICAL CHEMOTHERAPYCHEMOTHERAPY

►Comparisons between Intravesical Comparisons between Intravesical AgentsAgents

Mitomycin C Mitomycin C MMCMMC

► alkylating agent that inhibits DNA synthesisalkylating agent that inhibits DNA synthesis. . ► The drug is usually instilled weekly for 6 to 8 weeks The drug is usually instilled weekly for 6 to 8 weeks

at dose ranges from 20 to 60 mgat dose ranges from 20 to 60 mg► 7.67% of the patients in the BCG group and 9.44% 7.67% of the patients in the BCG group and 9.44%

of the patients in the MMC group developed tumor of the patients in the MMC group developed tumor progression Within median followprogression Within median follow--up of 26 months up of 26 months

► 38% reduction in tumor recurrence with MMC38% reduction in tumor recurrence with MMC► MMC a viable option for real risk of sepsisMMC a viable option for real risk of sepsis► For optimal effect , eliminating residual urine For optimal effect , eliminating residual urine

volume, overnight fasting, using sodium volume, overnight fasting, using sodium bicarbonate to reduce drug degradation, and bicarbonate to reduce drug degradation, and increasing concentration to 40 mg in 20 mL increasing concentration to 40 mg in 20 mL

Doxorubicin and Its Doxorubicin and Its DerivativesDerivatives

► anthracycline antibiotic that acts by binding DNA anthracycline antibiotic that acts by binding DNA base pairs, inhibiting topoisomerase II, and base pairs, inhibiting topoisomerase II, and inhibiting protein synthesis inhibiting protein synthesis

► doxorubicin demonstrated a 13% to 17% doxorubicin demonstrated a 13% to 17% improvement over TUR in preventing recurrence improvement over TUR in preventing recurrence but no advantage in preventing tumor progressionbut no advantage in preventing tumor progression

► The principal side effect is chemical cystitis, which The principal side effect is chemical cystitis, which

can occur in up to half of patientscan occur in up to half of patients

ThiotepaThiotepa

► It is an alkylating agent and is not cell cycle specificIt is an alkylating agent and is not cell cycle specific

► is the only chemotherapeutic agent approved by is the only chemotherapeutic agent approved by the FDA specifically for the intravesical treatment of the FDA specifically for the intravesical treatment of papillary bladder cancer papillary bladder cancer

► decrease tumor recurrence in 6 of 11 studies by up decrease tumor recurrence in 6 of 11 studies by up to 41%to 41% ( (mean decrease, 16%mean decrease, 16%).).

Novel AgentsNovel Agents

► Gemcitabine and the taxanes paclitaxel and Gemcitabine and the taxanes paclitaxel and docetaxel have demonstrated activity against docetaxel have demonstrated activity against metastatic bladder cancermetastatic bladder cancer

► Intravesical gemcitabine can be safely administered Intravesical gemcitabine can be safely administered

either weekly or twice weekly for six to eight either weekly or twice weekly for six to eight treatmentstreatments

► reduction of recurrence of 39% to 70%, including reduction of recurrence of 39% to 70%, including modest efficacy in heavily pretreated BCGmodest efficacy in heavily pretreated BCG--refractory patients refractory patients

Combination TherapyCombination Therapy

► Combining mechanisms of different agents is a Combining mechanisms of different agents is a logical and often successful approach to improve logical and often successful approach to improve response rates for systemic therapyresponse rates for systemic therapy. .

► However, studies have not identified clear benefit However, studies have not identified clear benefit to doing so in intravesical therapy to doing so in intravesical therapy

MANAGEMENT OF MANAGEMENT OF REFRACTORY DISEASEREFRACTORY DISEASE

► BCGBCG--refractoryrefractory ((nonimproving or worsening nonimproving or worsening disease despite BCGdisease despite BCG))

► BCGBCG--resistantresistant ((recurrence or persistence of lesser recurrence or persistence of lesser degree, stage, or grade after an initial course, degree, stage, or grade after an initial course, which then resolves with further BCGwhich then resolves with further BCG))

► BCGBCG--relapsingrelapsing ((recurrence after initial resolution recurrence after initial resolution with BCGwith BCG))

► BCGBCG--refractory patients in particular are an refractory patients in particular are an especially highespecially high--risk group and should be strongly risk group and should be strongly considered for immediate cystectomy if young and considered for immediate cystectomy if young and in generally good health in generally good health

► Declaring failure may take up to 6 months, because Declaring failure may take up to 6 months, because the response rate for patients with highthe response rate for patients with high--grade grade bladder cancer treated with BCG rose from 57% to bladder cancer treated with BCG rose from 57% to 80% between 3 and 6 months after therapy 80% between 3 and 6 months after therapy

► If the initial treatment was chemotherapy, a course If the initial treatment was chemotherapy, a course of BCG should be undertakenof BCG should be undertaken. . BCG has BCG has demonstrated superiority to chemotherapy in this demonstrated superiority to chemotherapy in this setting, as the latter will lead to approximately 20% setting, as the latter will lead to approximately 20% disease-free survivaldisease-free survival

► For patients who have failed BCG, a second course For patients who have failed BCG, a second course still gives a 30% to 50% response still gives a 30% to 50% response

► Further courses of BCG or chemotherapy beyond Further courses of BCG or chemotherapy beyond two are not recommended routinely, as they will fail two are not recommended routinely, as they will fail 80% of the time 80% of the time

The Role of “Early” CystectomyThe Role of “Early” Cystectomy

► Early Early ((3-month3-month) ) failure for T1 tumors after BCG is failure for T1 tumors after BCG is associated with an 82% progression rate, compared associated with an 82% progression rate, compared with a 25% progression rate in patients who do not fail with a 25% progression rate in patients who do not fail at 3 months at 3 months

► Each occurrence of T1 tumors is associated with a 5% Each occurrence of T1 tumors is associated with a 5% to 10% chance of metastasisto 10% chance of metastasis

► patients who undergo immediate cystectomy for patients who undergo immediate cystectomy for pathologic T1 tumors have accurate pathologic staging pathologic T1 tumors have accurate pathologic staging in addition to a 10-year diseasein addition to a 10-year disease--free survival of 92%free survival of 92%

► cystectomy was recommended for their patients with cystectomy was recommended for their patients with CIS refractory to two courses of intravesical BCG CIS refractory to two courses of intravesical BCG

Indecation of radical Indecation of radical cystectomycystectomy

► patients with non–muscle invasive bladder cancers patients with non–muscle invasive bladder cancers that are high grade and invading deeply into lamina that are high grade and invading deeply into lamina propria (T1 high grade)propria (T1 high grade)

► exhibit lymphovascular invasionexhibit lymphovascular invasion► are associated with diffuse CISare associated with diffuse CIS► are in diverticulaare in diverticula► substantially involve the distal ureters or prostatic substantially involve the distal ureters or prostatic

urethraurethra► are refractory to initial therapyare refractory to initial therapy► too large or anatomically inaccessible to remove in too large or anatomically inaccessible to remove in

their entirety endoscopicallytheir entirety endoscopically► It also can be used in patients who understand the It also can be used in patients who understand the

risks and benefits of bladder preservation versus risks and benefits of bladder preservation versus cystectomy and request definitive therapy cystectomy and request definitive therapy

SURVEILLANCESURVEILLANCE

► Urine Cytology Urine Cytology

► 11% of grade 1, 31% of grade 2, and only 11% of grade 1, 31% of grade 2, and only 60% of grade 3 tumors60% of grade 3 tumors

► cytology has very high specificity but has cytology has very high specificity but has

low sensitivity for both highlow sensitivity for both high--grade and lowgrade and low--grade tumors, including CIS in recently grade tumors, including CIS in recently published reports published reports

SURVEILLANCESURVEILLANCE

► Tumor MarkersTumor Markers

► Most of these have had adequate sensitivity but Most of these have had adequate sensitivity but poor specificity, resulting in substantial falsepoor specificity, resulting in substantial false--positive readings positive readings

Surveillance StrategiesSurveillance Strategies

Secondary Prevention Secondary Prevention StrategiesStrategies

► Unlike primary prevention, secondary prevention Unlike primary prevention, secondary prevention seeks to prevent recurrent tumors in patients who seeks to prevent recurrent tumors in patients who already carry a diagnosis of a specific canceralready carry a diagnosis of a specific cancer..

► Smoking cessation, increased fluid intake, and a Smoking cessation, increased fluid intake, and a lowlow--fat diet may all reduce the risk of recurrence fat diet may all reduce the risk of recurrence

► vitamin A have antioxidant and immunostimulatory vitamin A have antioxidant and immunostimulatory propertiesproperties

► The most promising data for secondary The most promising data for secondary chemoprevention of UC relate to the use of high chemoprevention of UC relate to the use of high doses of multivitamins doses of multivitamins

Thank you Thank you