CME INFORMATION Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

Projects In Knowledge designates this educational activity for up to 1.5 hours in Category 1 credit toward the AMAPhysician’s Recognition Award. Each physician should claim only those hours of credit that were actually spent onthe educational activity.

PILOT TESTING Projects In Knowledge thanks Thomas P. Alderson, MD, for pilot testing this activity.

LEARNING OBJECTIVES After participating in this activity, physicians will be better able to:

• Describe the epidemiology, risk factors, grading/staging, and natural history of superficial bladder cancer

• Evaluate patients with hematuria for bladder cancer using cystoscopy, cytology, and other urine-based tests, and

radiologic imaging

• Formulate appropriate treatment strategies for superficial bladder cancer using surgical approaches and

intravesical chemotherapy or immunotherapy

• Consider the latest data regarding bacillus Calmette-Guérin (BCG) and interferon combination therapy when

formulating treatment plans for patients with superficial bladder cancer

• Select appropriate candidates for BCG/interferon combination therapy and BCG monotherapy

• Select appropriate doses and treatment intervals for intravesical immunotherapy regimens

• Prevent and manage toxicities associated with BCG and interferon

• Diagnose and treat recurrences of superficial bladder cancer following initial therapy

Estimated Time for Completion: 1.5 hours

FOR CME CREDIT To receive documentation of your participation, complete the following steps:1. Read this publication carefully.2. Complete the Posttest, selecting the most appropriate choice for each question.3. Complete the Evaluation.4. Send photocopies of the Posttest and Evaluation to Projects In Knowledge, One Harmon Plaza,

Secaucus, NJ 07094, or fax to (201) 617-7333 before October 1, 2003.If you complete these steps and score 70% or higher, Projects In Knowledge will mail you an acknowledgment of your participation in this activity. Please note: If you score lower than 70%, you will be given another chance to take the Posttest.

1590

Education Initiative in Urology

Diagnostic and Treatment Issuesin Superficial Bladder Cancer

Education

Initiative in

Urology

Projects In Knowledge gratefully acknowledges the unrestricted educational grant from

Copyright © 2002, Projects In Knowledge, Inc. All rights reserved. Projects In Knowledge • One Harmon Plaza • Secaucus, NJ • 07094-9709

Release Date: October 1, 2002. This independent CME activity is planned

and produced in accordance with the ACCME Essential Areas and

Policies. This enduring activity will be reviewed within 1 year of this date

and rereleased or its designation for CME credit will become invalid.

A CME monograph designed for urologists who treat patients with superficial bladder cancer

M o n o g r a p h

For more information about BCG/interferon in superficial bladder cancer, download thefour-part Tx Reporter series, FAQs on Intravesical Immunotherapy for Superficial BladderCancer at www.projectsinknowledge.com. This series provides personal insights fromMichael A. O’Donnell, MD, principal investigator of BCG/interferon trials, as he answersreal questions from physicians like you.

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Table of ContentsOverview of Superficial Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Diagnosis of Superficial Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Surgical Modalities in the Treatment of Bladder Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Intravesical Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Intravesical Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

CME Information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Back Cover

Education Initiative in Urology

Copyright © 2002, Projects In Knowledge, Inc. All rights reserved.

PROJECTS IN KNOWLEDGEOne Harmon Plaza • Secaucus, NJ 07094Tel.: (201) 617-9700www.projectsinknowledge.com

ChairIhor S. Sawczuk, MDChairman, Department of UrologyHackensack University Medical CenterHackensack, New JerseyProfessor of UrologyCollege of Physicians and Surgeons, Columbia University New York, New York

Muhammad S. Choudhury, MDProfessor and ChairmanDepartment of UrologyNew York Medical CollegeValhalla, New York

FacultyCary N. Robertson, MDAssociate ProfessorDivision of UrologyDepartment of SurgeryDuke University Medical CenterDurham, North Carolina

Craig D. Zippe, MDCo-Director, Prostate CenterUrological InstituteCleveland Clinic FoundationCleveland, Ohio

Disclosure PolicyThe Disclosure Policy of Projects In Knowledge requires that the faculty participating in a CME activity disclose to the audience any significantrelationship they may have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of theirpresentation, as well as any relationship with the commercial supporter of this activity.

This independent CME activity is supported by an unrestricted educational grant from Schering Oncology/Biotech.

This activity may include a discussion of therapies that are unapproved for use or investigational, ongoing research, or preliminary data.

The opinions expressed during this activity are those of the faculty and do not necessarily reflect those of the sponsor or the commercial supporter.

Muhammad S. Choudhury, MD, is on the speakers bureau of Schering-Plough Pharmaceuticals.

Cary N. Robertson, MD, is on the speakers bureau of AstraZeneca Pharmaceuticals LP, Merck & Co, Inc, and Schering.

Ihor S. Sawczuk, MD, is on the speakers bureau of Schering Oncology/Biotech.

Craig D. Zippe, MD, is on the speakers bureau of AstraZeneca Pharmaceuticals LP, Pfizer Inc, and TAP Pharmaceuticals Inc.

Overview of Superficial Bladder Cancer

Ihor S. Sawzcuk, MD

Epidemiology and Risk FactorsBladder cancer is the fourth most common malignancyin men and the tenth most common in women.1,2 TheAmerican Cancer Society estimates that in 2002, therewill be 56,500 new cases of bladder cancer, of which73% (41,500) will be in men. In addition, bladder cancerwill cause an estimated 12,600 deaths in the UnitedStates in 2002.1 Lifetime risk varies by gender and race,such that white men have the highest risk (2.8%) andblack women the lowest (0.6%).3 Incidence is higher inthe Northeast United States than in the West, which isnot accounted for by differences in smoking, diet, orother lifestyle factors.4

Cigarette smoking is currently the single most importantrisk factor contributing to the development of bladdercancer. Risk of bladder cancer increases two- to fourfoldamong smokers, and declines, but does not return tobaseline, on smoking cessation. Other risk factors includeexposure to environmental carcinogens (eg, aromaticamines), chemotherapy with cyclophosphamide, andpelvic radiation. Occupations with the greatest risk ofexposure include textile workers, dye workers, tire andrubber workers, leather workers, bootblacks, painters,truck drivers, drill press operators, chemical workers,petroleum workers, and hairdressers. Fluid consumptionmay be an important modifiable risk factor, as onereport found that men who drink at least six cups ofwater a day cut their risk of bladder cancer in half,compared with men who drink less than one cup a day.5

PathologyIn the United States, transitional cell carcinoma (TCC)accounts for over 90% of bladder cancer. Of these, 70%are “superficial” (non–muscle-invasive) cancers. Super-ficial TCC has a high rate of recurrence (50%–70%) andmay progress to invasive disease, which is then asso-ciated with higher rates of morbidity and mortality.6

Squamous cell carcinoma (SCC) accounts for only 5% of bladder cancer cases in the United States, and it isusually associated with chronic cystitis resulting fromurinary calculi, long-term indwelling catheters, orbladder diverticula. Adenocarcinoma of the bladderaccounts for only 0.5% to 2% of bladder cancers and isusually of urachal origin.6

Grading and Staging of Bladder CancerThe American Joint Committee on Cancer TNM stagingof bladder cancer, as of 1998,7 is shown in Figure 1. Thefocus of this monograph is superficial bladder cancer,including:

• Ta lesions: papillary tumors confined to the mucosa,which account for about 70% of superficial TCCs.They are usually low grade, with low rates ofprogressive disease.6

• Carcinoma in situ (CIS or Tis): nonexophytic or “flat"lesions confined to the urothelium. These lesions,which are frequently multifocal, are often not visibleby cystoscopy, and can occur alone or in conjunctionwith papillary lesions. Tis lesions are, by definition,

high grade, and are associated with high recurrencerates, a high likelihood of invasion, and a substantialrisk of cause-specific death.6

• T1 lesions: papillary or nodular tumors that haveinvaded the lamina propria. These tumors are moreaggressive, with a greater likelihood of progressionthan Ta tumors. T1 tumors can be further subdividedinto T1a (tumors not involving the muscularismucosa) and T1b/T1c (tumors with deeper invasion to the muscularis mucosa or beyond).6

A number of different systems have been proposed for grading papillary tumors.8–11 Under the most recentgrading system, developed by the WHO and theInternational Society of Urological Pathology,10

urothelial neoplasms are grouped into the followingfour categories:

• Urothelial papillomas: discrete papillary growth witha central fibrovascular core lined by urothelium ofnormal thickness and cytology; no architectural orcytologic atypia

• Papillary urothelial neoplasm of low malignant potential (equivalent to WHO grade I8): orderly arrange-ment of cells within papillae, with minimal architec-tural or nuclear atypia, irrespective of cell thickness;lesions are generally thick with enlarged nuclei;mitoses are infrequent and limited to basal layer

• Papillary urothelial carcinoma, low grade (equivalentto WHO grade I8): overall orderly appearance withmoderately altered architectural/cytologic features;definite cytologic atypia; mitoses are infrequent,usually occur in lower half, and may be observed at any level of urothelium

• Papillary urothelial carcinoma, high grade (equivalentto WHO grades II and III8): totally disorderly appear-ance at low magnification; marked architectural andcytologic abnormalities; mitoses frequently seen at alllevels of urothelium

Natural HistoryImportant endpoints in the natural history of bladdercancer include recurrence, progression, and survival.Recurrence is defined as appearance of tumors of thesame stage and grade as the primary tumor. Recurrenceis common (60%–90%), and while not life threatening,impacts on quality of life as a result of the need forfrequent surveillance and cystoscopy, as well as intra-vesical therapy. Progression is defined as the develop-ment of higher grade tumors with muscle invasion or

T1(subepithelial

connective tissue)

T2a(superficial

muscle)

Ta(urothelium)

T2b(deep muscle)

T3a(perivesicalfat—micro)

Bladder

BladderMuscle

BladderOutside(Serosa)

Basement Membrane

Mucosa

Tis

T4b(pelvic or

abdominal wall)

T4a(prostate, uterus,

or vagina)

(carcinoma in situ)

T3b(perivesicalfat—macro)

Figure 1. TNM Staging of Bladder Cancer7

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References

1. American Cancer Society (ACS). Cancer Facts & Figures 2002. Atlanta, Ga; 2002:4.

2. SEER Cancer Statistics Review, 1973–1999. Available at: http://seer.cancer.gov/csr/1973_1999/. Accessed June 25, 2002.

3. Schatte E, Gruenenfelder J, Fradet Y, Miles BJ. Epidemiology of bladder cancer. In: Volgelzang NJ, Scardino PT, Shipley WU, Coffey DS, eds.Comprehensive Textbook of Genitourinary Oncology. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000:282-288.

4. Michaud DS, Clinton SK, Rimm EB, Willett WC, Giovannucci E. Risk of bladder cancer by geographic region in a U.S. cohort of male healthprofessionals. Epidemiology. 2001;12:719-726.

5. Amling CL. Diagnosis and management of superficial bladder cancer. Curr Probl Cancer. 2001;25:219-278.

6. Michaud DS, Spiegelman D, Clinton SK, et al. Fluid intake and the risk of bladder cancer in men. N Engl J Med. 1999;340:1390-1397.

7. American Joint Committee on Cancer, American Cancer Society. Manual for Staging of Cancer. 5th ed. Beahrs OH, Henson DE, Hutter RVP,Kennedy BJ, eds. Philadelphia, Pa: JB Lippincott Co; 1998.

8. Mostofi FK, Sobin LH, Torloni H. Histological typing of urinary bladder tumours. International Classification of tumours. No. 10. Geneva,Switzerland: World Health Organization; 1973.

9. Murphy WM, Beckwith JB, Farrow GM. Tumours of the kidney, bladder, and related urinary structures. Fasicle 11 of Atlas of Tumour Pathology.3rd ed. Washington, DC: Armed Forces Institute of Pathology; 1994.

10. Epstein JI, Amin MB, Reuter VR, Mostofi FK. The World Health Organization/International Society of Urological Pathology consensus classificationof urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol. 1998;22:1435-1448.

11. Mostofi FK, Davis CJ, Sesterhenn IA, Sobin LH. Histological Typing of Urinary Bladder Tumors. 2nd ed. Heidelburg, Germany: Springer Verlag;1998.

12. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, Palou J, Algaba F, Vicente-Rodriguez J. Primary superficial bladder cancer risk groupsaccording to progression, mortality, and recurrence. J Urol. 2000;164(pt 1):680-684.

13. Brausi M. Recent results of EORTC-GU group protocols in superficial bladder cancer: application of clinical trials to the patient care. UroOncology.2001;1:297-300.

14. Ick K, Schultz M, Stout P, Fan K. Significance of p53 overexpression in urinary bladder transitional cell carcinoma in situ before and after bacillusCalmette-Guérin treatment. Urology. 1997;49:541-547.

metastatic disease, and is associated with an increasedrisk of death. Survival, both progression-free andoverall, is the most important endpoint to consider inthe natural history and in clinical trials of variousinterventions for bladder cancer.6

Superficial bladder cancer comprises a heterogeneousgroup of tumors with varying natural histories. Prog-nostic factors that predict recurrence or progressioninclude stage, grade, presence of CIS, tumor size >5 cm,multiple (>3) tumors, tumor structure (papillary orsessile), age >50 years, and male gender. Of these, themost important are disease stage, grade, and number oftumors, which have been used to stratify patients intolow-, intermediate-, and high-risk groups with definedrisks of progression, mortality, and recurrence (Table 1).12

Stratification of patients into risk groups can potentiallyinfluence the development of risk-group based treatment.13

The accumulation of multiple genetic defects over timeis related to the severity of disease. Loss of chromosome5q is associated with dysplasia and often precedesinvasion of the lamina propria. Subsequent loss ofchromosomes 11p and 17p, as well as mutations in p53,are associated with muscle and lymphatic invasion,which can lead to systemic metastasis. Positive p53staining following BCG may also be predictive of pooroutcome.14 The number of genetic defects is more

relevant in terms of progression to metastasis than isthe order in which these defects appear.

ConclusionUrinary bladder cancer is a common malignancy in theUnited States, accounting for considerable morbidity andmortality, particularly among men. Cigarette smoking isthe most common risk factor. TCC accounts for over 90%of bladder cancer cases, of which 70% are superficial.Superficial TCC has a high rate of recurrence (50%–70%)and may progress to invasive disease, which is associatedwith higher rates of morbidity and mortality. Patients atgreatest risk for recurrence, progression, and mortalityinclude those with T1 tumors (especially if high-grade ormultiple tumors), high-grade Ta tumors, or CIS.

Table 1. Primary Superficial Bladder Cancer Risk Groups.12

Low Risk• Grade I, stage Ta disease• Single grade I, stage T1 tumorRecurrence 37%, progression 0%, mortality 0%

Intermediate Risk• Multiple grade I, stage T1 tumors• Grade II, stage Ta disease• Single grade II, stage T1 tumorRecurrence 45%, progression 1.8%, mortality 0.73%

High Risk• Multiple grade II, stage T1 tumors• Grade III, stage Ta or T1 disease• Carcinoma in situRecurrence 54%, progression 15%, mortality 9.5%

Diagnosis of Superficial Bladder Cancer

Craig D. Zippe, MD

Hematuria is the most common sign of bladder cancer,with about 80% of transitional cell carcinomas (TCCs)being diagnosed with either gross or microscopichematuria. Some patients, particularly those withcarcinoma in situ (CIS), will have symptoms of bladderirritability, including urinary frequency, urgency, anddysuria.1 Patients with hematuria and those withpersistent symptoms should receive a thoroughevaluation for bladder cancer.

Determining the Clinical Significance of HematuriaAlthough the majority of patients with bladder cancerhave hematuria, most patients with hematuria will nothave bladder cancer. About 15% with gross painlesshematuria will have bladder cancer,2 and 2% to 22%with microscopic hematuria will have a malignancy.3

Hematuria is a common sign of many benign condi-tions, including urinary tract stones and inflammatorydisorders. Hematuria may also be a predictor of bladdercancer, preceding diagnosis by as much as 5 to 6 years.4

Evaluation for bladder cancer is warranted if more thanthree to five red blood cells per high-power field is a

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persistent finding on microscopic evaluation. A bladdercancer workup is indicated for any hematuria, unless analternate cause of hematuria is clearly present (eg, cystitisin a young woman, known glomerulopathy).1 In evalu-ating patients with hematuria, it is necessary to assess theentire urinary tract. Because no single imaging techniquereliably detects most bladder cancers, multiple diagnostictechniques are needed (eg, upper tract imaging, cysto-scopy, cytology). Figure 1 summarizes the AmericanUrological Association’s Best Practice Policy Recom-mendations regarding evaluation of asymptomaticmicroscopic hematuria.5

CystoscopyCystoscopy is the gold standard for diagnosis of bladdercancer since it allows complete visualization of theurethral and bladder mucosa. Lesions visualized duringcystoscopy are biopsied and/or resected. Disadvantagesof rigid cystoscopy include its invasiveness, requirementfor anesthesia, and postoperative discomfort. With fiber-optic flexible instruments, outpatient cystoscopy withminimal patient discomfort using topical intraurethralanesthesia can be performed. The standard schedule forcystoscopic surveillance (ie, every 3–4 months) has notbeen clinically validated.

Cystoscopy is 73% sensitive and 51% specific in diag-nosing bladder cancer. Investigational studies havesuggested that sensitivity can be improved to 97% withintravesical instillation of 5-aminolevulinic acid, whichinduces porphyrin fluorescence, prior to cystoscopy, anduse of a violet light from a krypton ion laser (wave-length 406.7 nm).6

CytologyUrine cytology is a noninvasive, tumor-specificmarker test used as an adjunct to cystoscopy. Apositive urine cytology is highly predictive of TCC,even in patients with normal cystoscopy findings,because malignant cells may appear in the urinebefore lesions become visible. The major role of urinecytology is in detecting high-grade tumors and CIS,the latter of which is often difficult to visualizecystoscopically.

Voided urine cytology has a sensitivity of 35% to 40%and a specificity of 90% to 95%.7 Sensitivity can beimproved when three voided specimens are obtained on 3 separate days. Urine cytology is most accurate inhigh-grade tumors, but has poor sensitivity in detectinglow-grade tumors, the cells of which more closelyresemble normal urothelium. It is most helpful indiagnosis and follow-up of CIS or high-grade T1 or Ta tumors.

Radiologic ImagingIntravenous pyelography (IVP) with or without con-comitant retrograde pyelography outlines the upperurinary tract. It is less sensitive in the bladder. Malig-nant disease should be suspected if radiolucent fillingdefects are observed in the calyces, renal pelvis, ureter,or bladder, or if unexplained hydronephrosis or non-function is present.1

Ultrasonography detects and determines the nature of arenal mass, and identifies upper urinary tract stones orhydronephrosis, but is inadequate for detecting fillingdefects consistent with TCC in the urothelium.1

CT may be useful in the initial evaluation of hematuria,being more sensitive than IVP for detecting small renalmasses, small urinary calculi (on noncontrast images),and nonurologic disease processes. The main disadvan-tage of CT is the inability to visualize small (<1 cm)urothelial lesions.1

Tumor MarkersCystoscopy, cytology, and urinalysis together do notdetect 100% of all bladder cancers. This, coupled with adesire to avoid the need for frequent cystoscopy todetect recurrences, has led to the investigation of new

Low Risk* High Risk

Upper Tract Imaging Complete Eval. (Upper TractImaging, Cytology, Cystoscopy)

Cytology

+, Atypical,or

Suspicious

Cystoscopy –

+ Treat

+ –

Urinalysis, Blood Pressure,Cytology at 6, 12, 24, 36 mo

Negative for3 Years:

No FurtherMonitoring

PersistentHematuria,

Hypertension,Proteinuria,GlomerularBleeding:

Evaluate forPrimary

Renal Disease

Gross Hematuria,AbnormalCytology,

Irritative VoidingSymptomsWithoutInfection:

RepeatComplete Eval.

Cystoscopy

+ Treat

Consider

Figure 1. Urologic Evaluation of Asymptomatic Microscopic Hematuria.Adapted from: Urology, Vol 57, Grossfeld GD, Wolf JS, Litwin MS, et al.Evaluation of asymptomatic microscopic hematuria in adults: the AmericanUrological Association best practice policy recommendations. Part II, pp 604-610, Copyright © 2001, with permission from Elsevier Science.

*Low risk = age <40 years, no smoking history, no history of chemicalexposure, no irritative voiding symptoms, no history of gross hematuria,and no history of urologic disorder or disease.

Table 1. Urine Tests for Detecting TCC.Test N Sensitivity Specificity

Cytology* 906 49% 96%NMP-22* 1031 71% 75%BTA* 911 44% 78%BTA stat®* 770 66% 70%BTA TRAK®* 216 72% 75%FDP* 322 79% 81%ImmunoCyt™* 264 86% 79%UroVysion™* 265 81% 96%Telomerase 156 71% 88%Quanticyt 341 52% 82%FISH 40 73% 100%Flow cytometry 206 59% 84%Lewis X antigen 260 80% 86%Hyaluronic acid 144 92% 93%Hyaluronidase 139 100% 89%

Adapted with permission from El-Gabry EA, Strup SE, Gomella LG. SuperficialBladder Cancer—Current Treatment Modalities and Future Directions. Parts I &II, AUA Update Series #20. Houston, Tex: American Urological Association,Office of Education; 2000. *FDA approved.

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• Tumor-related antigens– M344, 19A211, T138

• Proliferating antigens– Ki-67, PCNA

• Blood group antigens– ABH, Lewis

• Oncogenes– c-ras, mdm2, c-erbB2,

c-myc, c-jun

• Cellular adhesion molecules– E-cadherin, integrins

• DNA ploidy– ICM, LSCM, FISH, FLOW

• Growth factors– EGF, TGF, FGF, VEGF

• Angiogenesis and inhibitors– Thrombospondin-1,

angiostatin

• Cell cycle proteins– p53, pRB, cyclins, p21

• Apoptosis pathway– bcl-2/BAX ratio– Increase bcl-2: immortalized– Increase BAX: apoptosis

Table 2. Bladder Cancer Prognostic Biomarkers.10

urine-based bladder cancer tests and various tumormarkers to aid in the detection and monitoring ofbladder cancer.

Most urine-based bladder cancer tests have highersensitivity than cytology but low specificity (Table 1).8

High rates of false-positive results have limited their use as single markers. Their role in the detection andmonitoring of patients with bladder cancer is underevaluation. Several of these markers (indicated with an *) are currently approved by the US Food and Drug Administration (FDA).9,10

Identification of bladder cancer prognostic biomarkers isan area of active research. Some of the biomarkerscurrently under investigation are shown in Table 2.None of these has been approved by the FDA.10

Currently, no single tumor marker can replacecystoscopy. However, bladder cancer marker results may

still influence clinical practice. With a negative result, aless aggressive workup may be warranted, with eitherno cystoscopy, delayed cystoscopy, or cystoscopy underlocal anesthesia. A positive result might trigger a moreaggressive evaluation, including an earlier and morethorough cystoscopy under general anesthesia, andevaluation of the upper urinary tracts.

ConclusionPatients with persistent macro- or microscopichematuria should be evaluated for urothelial cancer.Multiple diagnostic modalities are necessary, includingcystoscopy, cytology, and urinalysis, which, together,still will not detect all cases of bladder cancer.Radiologic imaging (eg, IVP or CT) is necessary forevaluation of the upper urinary tract. Bladder cancerbiomarkers, although not a replacement for cytology,may serve in an adjuvant role.

References

1. Amling CL. Diagnosis and management of superficial bladder cancer. Curr Probl Cancer. 2001;25:219-278.

2. Turner AG, Hendry WF, Williams GB, Wallace DM. Haematuria diagnostic service. BMJ. 1977;2:29-31.

3. Carson CC III, Segura JW, Greene LF. Clinical importance of microhematuria. JAMA. 1979;241:149-150.

4. Friedman GD, Carroll PR, Cattolica EV, Hiatt RA. Can hematuria be a predictor as well as a symptom or sign of bladder cancer? Cancer EpidemiolBiomarkers Prev. 1996;5:993-996.

5. Grossfeld GD, Wolf JS Jr, Litwin MS, et al. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policyrecommendations. Am Fam Physician. 2001;63:1145-1154.

6. Kriegmair M, Baumgartner R, Knuchel R, Stepp H, Hofstadter F, Hofstetter A. Detection of early bladder cancer by 5-aminolevulinic acid inducedporphyrin fluorescence. J Urol. 1996;155:105-110.

7. Wiener HG, Vooijs GP, van’t Hof-Groontenboer B. Accuracy of urinary cytology in the diagnosis of primary and recurrent bladder cancer. Acta Cytol. 1993;37:163.

8. El-Gabry EA, Strup SE, Gomella LG. Superficial Bladder Cancer—Current Treatment Modalities and Future Directions. Parts I & II, AUA UpdateSeries #20. Houston, Tex: American Urological Association, Office of Education; 2000.

9. Pirtskalaishvili G, Getzenberg RH, Konety BR. Use of urine-based markers for detection and monitoring of bladder cancer. Tech Urol. 1999;5:179-184.

10. Burchardt M, Burchardt T, Shabsich A, De La Taille A, Benson MC, Sawczuk I. Current concepts in biomarker technology for bladder cancers. Clin Chem. 2000;46:595-605.

Surgical Modalities in the Treatmentof Bladder Cancer

Craig D. Zippe, MD

Transurethral resection (TUR) of all visible lesions is thestandard initial treatment of superficial bladder cancer.TUR removes the tumor and allows for pathologicanalysis of the resected specimen, establishing thediagnosis and providing important information aboutthe tumor grade and depth of bladder invasion. Othersurgical/nonpharmacologic treatment approachesinclude laser treatment and photodynamic therapy,which are therapeutic but less commonly used as initialtherapy because they do not supply grading and staginginformation. High risk for progressive disease, or failureof conservative approaches (in conjunction with intra-vesical pharmacologic therapy) should prompt consid-eration of cystectomy.

Transurethral ResectionDuring TUR, the primary lesion is completely resectedwith an electrosurgical loop and sent for pathologicanalysis. A separate sampling of the tumor basedetermines whether the tumor has been completelyremoved and whether there is invasive disease.

During TUR, areas of mucosa away from the primary

lesion should be biopsied and examined for carcinomain situ (CIS). Transurethral prostatic sampling should beperformed to rule out CIS of the prostatic urethra orducts, particularly for patients who may be candidatesfor orthotopic urinary diversion.

Laser and Photodynamic TherapyLaser therapy, most commonly with the neodymium:yttrium-aluminum-garnet laser with an end-firenoncontact fiber, can be used for tumor ablation, butdoes not allow for pathologic analysis. Thus, it is morecommonly reserved for treatment of recurrences so thatpathologic analysis can be performed on the initialtumor. Advantages compared with TUR include minimalbleeding, use of flexible cystoscopes, and less post-operative bladder irritation.

Photodynamic therapy uses a photosensitizer (a hematoporphyrin preparation) to enhance thephotosensitization of cancerous cells to subsequentadministration of light therapy. The photosensitizingdrug can be instilled intravesically before lightadministration. The whole bladder is illuminated for12 to 20 minutes via laser light with an optical fiberpassed through a standard cystoscope, with the patient under general or modified local anesthesia.1

Photodynamic therapy’s most common use is forpatients who do not respond to intravesical therapy. It is more effective for small than for large tumors.

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Is TUR Enough?Recurrence of bladder cancer following TUR isextremely common (60%–70%), and 20% to 30% of recurrent tumors progress to higher stage or gradedisease.2 As a result, use of induction and maintenanceintravesical therapies following TUR is now commonclinical practice for many patients. The goals of intra-vesical therapy are to eradicate existing disease and toprevent recurrence and sometimes progression, whilesparing the bladder.

Patients with small, solitary, well-differentiated Tatumors have a low risk of recurrence following TUR.Thus, intravesical therapy may be unnecessary in thispopulation. However, superficial bladder cancer patientswith multiple tumor recurrences or a recurrence within3 to 6 months of resection, lamina propria invasion,multifocal or high-grade disease, T1 tumor of anygrade, a large (>5 cm) solid tumor, CIS, or a positivecytology after TUR (in the presence of a negativecomplete work-up for upper urinary tract disease) areall candidates for induction and maintenanceintravesical therapy. Intravesical therapies will bediscussed in detail in subsequent sections of thismonograph.

CystectomyAlthough bladder preservation is clearly preferable tocystectomy, this should not override patient survivaland curative potential. Cystectomy is associated withexcellent recurrence-free overall survival rates (median10.2 years in those with accurate preoperative staging).3

Following treatment with intravesical immunotherapy,cystectomy should be recommended for patients withincreasing grade and/or stage, abnormal p53, high-grade disease, CIS, or lamina propria-invasive transi-tional cell carcinoma.

In patients who are at high risk of progression,metastases, and death (eg, those with muscle-invasivedisease), radical cystectomy may be an option as initialtherapy. Concerns about clinical understaging provideanother rationale for early cystectomy. Clinicalunderstaging occurs in 34% to 62% of cases4 and isassociated with worse cancer-specific survival rates.5

Historically, urinary tract reconstruction after radicalcystectomy entailed use of the ileum as a urinaryconduit and urostomy, which required an externalurine-collecting device. The social impact and effects onquality of life made this an unappealing option formany patients. Subsequent options allowed for use ofthe small intestine to make a continent cutaneousreservoir, which could be drained using intermittentcatheterization. The newest surgical technique(orthotopic neobladder) allows connection of the smallbowel pouch to the urethra, eliminating the need forexternal appliances. Orthotopic diversion is associatedwith complication rates similar to those of standard ilealconduit urinary diversion.4 These options have been metwith greater patient satisfaction, and lessened the socialimpact and reduced the negative effects of cystectomyon quality of life.

ConclusionTUR remains the standard initial treatment for bladdercancer, usually in conjunction with intravesical pharma-cologic therapy in all but the lowest-risk patients. TURhas the advantage of providing grading and staging aswell as pathologic information. Laser and phototherapyare usually reserved for treatment of recurrences or forpatients who have failed intravesical therapy. Cystectomyis recommended as initial therapy for high-risk patientsand for those with a high risk of progressive disease afterfailure of more conservative options.

References

1. Shackley DC, Briggs C, Gilhooley A, et al. Photodynamic therapy for superficial bladder cancer under local anaesthetic. BJU Int. 2002;89:665-670.

2. Amling CL. Diagnosis and management of superficial bladder cancer. Curr Probl Cancer. 2001;25:219-278.

3. Freeman JA, Esrig D, Stein JP, et al. Radical cystectomy for high risk patients with superficial bladder cancer in the era of orthotopic urinaryreconstruction. Cancer. 1995;76:833-839.

4. Stein JP. Indications for early cystectomy. Semin Urol Oncol. 2000;18:289-295.

5. Amling CL, Thrasher JB, Frazier HA, et al. Radical cystectomy for stages Ta, Tis, and T1 transitional cell carcinoma of the bladder. J Urol.1994;151:31-35.

Intravesical Chemotherapy

Muhammad S. Choudhury, MD

Commonly used intravesical chemotherapy agentsinclude thiotepa, mitomycin C, and doxorubicin (Table 1). However, use of intravesical chemotherapyfollowing transurethral resection (TUR) is controversial,with conflicting data regarding net effect on the rate ofrecurrence or risk of progression in patients withsuperficial bladder cancer. The one exception may beimmediate post-TUR administration of mitomycin C,which was recently found to significantly reducerecurrence compared with later administration.

Impact on Recurrence and Progression RatesTable 2 shows the minimal net benefit of intravesicalchemotherapy on recurrence and progression rates, asdetermined by a review of 22 prospective, randomized,controlled trials involving nearly 4000 patients.1

Prophylactic adjuvant chemotherapy reduced the rate of recurrence by only 14% overall. Although 13 trialsreported a statistically significant decrease in tumorrecurrence with varying durations of follow-up, long-term studies have shown that adjuvant intravesicalchemotherapy does not decrease the risk of recurrencecompared with TUR alone. Among nine prospective,randomized, controlled trials that reported progressiondata, none demonstrated a significant decrease in therate of progression among patients treated with adju-vant intravesical chemotherapy.1 Among 1039 patientstreated with thiotepa, mitomycin C, or doxorubicin,there was no net improvement in the rate of progres-sion. Overall, among 2011 randomized patients,progression occurred in 7.5% of patients treated withintravesical chemotherapy versus 6.9% of patientstreated with surgery alone.

Similar results were reported from a meta-analysis offour European Organization for the Research andTreatment of Cancer (EORTC) and two Medical Research

References

1. Lamm DL, Riggs DR, Traynelis CL, et al. Apparent failure of current intravesical chemotherapy prophylaxis to influence the long-term course ofsuperficial transitional cell carcinoma of the bladder. J Urol. 1995;153:1444-1450.

2. Pawinski A, Sylvester R, Kurth KH, et al. A combined analysis of European Organization for Research and Treatment of Cancer, and MedicalResearch Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. J Urol. 1996;156:1934-1940.

3. Huncharek M, McGarry R, Kupelnick B. Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinomaof the bladder: results of a meta-analysis. Anticancer Res. 2001;21:765-769.

4. Kaasinen E, Rintala E, Hellström P, et al. The significance of perioperative mitomycin C instillation in frequently recurrent superficial bladder carci-noma [abstract 665]. J Urol. 2000;149:1293.

5. Amling CL. Diagnosis and management of superficial bladder cancer. Curr Probl Cancer. 2001;25:219-278.

6. Valstar [package insert]. Rochester, NY: Medeva Pharmaceuticals, Inc; 2001.

Council (MRC) phase III randomized trials that enrolledpatients with primary or recurrent stage Ta or T1transitional cell carcinoma.2 The majority of patientsenrolled in these trials were previously untreated andhad solitary primary tumors. Only a small proportion of patients had high-grade disease (12% grade 3),multifocal disease (28%), or recurrent tumors (18%).Thus, the risk of recurrence was fairly low. Among1629 patients treated with intravesical chemotherapy,53% remained disease free at 10 years compared with47% of 906 patients treated with TUR only. Theseresults support the conclusion that prophylacticadjuvant intravesical chemotherapy produces only amarginal improvement in the rate of recurrence inpatients with superficial bladder cancer.

In contrast to these reports, a recent meta-analysis byHuncharek et al3 found that intravesical chemotherapyhas “a major impact on decreasing the chance ofrecurrence of recurrent superficial bladder cancer." Thisreview of eight randomized trials concluded that theodds ratios for recurrence were 0.62, 0.46, and 0.35with adjuvant chemotherapy versus TUR alone at years1, 2, and 3, respectively, representing a 38% reductionat 1 year and up to a 70% reduction at 3 years. The 2-and 3-year data were found to be heterogeneousaccording to drug type, with doxorubicin having theleast impact on rate of recurrence.

Mitomycin CImmediate administration of mitomycin C in theperioperative period following TUR may reducerecurrence rates. In an analysis of 205 patients withfrequently recurrent stage Ta or T1 tumors from theFinnbladder IV study, rates of recurrence-free survivalat 2 years were significantly improved when mitomycin Cwas administered the day of surgery: 63% versus 44%for patients who received the first dose 1 or more daysafter surgery (P = .0006).4 Mitomycin should be admin-istered immediately, or within 2 hours of completion ofTUR, as long as there is no significant bleeding orsuspicion of bladder perforation. It is given via a three-way Foley catheter, which is clamped for 1 hour whilethe patient’s intravenous fluids are reduced. Thereafter,the bladder is allowed to drain by gravity and is flushedwith 1 L of briskly flowing sterile water or saline. TheFoley catheter may then be removed. Variables such aslow urine pH, high urine output, and incompleteemptying may impact on mitomycin response rates.

ConclusionOverall net benefit of intravesical chemotherapy is small,and these agents are associated with considerable toxic-ity. Thus, use of intravesical chemotherapy is usuallyreserved for patients who are not candidates for immuno-therapy, or in whom immunotherapy has failed. Periop-erative mitomycin C is a novel option in reducing recurrences.

Table 1. Intravesical Chemotherapy Agents.5,6

ChemotherapyAgent Recommended Dose* Side Effects

Thiotepa 30 mg diluted in Leukopenia/30 mL water, given thrombocytopenia,weekly x 6 weeks, then irritative voidingmonthly for up to 1 year symptoms; treatment-

related deaths havebeen reported

Doxorubicin 30–100 mg at a Chemical cystitis, allergicconcentration of 1 mg/mL. reactions, GI side effects,Instillation schedules vary irritative bladderfrom weekly to every symptoms, fever,3 weeks; maintenance malaisetherapy common but nodemonstrated benefit

Mitomycin C 20–60 mg at a concentration Leukopenia/of 0.5 to 2 mg/mL, given thrombocytopenia,weekly x 8 weeks, then chemical cystitis, allergicmonthly for up to 1 year reactions/delayed

hypersensitivity reaction

Valrubicin 800 mg (20 mL) in 55 mL Irritative bladder(for BCG- saline given weekly x symptomsrefractory CIS) 6 weeks

*Following intravesical administration, these agents should be retained in thebladder for 1–2 hours. BCG = bacillus Calmette-Guérin; CIS = carcinoma in situ.

Adapted by permission of Lippincott Williams and Wilkins from Lamm DL, RiggsDR, Traynelis CL, et al. Apparent failure of current intravesical chemotherapyprophylaxis to influence the long-term course of superficial transitional cellcarcinoma of the bladder. J Urol. 1995;153:1444-1450.

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Table 2. Intravesical Chemotherapy After TUR: Net Effect on Recurrence and Progression Rates.

Recurrence

No. of Rate (%) NetAgent Studies Patients Control Treatment Benefit (%)

Effect on Recurrence RatesThiotepa 9 1130 61 49 12Mitomycin C 6 1157 53 44 9Doxorubicin 5 1389 53 38 15Overall* 22 3899 54 40 14

Effect on Progression RatesThiotepa 3 314 6 5 1Mitomycin C 3 336 8 4 4Doxorubicin 3 389 13 15 -2Overall* 9 1039 9 8 1

*Includes 2 additional trials on ethoglucid and epirubicin, not shown.

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Intravesical Immunotherapy

Muhammad S. Choudhury, MD, and Cary N. Robertson, MD

Bacillus Calmette-Guérin (BCG) is considered the goldstandard for initial treatment of superficial bladdercancer following transurethral resection (TUR). Incontrast to the modest benefits of chemotherapy, BCG ishighly effective. However, it is associated with dose-limiting toxicity, and the majority of patients treatedwith BCG eventually experience disease recurrence orprogression. Recent evidence suggests that combiningBCG with intravesical interferon may produce syner-gistic efficacy without increasing toxicity. Moreover,combination therapy may allow lower doses of BCG to be used in BCG-sensitized patients without compro-mising overall response.

BCG MonotherapyBCG is a live, attenuated mycobacteria. Therefore,certain measures and precautions must be taken tomaximize efficacy and minimize complications. BCGshould not be administered within 10 to 14 days of anyinvasive procedure (including TUR and biopsy), whichpotentially provides a means for BCG entry into thebloodstream. Patients should be instructed to avoid fluidintake for 4 hours prior to instillation and to emptytheir bladder before the instillation. A urethral catheteris used to drain the bladder, and treatment should beaborted if traumatic catheterization occurs. The recon-stituted BCG suspension is instilled slowly by gravity(not forced). Patients should be instructed to retain thesolution for 2 hours, if possible, during which time theymay be ambulatory. Patients should void in a seatedposition to avoid splashing. For the next 6 hours,patients should disinfect voided urine with householdbleach, delaying 15 minutes before flushing. Excessivefluid intake is not necessary after BCG treatment. Ifprophylactic antibiotics are medically indicated in aBCG patient, it is important to avoid fluoroquinolones,macrolides, tetracyclines, and aminoglycosides becausethey are capable of rendering BCG nonviable andineffective. (However, they can be used to treat BCGtoxicity.) Condoms are recommended during sex todecrease the theoretical risk of BCG infection of thepartner, since BCG is shed from the urethra for at least48 hours and for up to 1 week after treatment.

EfficacyIntravesical BCG is substantially more effective thanintravesical chemotherapy in reducing the rate ofrecurrence and progression (Table 1). In a retrospectivecomparative review of 3405 patients treated withchemotherapy versus 496 BCG patients, intravesicalBCG produced a 40% decrease in the rate of recurrenceand a 10% decrease in the rate of progression (P = .003).1 In contrast, intravesical chemotherapyproduced only a 13% decrease in the rate of recurrenceand no benefit in terms of the rate of progression.

A study of long-term outcomes further supported theuse of intravesical BCG as an initial bladder-sparingstrategy.2 In this study, 98 patients with grade I to III Taor T1 cancer (20 of whom also had CIS) were treatedwith TUR and at least one course of BCG between 1981and 1989. After a minimum of 10 years of follow-up,25% had progressed to grade III T2 disease after amedian 19.1 months (range 1.2–143.7 months)

following BCG. Ten-year progression-free probabilitywas 70% overall, but was adjusted to 60% after takinginto account 10 patients who underwent cystectomy for recurrent high-risk disease. Sixty-six patients died,13 (13%) of transitional cell carcinoma (TCC) at amedian 66.6 months (range, 10.5–180.4 months).Kaplan-Meier estimated 10-year disease-specificsurvival was 86% overall.2

Thus, a single 6-week course of BCG delays, but maynot prevent, progression. There is no predictability ofresponse prior to treatment. Patients who experience arecurrence early following BCG therapy generally havea poor prognosis.

Maintenance TherapyMaintenance therapy following an initial inductioncourse of BCG has become common practice, althoughthere is conflicting evidence about the potentialbenefits.3,4 This clinical practice is based largely on astudy by the Southwest Oncology Group.4 This studydemonstrated that a 3-week maintenance regimen given at months 3 and 6 and then every 6 months for a total of 3 years was associated with a doubling ofrecurrence-free survival in patients considered at highrisk for recurrence. The median recurrence-free survivalwas 77 months for induction plus maintenance therapyversus 36 months for induction therapy alone (P<.0001).In addition, BCG maintenance therapy significantlyimproved progression-free survival, with a trend towardimproved overall 5-year survival as well.

SafetyCystitis (91%), hematuria (43%), and mild flulikesymptoms, including low-grade fever (29%), malaise(24%), and nausea (5%) are the most common adverseevents associated with bladder instillation of BCG. Thesesymptoms can usually be managed symptomatically (eg, with oxybutynin, phenazopyridine, and nonsteroidalanti-inflammatory drugs [NSAIDs], particularly COX-2inhibitors) and clear within 12 to 24 hours of treatment.Cystitis usually responds to fluoroquinolone antibioticsand/or isoniazid or rifampin, and prednisone (note thatthe antibiotics must be continued throughout and for2 weeks after the prednisone therapy). Severe localsymptoms lasting more than 48 hours and notresponding to usual symptomatic management may be prevented/alleviated with isoniazid 300 mg/d for3 days starting the day before the next dose of BCG.

BCG sepsis (high fever/shaking chills with hemodynamiccollapse [hypotension]) may be life threatening! BCGsepsis should be treated immediately with intravenousfluid plus isoniazid 300 mg, rifampin 600 mg,ethambutol 1200 mg, and prednisolone 40 mg, and noadditional BCG courses should be given. Fluoroquino-lones should be added to the regimen if there are severe

Table 1. BCG Is More Effective Than Chemotherapy forReducing Rate of Recurrence and Progression.

Recurrence ProgressionRate (%) Rate (%)

No. Net Net PAgent Patients Ctrl Rx Benefit Ctrl Rx Benefit Value

Chemotherapy 3405 51 38 13 7 6 1 NSBCG 496 72 32 40 23 13 10 .03

NS = not significant.

Adapted with permission from Lamm DL. BCG in perspective: advances in thetreatment of superficial bladder cancer. Eur Urol. 1995;27(suppl 1):2-8.

complications, one of the standard antituberculosisdrugs is not tolerated, or gram-negative sepsis is a concern. BCG is now known to be resistant tocycloserine, which should no longer be used to treatBCG sepsis.

Other serious adverse events, which may be dose-limiting or require treatment discontinuation, includehigh uncontrollable fever (3%), granulomatousprostatitis (1%), major hematuria (1%), hepatitis/pneumonitis (0.7%), arthritis (0.5%), epididymo-orchitis(0.4%), ureteral obstruction (0.3%), and contractedbladder (0.2%). Patients with prolonged temperature101.5°F should be treated with isoniazid 300 mg/d for3 months. As a general rule, additional BCG dosesshould be deferred until the patient is asymptomatic.

Since reduced doses of BCG are associated with lesstoxicity, several studies have investigated the efficacyand safety of lower doses. Most of these studies5-8—withthe exception of one9—have shown that reduced doses(one half to one third of the standard dose) appear to beas effective as, and less toxic than, standard-dose BCG.An optimal dose has not been identified.

Three strains of BCG are available: Connaught strain(Theracys®), Pasteur strain (Tice®), and Armand-Frappierstrain (Pacis®). Bioequivalence is measured in colony-forming units (CFUs). Gram weights differ in variousstrains (eg, Tice 50 mg is equivalent to Theracys 81 mg).All commercially available strains are thought to beessentially identical in terms of their intrinsic biologicactivity, but there may be differences in processing andpackaging that affect stability in solution, shelf life, andthe total CFU count.

Interferon Monotherapy

EfficacySeveral trials have investigated intravesical interferonalfa-2b in patients with residual papillary transitionalcell carcinoma (pTCC) or carcinoma in situ (CIS) orfollowing TUR.10-14 Response rates (complete response[CR] plus partial response [PR]) ranging from 25% to75% have been reported in patients with residual pTCCtreated with ≥50 million units (mIU) of interferon alfa-2b. Response rates up to 66% have been reported inpatients with CIS. In CIS patients, Glashan12 observed a43% CR rate to 100 mIU interferon alfa-2b, with amedian duration of CR >12 months, and a lowerresponse rate (5%) with a dose of only 10 mIU, hintingat a possible dose-response relationship.

The efficacy of intravesical interferon alfa in preventingrecurrence and progression of superficial bladder cancerfollowing complete TUR has been evaluated in severalstudies.15-19 Recurrence rates ranged from 21% to 60%,which are somewhat higher than the recurrence ratesobserved with BCG. However, observations that intra-vesical interferon alfa-2b therapy has substantialactivity in up to 20% of patients who failed BCGtherapy20,21 are extremely encouraging and suggest that one important application of interferon alfa-2b is in the treatment of BCG failures.

SafetyIntravesical interferon alfa is associated with minimallocal toxicity. The most common adverse events aremild fever and flulike symptoms, which occur in <30%of treated patients.22 No dose-limiting toxicity has been

observed up to a dose of 1000 mIU per instillation. Theside effects of intravesical interferon alfa therapy can becontrolled with NSAIDs.

BCG/Interferon Combination TherapyThe biologic activities of interferon alfa and BCG arecomplementary,23,24 and there is evidence of synergisticactivity. BCG and interferon alfa are biocompatible andcan be instilled simultaneously into the bladder.24

Mechanisms of Action

BCG antigens are taken up by macrophages and otherantigen-presenting cells and presented to T cells, whichstimulate a cellular immune response. The BCG-activatedmacrophages produce cytokines, including interleukin(IL)-12 and tumor necrosis factor alpha (TNF-α). IL-12plays a dominant role in the induction of interferongamma (IFN-γ) production,26 whereas TNF-α has directantitumor activity. Activated T helper type 1 (TH1) cellsproduce IL-2 and IFN-γ, both of which correlate withclinical response.27,28 Exogenous intravesical interferonalfa augments the production of IFN-γ by TH1 cells,which in turn enhances BCG antigen presentation andfurther amplifies the cellular immune response.Intravesical interferon alfa also upregulates humanleukocyte antigen and Fas expression on the bladdercancer cells, which increases presentation of BCGantigens by tumor cells and enhances tumor cell lysis by activated cytotoxic T lymphocytes.29 The end result is an effective anticancer immune response.

In addition to these synergistic immunomodulatoryactivities, in vitro studies have shown that BCG andinterferon alfa-2b also have synergistic antiproliferativeeffects. In these experiments, two different bladdercancer cell lines (UCRU-BL-28 and J82) were incubatedwith either BCG alone at two doses (5 and 50 µg/mL),interferon alfa-2b alone at three doses (1, 100, and1000 U/mL), or interferon alfa-2b plus BCG.30 Both BCG and interferon alfa-2b alone had dose-dependentantiproliferative effects on the UCRU-BL-28 cell line;however, the combination had dramatically greaterdose-dependent effects on proliferation. Likewise,although the J82 cell line did not appear to be sensitive to either BCG or interferon alfa-2b alone, the combination of BCG plus interferon alfa-2b had an antiproliferative effect.

EfficacyBased on the clinical rationale for combining BCG and interferon alfa-2b, a number of centers haveinvestigated this combination in patients withsuperficial bladder cancer. These studies suggest thatBCG/interferon alfa-2b may be superior to either agentalone and may allow BCG dose reduction withoutcompromising antitumor efficacy.

Stricker et al31 combined 60 mg (1/2 dose) BCG (Pasteurstrain) with 10 to 100 mIU interferon. This regimen waswell tolerated and produced favorable response rates inpatients with papillary tumors (60% no evidence ofdisease [NED], 40% PR), and CIS (86% CR) at a medianof 1 year of follow-up. A randomized trial reported byBercovich et al32 demonstrated that combination therapywith interferon alfa-2b (10 mIU) plus 1/2-dose BCG(Pasteur strain) yielded a lower rate of recurrencecompared with full-dose BCG (22% versus 28%) andwas associated with fewer BCG-related adverse events.

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O’Donnell et al33 treated 40 patients who failed one ormore courses of BCG therapy with 1/3-dose BCG plus50 mIU interferon alfa-2b for 6 to 8 weeks as inductiontherapy, followed by three 3-week maintenance treat-ments with 1/100- to 1/10-dose BCG plus 50 mIUinterferon (titrated to symptoms) as maintenancetherapy at months 5, 11, and 17. Patients in this studywere at high risk of recurrence or progression: nearly all(98%) had multifocal disease and 85% had failed priortherapy within 6 months of treatment. More than threequarters had aggressive histology (CIS or grade III, stageT1 disease). More than half had multirecurrent disease,and 52% failed more than one course of BCG therapy.One third of the population had a disease duration ofmore than 4 years. Cystectomy had already been offeredas a treatment option to 22 of the 40 patients.

After a median follow-up of 30 months, 63% weredisease free at 12 months and 53% were disease free at24 months (Fig. 1). There were no differences inresponse according to stage, grade, presence of CIS,number of previous recurrences, or number of priorBCG treatments. This low rate of recurrence isencouraging among this group of high-risk patients.Moreover, the 55% NED rate at 2 years comparesfavorably with that reported in historical series foreither agent alone or for intravesical chemotherapy.33

The majority of treatment failures occurred within thefirst 4 months (78% at first cystoscopy), thus permittingearly radical cystectomy. None of the patients with earlyfailure had metastasis or subsequently died of bladdercancer. Among four late recurrences (at 8, 21, 22, and24 months), two were low-grade, low-stage tumorstreated with TUR and two were extravesical disease.There were no recurrences after 24 months, and nopatients who received all three planned maintenancetherapy cycles had recurrence. Of the 22 patients forwhom cystectomy had been recommended, 12 (55%)were disease free with a normally functioning bladderat the end of the study.33

Researchers at the University of Florida investigated1/3-dose BCG plus 50 mIU interferon alfa-2b combi-nation therapy versus valrubicin (800 mg QW x6 weeks) in 24 high-risk TCC patients. All hadpreviously been treated with at least one course ofBCG, and 11 had also received courses of chemotherapy.Patients who responded to BCG plus interferon induc-tion therapy were given maintenance therapy with three weekly instillations every 3 months. Among the15 patients treated with BCG/interferon, there were nineCRs, four after one course, four more after a secondcourse, and an additional one after TUR was performedafter the first course. Despite the delay in cystectomywhile these patients underwent intravesical therapy, nopatients died of bladder cancer, and no muscle-invasivedisease was found among the nine patients whoultimately underwent cystectomy after failing one or more of the investigational regimens (BCG plusinterferon or valrubicin).34

Current, prospective, randomized trials are comparingthe efficacy of combination therapy with that of single-agent (full- or reduced-dose) BCG. A randomized,phase IIB trial in Singapore found the combination ofinterferon alfa-2b (10 mIU) plus 1/3-dose BCG (27 mgConnaught strain) produced a lower recurrence rate(10%) at a median follow-up of 19 months than either1/3-dose (30%) or full-dose (50%) BCG alone. Moreover,

the incidence of BCG-associated adverse events (localand systemic) was significantly reduced (P<.01) inpatients who received either reduced-dose BCG alone orthe combination regimen.35 This study suggests apositive synergistic effect between BCG and interferonalfa-2b; however, a much larger, multicenter,randomized study is needed to confirm this.

As a result of these data, BCG/interferon combinationtherapy is increasingly being evaluated as an intra-vesical immunotherapy in the treatment of bladdercancer failing to respond to BCG therapy alone.BCG/interferon is also being investigated in BCG-naivepatients. O’Donnell reported preliminary findingsindicating a disease-free rate of 68% at 2 years among22 high-risk BCG-naive patients treated with full-doseBCG/interferon.33

SafetyCombination therapy with interferon alfa-2b plus BCG(full or reduced dose) was safe and well tolerated inthe study by O’Donnell et al.33 Adverse events ofcombination therapy were generally no worse thanwith BCG alone, with the most common side effectsbeing local cystitis, transient hematuria, flulikesymptoms, and fever. There were no treatmentdiscontinuations during the first maintenance cycle,but three patients discontinued during cycle 2 andanother six during cycle 3, when side effects tendedto peak. Ultimately, 40% of patients terminatedmaintenance therapy due to adverse events. There was only one serious adverse event: BCG-osis withgranulomatous hepatitis, which responded well toantituberculosis therapy with isoniazid and rifampin.

A recent evaluation by O’Donnell et al36 of1100 patients recruited into a multicenter phase IIstudy of BCG/interferon detected 10 cardiac events(ischemia, congestive heart failure, and arrhythmia),eight of which were not drug-related, and sixreversible neurologic events (confusion, transientischemic attack/cerebrovascular accident, weakness).Conversely, BCG/interferon is associated with fewerepisodes of BCG sepsis than BCG alone (0.1% versus0.4%, respectively), due not only to the lower BCGdoses but also to a protective effect of interferon alfa,which enhances BCG clearance.

Frac

tion

Free

of

Canc

er

0 4 8 12 16 20 24 28 32 36 40 440.0

0.2

0.4

0.6

0.8

1.0

63%53%

Median Follow-up = 30 Months

40 40 40 39 37 31 25 15 10 8 4 2No. Patients Available at Follow-up

Months After Treatment Initiation

(Actual Disease Free = 55%)

48

Figure 1. BCG Plus Interferon alfa-2b in BCG Failures: Disease-FreeSurvival. Reprinted by permission of Lippincott Williams and Wilkins fromO'Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy withinterferon-α2b plus low dose bacillus Calmette-Guérin is effective in patientswith superficial bladder cancer in whom bacillus Calmette-Guérin alone pre-viously failed. J Urol. 2001:166:1300-1305.

References

1. Lamm DL. BCG in perspective: advances in the treatment of superficial bladder cancer. Eur Urol. 1995;27(suppl 1):2-8.

2. Davis JW, Sheth SI, Doviak MJ, Schellhammer PF. High risk or recurrent superficial bladder carcinoma treated with BCG: progression free anddisease specific survival with minimum 10 year follow-up [abstract 777]. Presented at: American Urological Association 2001 Annual Meeting;June 2-7, 2001; Anaheim, Calif.

3. Palou J, Laguna P, Millan-Rodriguez F, Hall RR, Salvador-Bayarri J, Vincente-Rodriguez J. Control group and maintenance treatment with bacillusCalmette-Guérin for carcinoma in situ and/or high grade bladder tumors. J Urol. 2001;165:1488-1491.

4. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guérin immunotherapy for recurrent TA, T1 and carcinoma in situtransitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol. 2000;163:1124-1129.

5. Pagano F, Bassi P, Milani C, et al. A low dose bacillus Calmette-Guérin regimen in superficial bladder cancer therapy: is it effective? J Urol.1991;146:32-35.

6. Hurle R, Losa A, Ranieri A, et al. Low dose Pasteur bacillus Calmette-Guérin regimen in stage T1, grade 3 bladder cancer therapy. J Urol.1996;156:1602-1605.

7. Martinez-Pineiro JA, Solsona E, Flores N, et al. Improving the safety of BCG immunotherapy by dose reduction. Cooperative Group CUETO. Eur Urol. 1995;27(suppl 1):13-18.

8. Martinez-Pineiro JA, Flores N, Isorna S, et al. Long-term follow-up of a randomized prospective trial comparing a standard 81 mg dose ofintravesical bacille Calmette-Guérin with a reduced dose of 27 mg in superficial bladder cancer. BJU Int. 2002;89:671-680.

9. Morales A. From the 19th to the 21st centuries: BCG in the treatment of superficial bladder cancer. Eur Urol. 1992;21(suppl 2):2-6.

10. Oliver RTD, Waxman JH, Kwok H, et al. Alpha lymphoblastoid interferon for non-invasive bladder cancer [abstract]. Br J Cancer. 1986;53:432.

Clinical Recommendations

Currently, BCG/interferon therapy is consideredinvestigational. It appears that the most appropriatecandidates for first-line BCG/interferon therapy maybe patients with high-risk bladder cancer (eg, T1grade III or multifocal CIS), who are likely to receiveonly a single course of intravesical therapy prior tocystectomy. Combination therapy may also be indi-cated for patients with CIS or multifocal stage Tagrade II-III TCC who have failed a course of BCG. In addition, BCG/interferon may be appropriate forpatients who fail two courses of BCG inductiontherapy but are not yet considered appropriatecandidates for cystectomy.

Optimal doses of BCG and interferon have not yetbeen determined. Table 2 provides the dosing protocol used by O’Donnell et al in their studies of BCG/interferon. For BCG/interferon combinationtherapy, only the powder formulation of interferonshould be used, since the solvent in the pre-mixedform contains bacteriostatic preservatives that couldrender BCG inactive. The interferon powder should bereconstituted in accordance with the manufacturer’sinstructions. BCG and interferon should then becombined and administered together at the dosesdescribed in Figure 2.

Cystoscopic evaluation should be staggered with theinduction and maintenance cycles of BCG/interferonso that 4 to 6 weeks elapse after each treatmentbefore cystoscopy is performed.

The precautions and patient instructions necessary inadministering BCG/interferon are similar to thosedescribed for BCG monotherapy. The strategies formanaging BCG side effects are also applicable.

ConclusionPreclinical and clinical data suggest that BCG andinterferon alfa have complementary and potentiallysynergistic immunomodulatory and antitumor activity. Both enhance the TH1 cellular immune response andpotentiate interferon-γ production. Open-label trialshave demonstrated combination therapy to be welltolerated and to allow BCG dose reduction withoutcompromising antitumor efficacy in patients withsuperficial bladder cancer. Moreover, BCG/interferonalfa appears safe and effective in patients with prior

BCG failure, even in those who are considered “BCGrefractory" (ie, those who had recurrence within6 months of treatment) and those who have alreadyfailed at least two courses of BCG. Current investiga-tions are focused on BCG-naive patients.

Prior BCG FailuresInduction: 1/3-dose BCG +

50 mIU IFN QW x 6 wk*†‡

BCG NaiveInduction: Full-dose BCG +

50 mIU IFN‡ QW x 6 wk*

~6 wk after last induction dose: cystoscopy, biopsy, cytology

Disease free?

Disease free?

Recurrence during

maintenance?

YES

YES

YES

NO

NO

NO

Maintenance Therapy3 weekly miniseries

For each seriesDose 1: 1/3-dose BCG + 50 mIU IFN‡

Doses 2 & 3: 1/10-dose BCG + 50 mIU IFN‡

Schedule (after induction); includes quarterly cystoscopy 3 mo Series A Cysto. x 2 9 mo Series B Cysto. x 215 mo Series C

Reinduction (if candidate for continued immunotherapy)

1/10-dose BCG + 100 mIU IFN‡

QW x 6 wk*Cystoscopy ~6 wk after last dose

Maintenance Therapy3 weekly miniseries

For each seriesAll 3 doses: 1/10-dose BCG + 50 mIU IFN‡

Schedule: same as for maintenance after induction

Stop BCG/IFN;Cystectomy, if appropriate

Cystectomy, if appropriate

Complete maintenance schedule; continue monitoring for recurrence post-Tx

Figure 2. BCG/Interferon Dosing Algorithm. Adapted from O’Donnell MA, et al33 with updates courtesy of Michael A. O’Donnell, MD.

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The combination of BCG and interferon alfa-2b is considered investigationaltherapy.

*8 weeks of induction therapy was given in the initial half of the study, but lateradministrations were associated with an increased rate of side effects withoutobvious additional clinical benefit. †1/3 of an 81-mg vial of Connaught strain BCG equal to 27 mg diluted in 50 cc buffered saline, in which 1 cc of freshlyreconstituted 50 mIU interferon is added. ‡BCG dose may be reduced ingradations of 1/3 (to 1/10, 1/30, or 1/100) as necessary for treatment intoleranceby reducing the amount of BCG concentrate delivered into the standard 50 ccbuffered saline volume. IFN dose should be increased to 100 mIU. Treatmentdelays up to 2 weeks are also permitted.

Diagnostic and

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M o n o g r a p h

12

11. Torti FM, Shortliffe LD, Williams RD, et al. Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group Study. J Clin Oncol. 1988;6:476-483.

12. Glashan RW. A randomized controlled study of intravesical alpha-2b-interferon in carcinoma in situ of the bladder. J Urol. 1990;144:658-661.

13. Sarosdy MF, Lowe BA, Schellhammer PF, et al. Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial.Urology. 1996;48:21-27.

14. Niijima T. Intravesical treatment of bladder cancer with recombinant human interferon-beta. Intravesical GKT-beta Chemotherapy Research Group.Cancer Immunol Immunother. 1989;30:81-85.

15. Kostakopoulos A, Deliveliotis C, Mavromanolakis E, et al. Intravesical interferon alfa-2b administration in the treatment of superficial bladdertumors. Eur Urol. 1990;18:201-203.

16. Portillo J, Martin B, Hernandez R, et al. Results at 43 months’ follow-up of a double-blind, randomized, prospective clinical trial using interferonalpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder. Urology. 1997;49:187-190.

17. Bartoletti R, Massimini G, Criscuolo D, et al. Interferon alfa 2a in superficial bladder cancer prophylaxis: toleration and long-term follow-up. A phase I-II study. Anticancer Res. 1991;11:2167-2170.

18. Boccardo F, Cannnata D, Rubagotti A, et al. Prophylaxis of superficial bladder cancer with mitomycin or interferon alfa-2b: results of amulticentric Italian study. J Clin Oncol. 1994;12:7-13.

19. Hoeltl W, Hasun R, Albrecht W, Marberger M. How effective is topical alpha-2b interferon in preventing recurrence of superficial bladder cancer?Br J Urol. 1991;68:495-498.

20. Glashan RW. A randomized controlled study of intravesical alpha-2b-interferon in carcinoma in situ of the bladder. J Urol. 1990;144:658-661.

21. Williams R, Gleason D, Smith AY, et al. Pilot study of intravesical alfa-2b interferon for treatment of bladder carcinoma in situ following BCGfailure [abstract]. J Urol. 1996;155:494.

22. Malmström PU. Randomized comparative dose-ranging study of interferon-α and mitomycin-C as an internal control in primary or recurrentsuperficial transitional cell carcinoma of the bladder. BJU Int. 2002;89:681-686.

23. Keeley FX Jr, Lattime E, McCue P, et al. A comparison of the local immune response to intravesical alpha-interferon and bacillus Calmette-Guérin(BCG) in patients with superficial bladder cancer [abstract]. J Urol. 1994;151:473A.

24. Fujimoto T, O'Donnell MA, Szilvasi A, et al. Bacillus Calmette-Guérin plus interferon-2 and/or granulocyte/macrophage-colony-stimulating factorenhances immunocompetent cell production of interferon-gamma, which inhibits B16F10 melanoma cell growth in vitro. Cancer ImmunolImmunother. 1996;42:280-284.

25. Downs TM, Szilvasi A, O'Donnell MA. Pharmacological biocompatibility between intravesical preparations of BCG and interferon alfa-2b. J Urol.1997;158:2311-2315.

26. O'Donnell MA, Luo Y, Chen X, et al. Role of IL-12 in the induction and potentiation of IFN-gamma in response to bacillus Calmette-Guérin.J Immunol. 1999;163:4246-4252.

27. Kaempfer R, Gerez L, Farbstein H, et al. Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 geneexpression. J Clin Oncol. 1996;14:1778-1786.

28. Saint F, Patard JJ, Hoznek A, et al. Prognosis value of a Th1 urinary cytokine response following intravesical BCG treatment [abstract 1511]. J Urol. 1997;157(suppl):386.

29. Lattime EC, Gomella LG, McCue PA. Murine bladder carcinoma cells present antigen to BCG-specific CD4+ T-cells. Cancer Res. 1992;52:4286-4290.

30. Pryor K, Stricker P, Russell P, et al. Antiproliferative effects of bacillus Calmette-Guérin and interferon alpha 2b, on human bladder cancer cells invitro. Cancer Immunol Immunother. 1995;41:309-316.

31. Stricker P, Pryor K, Nicholson T, et al. Bacillus Calmette-Guérin plus intravesical interferon alpha-2b in patients with superficial bladder cancer.Urology. 1996;48:957-962.

32. Bercovich E, Deriu M, Manferrari F, et al. [BCG vs. BCG plus recombinant alpha-interferon 2b in superficial tumors of the bladder]. Arch Ital UrolAndrol. 1995;67:257-260.

33. O'Donnell MA, Krohn J, DeWolf WC. Salvage intravesical therapy with interferon-α2b plus low dose bacillus Calmette-Guérin is effective inpatients with superficial bladder cancer in whom bacillus Calmette-Guérin alone previously failed. J Urol. 2001;166:1300-1305.

34. Luciani LG, Neulander E, Murphy WM, Wajsman Z. Risk of continued intravesical therapy and delayed cystectomy in BCG-refractory superficialbladder cancer: an investigational approach. Urology. 2001;58:376-379.

35. Esuvaranathan K, Kamaraj R, Mohan RS, et al. A phase IIb trial of BCG combined with interferon alpha for bladder cancer [abstract 675]. J Urol.2000;163(suppl):152.

36. O’Donnell MA, Hartman K, National Phase II BCG IFN-Alpha Investigator Group. An evaluation of BCG plus interferon-alpha-2b toxicity in anational multicenter phase II trial [abstract 760]. Presented at: 97th Annual Meeting of the American Urological Association; May 25-30, 2002;Orlando, Fla.

Summary

Bladder cancer is a major health concern, resulting inconsiderable morbidity and mortality, particularly inmen. This common malignancy is caused primarily bycigarette smoking and exposure to environmental car-cinogens. Superficial (non–muscle-invasive) bladdercancer comprises a heterogeneous group of tumors withvarying prognoses. Tumors with the greatest risk of re-currence, progression, and mortality include stage T1tumors, carcinoma in situ, and high-grade Ta tumors.Hematuria (micro- or macroscopic) is the most commonsign and should prompt an evaluation with cystoscopy,cytology, urinalysis, and radiologic imaging. Bladdercancer biomarkers may provide additional information.

Initial treatment for superficial bladder cancer consists oftransurethral resection of the bladder tumor, followed in

most cases by intravesical immunotherapy. Perioperativeadministration of mitomycin C is a recent approach thatmay also improve outcomes. Bacillus Calmette-Guérin(BCG) induction and maintenance therapy is consideredthe gold standard for intravesical immunotherapy, but itstoxicity and high rates of recurrence indicate the needfor alternative treatments. Recent investigations haveshown that when BCG and interferon are combined, they have potentially synergistic activity and increasedefficacy. This combination has been well tolerated andmay allow for lower doses of BCG to be used, particu-larly in patients with previous BCG exposure who are atthe greatest risk for toxicity. Randomized phase III trialscomparing BCG/interferon with BCG monotherapy areunderway, and reports from phase II studies ofBCG/interferon are promising.

CME INFORMATION Projects In Knowledge is accredited by the Accreditation Council for Continuing Medical Education to provide

continuing medical education for physicians.

Projects In Knowledge designates this educational activity for up to 1.5 hours in Category 1 credit toward the AMAPhysician’s Recognition Award. Each physician should claim only those hours of credit that were actually spent onthe educational activity.

PILOT TESTING Projects In Knowledge thanks Thomas P. Alderson, MD, for pilot testing this activity.

LEARNING OBJECTIVES After participating in this activity, physicians will be better able to:

• Describe the epidemiology, risk factors, grading/staging, and natural history of superficial bladder cancer

• Evaluate patients with hematuria for bladder cancer using cystoscopy, cytology, and other urine-based tests, and

radiologic imaging

• Formulate appropriate treatment strategies for superficial bladder cancer using surgical approaches and

intravesical chemotherapy or immunotherapy

• Consider the latest data regarding bacillus Calmette-Guérin (BCG) and interferon combination therapy when

formulating treatment plans for patients with superficial bladder cancer

• Select appropriate candidates for BCG/interferon combination therapy and BCG monotherapy

• Select appropriate doses and treatment intervals for intravesical immunotherapy regimens

• Prevent and manage toxicities associated with BCG and interferon

• Diagnose and treat recurrences of superficial bladder cancer following initial therapy

Estimated Time for Completion: 1.5 hours

FOR CME CREDIT To receive documentation of your participation, complete the following steps:1. Read this publication carefully.2. Complete the Posttest, selecting the most appropriate choice for each question.3. Complete the Evaluation.4. Send photocopies of the Posttest and Evaluation to Projects In Knowledge, One Harmon Plaza,

Secaucus, NJ 07094, or fax to (201) 617-7333 before October 1, 2003.If you complete these steps and score 70% or higher, Projects In Knowledge will mail you an acknowledgment of your participation in this activity. Please note: If you score lower than 70%, you will be given another chance to take the Posttest.

1590

Education Initiative in Urology

Diagnostic and Treatment Issuesin Superficial Bladder Cancer

Education

Initiative in

Urology

Projects In Knowledge gratefully acknowledges the unrestricted educational grant from

Copyright © 2002, Projects In Knowledge, Inc. All rights reserved. Projects In Knowledge • One Harmon Plaza • Secaucus, NJ • 07094-9709

Release Date: October 1, 2002. This independent CME activity is planned

and produced in accordance with the ACCME Essential Areas and

Policies. This enduring activity will be reviewed within 1 year of this date

and rereleased or its designation for CME credit will become invalid.

A CME monograph designed for urologists who treat patients with superficial bladder cancer

M o n o g r a p h

For more information about BCG/interferon in superficial bladder cancer, download thefour-part Tx Reporter series, FAQs on Intravesical Immunotherapy for Superficial BladderCancer at www.projectsinknowledge.com. This series provides personal insights fromMichael A. O’Donnell, MD, principal investigator of BCG/interferon trials, as he answersreal questions from physicians like you.

Instructions for Documentation of Participation for CME

To receive documentation of your participation in this CME activity for a total of 1.5 hours of CME credit, please complete the following steps:

● Read this monograph.

● Complete the CME posttest and evaluation.

● Complete the CME Evaluation.

● Mail or fax the completed posttest and evaluation to Projects In Knowledge, One Harmon Plaza, Secaucus, NJ 07094; fax: 1-201-617-7333.

Projects In Knowledge will mail you an acknowledgment of your participation in this activity if your combined score on the posttest is 70% or better. If your

combined score is lower than 70%, you will be notified by mail and will be given another opportunity to take the posttest.

Name Degrees/Credentials

Mailing Address

City State ZIP

Phone Fax

E-mail

Please indicate your answers below (circle one).

1. Which of the following tumor stages accounts for about 70% of all superficial bladder cancers?

a. Ta b. T1 c. CIS

2. Which of the following groups has the highest risk of bladder cancer?

a. Black men b. Black women c. White men d. White women

3. Which of the following would not be considered high-risk bladder cancer?

a. Multiple grade II, stage T1 tumors b. A single grade II, stage T1 tumor

c. Grade III, stage Ta disease d. CIS

4. The majority of patients with hematuria:

a. Have bladder cancer b. Do not have bladder cancer

5. Compared with cytology, most urine-based bladder cancer tests are:

a. More sensitive and more specific b. More sensitive but less specific

c. Less sensitive but more specific d. Less sensitive and less specific

6. Laser therapy:

a. Is therapeutic in superficial bladder cancer

b. Is rarely used as initial therapy because it does not allow pathologic analysis

c. Is associated with less bleeding and postoperative bladder irritation than TUR

d. All of the above

Education Initiative in Urology

CME PosttestDiagnostic and Treatment Issuesin Superficial Bladder Cancer

1590PT—Page 1 of 2

7. TUR alone is sufficient treatment in the majority of patients, resulting in low rates of recurrence and progression.

a. True b. False

8. With the newest surgical technique (orthotopic neobladder), external appliances are no longer necessary following cystectomy.

a. True b. False

9. Which of the following offers the greatest reduction in recurrence rates when given intravesically after a TUR?

a. Chemotherapy (eg, doxorubicin, thiotepa)

b. Immunotherapy (BCG or BCG/interferon)

c. Both produce equivalent reductions in recurrence rates

10. The effectiveness of mitomycin C appears to be greatest when given:

a. 1 or more days after TUR b. Perioperatively (within 2 hours of TUR)

c. At any time (effectiveness is the same regardless of when it is given)

11. Following a TUR and biopsy, BCG administration:

a. Can be performed immediately b. Can be performed after 5 to 7 days

c. Can be performed after 10 to 14 days d. Should be delayed at least 1 month

12. Following treatment with BCG, patients:

a. Should remain as still as possible in a prone position for 2 hours before voiding

b. Drink at least 12 glasses of water over the next 24 hours to flush out BCG

c. Disinfect voided urine with household bleach for 15 minutes during the 6 hours posttreatment

d. Should avoid sexual intercourse for up to 1 month posttreatment

13. Which of the following should not be used in the treatment of BCG sepsis?

a. Cycloserine b. Isoniazid c. Prednisolone

d. Rifampin e. All of the above are OK to use

14. In a study by O’Donnell et al, a 2-year recurrence-free survival rate of 53% was observed when BCG failures were re-treated with:

a. Full-dose BCG monotherapy

b. 1/3-dose BCG monotherapy

c. 100 mIU interferon alfa-2b monotherapy

d. 1/3-dose BCG + 50 mIU interferon alfa-2b

e. 1/3-dose BCG + 100 mIU interferon alfa-2b

f. Full-dose BCG + 50 mIU interferon alfa-2b

15. Which formulation of interferon alfa-2b should be used in combination with BCG?

a. Powder b. Solution c. Either one is acceptable

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Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CME Evaluation Survey

Diagnostic and Treatment Issues in Superficial Bladder Cancer

Instructions

Please complete this survey, along with the CME Posttest, and mail or fax (both sides) to Projects In Knowledge, One Harmon Plaza, Secaucus, NJ 07094;fax: 1-201-617-7333.

1. Please rate the extent to which you achieved the learning objectives: Excellent Very Good Good Satisfactory Poor

• Describe the epidemiology, risk factors, grading/staging,and natural history of superficial bladder cancer ❑ ❑ ❑ ❑ ❑

• Evaluate patients with hematuria for bladder cancer using cystoscopy,cytology, and other urine-based tests, and radiologic imaging ❑ ❑ ❑ ❑ ❑

• Formulate appropriate treatment strategies for superficial bladder cancer using surgical approaches and intravesical chemotherapy or immunotherapy ❑ ❑ ❑ ❑ ❑

• Consider the latest data regarding bacillus Calmette-Guérin (BCG) and interferon combination therapy when formulating treatment plans for patients with superficial bladder cancer ❑ ❑ ❑ ❑ ❑

• Select appropriate candidates for BCG/interferon combination therapy and BCG monotherapy ❑ ❑ ❑ ❑ ❑

• Select appropriate doses and treatment intervals for intravesical immunotherapy regimens ❑ ❑ ❑ ❑ ❑

• Prevent and manage toxicities associated with BCG and interferon ❑ ❑ ❑ ❑ ❑

• Diagnose and treat recurrences of superficial bladder cancer following initial therapy ❑ ❑ ❑ ❑ ❑

2. Please rate the overall value of this enduring material: ❑ ❑ ❑ ❑ ❑

Strongly StronglyAgree Agree Disagree Disagree

3. Course was free from commercial bias: ❑ ❑ ❑ ❑

If you “Disagree” or “Strongly Disagree,” why? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Just Right Too Advanced Too Basic

4. Please rate the level of the material presented: ❑ ❑ ❑

5. Please list any changes in your practice that you would consider making as a result of participating in this activity:

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Education Initiative in Urology

CME EvaluationDiagnostic and Treatment Issuesin Superficial Bladder Cancer

Name . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6. Please rate your interest in self-directed or distancelearning in the following formats: Very Interested Moderately Interested Not Interested

a. Audioconference ❑ ❑ ❑

b. Videoconference ❑ ❑ ❑

c. Enduring materials (audiocassettes, videotapes, monographs) ❑ ❑ ❑

d. Internet (on-line discussions with experts, educational activities) ❑ ❑ ❑

e. Multimedia (on-line, CD-ROM) ❑ ❑ ❑

7. Please tell us how long it took you to complete this course: . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8. Please list topics and/or experts you would find interesting and professionally relevant for future CME activities:

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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9. Follow-up:As part of our ongoing continuous quality-improvement effort, we conduct postactivity follow-up surveys to assess the impact of our CME courses on professional practice. Please indicate your willingness to participate in such a survey:

❑ Yes, I would be interested in participating in a follow-up survey.

❑ No, I’m not interested in participating in a follow-up survey.

Additional comments about this activity:

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Thank you for your participation.

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