bladder

Bladder CancerIncluding Upper Tract Tumors andTransitional Cell Carcinoma of the Prostate

Version 1.2003

Clinical Practice Guidelines in Oncology – v.1.2003

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Guidelines Index

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Staging, MS, ReferencesNCCN® Practice Guidelinesin Oncology – v.1.2003

Version 1.2003, 11-21-02 © 2003 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Bladder Cancer Panel Members

James E. Montie, MD/ChairUniversity of Michigan Comprehensive Cancer Center

Robert R. Bahnson, MDArthur G. James Cancer Hospital & Richard J. SoloveResearch Institute at the Ohio State University

Samuel M. Cohen, MD, PhDUNMC Eppley Cancer Center at the University ofNebraska Medical Center

Mario A. Eisenberger, MDThe Sidney Kimmel ComprehensiveCancer Center at Johns Hopkins

Rizk El-Galley, MDUniversity of Alabama at BirminghamComprehensive Cancer Center

Harry W. Herr, MD,Memorial Sloan-Kettering Cancer Center

Gary Hudes, MDFox Chase Cancer Center

Timothy Kuzel, MDRobert H. Lurie Comprehensive Cancer Center ofNorthwestern University

Beverly Drucker, MDMemorial Sloan-Kettering Cancer Center

Paul H. Lange, MDFred Hutchinson Cancer Research Center/SeattleCancer Care Alliance

Jerome P. Richie, MDDana-Farber Cancer Institute

John Seigne, MDH. Lee Moffitt Cancer Center & Research Instituteat the University of South Florida

William U. Shipley, MDMassachusetts General Hospital

Eric J. Small, MDMount Zion UCSF

Timothy G. Wilson, MDCity of Hope Cancer Center

Anthony Patterson, MDUniversity of Tennessee Health Sciences Center

Alan Pollack, MD, PhDFox Chase Cancer Center

Donald L. Trump, MDRoswell Park Cancer Institute

Phillip J. Walther, MD, PhD, MBADuke Comprehensive Cancer Center

Bladder Cancer

* Writing Committee member

*

*

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Guidelines Index

Bladder Cancer TOC



Table of Contents

Bladder Cancer:

Upper Tract Tumors:

NCCN Bladder Cancer Panel Members

Clinical Presentation and Workup (BL-1)�

�

�

�

�

�

�

�

�

�

Noninvasive or CIS (BL-2)

Follow-up for Noninvasive (BL-3)

Muscle Invasive or Metastatic (BL-4)

Follow-up for Invasive or Metastatic Disease ( BL-7)

Principles of Surgical Management (BL-A)

Probability of Recurrence and Progression (BL-B)

Principles of Chemotherapy Management (BL-C)

Principles of Radiation Management of Invasive Disease (BL-D)

Non-TCC Bladder Cancer (BL-E)

Renal Pelvis (UTT-1)

Ureter (UTT-2)

Transitional Cell Carcinoma of the Prostate (TCCP-1)

Guidelines Index Print the Bladder Cancer Guideline

�

�

Bladder Cancer

These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. ©2003.

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Staging

Manuscript

References

Clinical Trials:

Categories of Consensus:NCCN

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

To find clinical trials online at NCCNmember institutions,

All recommendations are Category2A unless otherwise specified.

See

NCCN

click here:nccn.org/clinical_trials/physician.html

NCCN Categories of Consensus

http://www.nccn.org/clinical_trials/physician.html

Guidelines Index

Bladder Cancer TOC



Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

CLINICALPRESENTATION

CYSTOSCOPICAPPEARANCE

WORKUP

Hematuria�

�

H&POfficecystoscopy

Noninvasivedisease

Muscle invasive(See BL-4)

Papillaryor solid

�

�

�

Imaging of upper tractcollecting systemCytology x 1Consider pelvic CTbefore TURBT if sessileor high grade

a

�

�

�

Examination underanesthesia(bimanual)TURBTIf sessile, high gradecytology orsuspicious for CIS:

Random biopsyConsider TURbiopsy of prostate

b

�

�

CIS

See BL-2

See BL-2

Metastatic(See BL-4)

Bladder Cancer

PRIMARY TREATMENT

aImaging may include IVP, CT urography (if available), retrograde pyelogram,

or MRI urogram.

bSee Principles of Surgical Management (BL-A).Return to Bladder CancerTable of Contents

BL-1

Guidelines Index

Bladder Cancer TOC





Papillaryor solid

AnyCIS/Tisabnormalmucosa

Observe or Intravesical chemotherapy�

�

BCG (preferred)orMitomycin

BCG(category 1)orMitomycinorConsiderradicalcystectomyorResectio4-8 wkb

n at

ObserveorConsider single dose intravesical chemotherapywithin 24 hours (not immunotherapy)f

FOLLOW-UPADJUVANT TREATMENT(INTRAVESICAL) e

Positive

Negative

CystectomyorBCG

b

BCG(optional)

�

�

�

Cystoscopy and urinecytology every 3 mo for 2yr, then every 6 mo for 2yr, then annually

Imaging of upper tractcollecting system every1–2 yr

Investigative markers(optional)

a

Cystoscopy at 3 mo,increasing intervalas appropriate

Ta, G1-2

Ta, G3T1, G1-2

T1, G3

BCG

See RecurrentorPersistentDisease(BL-3)

T2 orgreater

See MuscleInvasive (BL-4)

Bladder CancerPATHOLOGYc,d

aImaging may include IVP, CT urography (if available), retrograde pyelogram, or MRI urogram.

Grading of these protocols refers to the World Health Organization International Histological Classification of Tumours, Edition 1, published 1973.

b

c

d

f

See Principles of Surgical Management (BL-A).

See Probability of Recurrence and Progression (BL-B) Non-Transitional Cell Carcinoma (TCC) Bladder Cancer (BL-E).and

e Indications for adjuvant therapy: Based on probability of recurrence and progression to muscle invasive disease: (1) size; (2) number; (3) grade.

Immediate intravesical chemotherapy, not immunotherapy, may decrease recurrence.

BL-2

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Cystoscopy

positive

�

�

�

Cytology

positive

Imaging

negative

Cystoscopy

negative

CIS recurrence

or persistence

TURBTb

Adjuvant

based on

and grade

therapy

tumore

Follow-up every 3 mo

Follow-up every 3 mo

or

BCGRandom biopsies

including TUR

biopsy prostateb

Negative

T1, G3

Persistent disease

in bladder at 6 mo

BCG

or

Cystectomyb

BCG

Complete

response

Incomplete

response

Incomplete

response

Maintenance

BCG

(optional)

Cystectomyb

Cystectomy

or

Consider other

intravesical

chemotherapy

b

or

immunotherapy

Positive

POSTTREATMENT Ta, T1, CISPERSISTANT OR RECURRENTDISEASE

TREATMENT OF RECURRENT/PERSISTENT DISEASE

Muscle Invasive See BL-4

Bladder Cancer

bSee Principles of Surgical Management (BL-A).

eIndications for adjuvant therapy: Based on probability of recurrence and progression to muscle invasive disease: (1)

size; (2) number; (3) grade. Return to Bladder CancerTable of Contents

BL-3

Guidelines Index

Bladder Cancer TOC



SeeFollow-up(BL-7)



Muscleinvasive

�

�

�

�

�

�

�

CBCChemistry profile,including alkalinephosphataseChest x-rayImaging of upper tractswith CT or MRI ofabdomen and pelvisExamination underanesthesia/cystoscopyTURBTBone scan (optional)

b

T3

Notumor

ObservationorChemotherapyorAdjuvantchemotherapy

g

g

+ RTh

Tumor

Consider adjuvant chemotherapybased on pathologic risk (positivenodes, high-grade transmural)g

Radicalcystectomyb

T2

� Radical cystectomy and

consider neoadjuvant

chemotherapy

b

or

Segmental cystectomy(solitary lesion in a suitablelocation; no CIS)

or

�b

� Selective bladder sparingfollowing maximal TURbased on tumor response,(only for patients withouthydronephrosis)(category 2B) :

Chemotherapy + RTChemotherapy aloneRT aloneTURBT alone

f

g h

g

h

b

�

�

�

�

Evaluate withcystoscopyand TURBT

T4a, T4b

CLINICALSTAGING

PRIMARY TREATMENT ADJUVANT TREATMENTWORKUP

See BL-5

See BL-6

�

�

�

�

�

�

�

CBCChemistry profileBone scanChest x-rayCT/MRI of abdomenand pelvisECGCreatinine clearance

Metastatic See BL-6

Bladder Cancer

b

f

g

h

There is data to support equivalent survival rates, but not uniform consensus about the role of these approaches. Not all institutions have

experience with these multidisiplinary treatment approaches which require a dedicated team.


See Principles of Chemotherapy Management (BL-C).

See Principles of Radiation Management of Invasive Disease (BL-D).

Return to Bladder CancerTable of Contents

Consider adjuvant chemotherapy based onpathologic risk (positive nodes, high-gradetransmural)g

BL-4

Guidelines Index

Bladder Cancer TOC



T3

Selective bladdersparing followingmaximal TURBTbased on response tochemotherapy + RT(only for patientswithout hydronephrosis)

b

g h

Radical cystectomy

or

b

and considerneoadjuvantchemotherapy

Consider adjuvant chemotherapybased on pathologic risk (high-grade transmural, positive nodes)

g

Notumor

Tumor

ObserveorConsolidationchemotherapy + RTorAdjuvant chemotherapy

g h

g

Resectable

Unresectable

Cystectomyb

T4a,T4b See BL-6

Consider salvagetherapy

CLINICALSTAGING

PRIMARY TREATMENT ADJUVANT TREATMENT

Evaluate withcystoscopy,biopsy, cytology

SeeFollow-up(BL-7)

Bladder Cancer




BL-5

b

g

h


See Principles of Chemotherapy Management (BL-C)


.

Guidelines Index

Bladder Cancer TOC





T4a,T4b

CLINICALSTAGING

PRIMARY TREATMENT ADJUVANT TREATMENTWORKUP

Biopsynodes

Positivenodes

2 cm�

Negativenodes

2–3 cyclesof chemotherapy

Considerconsolidationchemotherapy

orSurgery

g

h

b

±RT

Response

Noresponse

Chemotherapy/RTorChangechemotherapy

g,h

g

Evaluate withcystoscopy + CT

Positivenodes onbiopsy

Negativenodes onbiopsy or CT

ChemotherapyorChemotherapy + RT

g

g h

ChemotherapyorChemotherapy+ RT

g

g

h

or

Surgery ±chemotherapy(select T4apatients only)

Cystoscopy

No tumor

ObserveorBoost with RTorSurgeryb

Tumorpresent

See SalvageTherapy(BL-7)Metastatic

Disseminated Chemotherapyg

Node only

CT

See Salvage Therapy (BL-7)

SeeFollow-up(BL -7)

Bladder Cancer

b

g

h


See Principles of Chemotherapy Management (BL-C)


. Return to Bladder CancerTable of Contents

SeeFollow-up(BL -7)

BL-6

Guidelines Index

Bladder Cancer TOC





FOLLOW-UP RECURRENCE

Local recurrencePreserved bladder

Positive cytologyPreserved bladderC/E, EUA, randombiopsy negative

If cytology ispositive,

or

SeeUpper TractTumors (UTT-1)

ProstaticUrethral guideline(TCCP-1)

Retrograde selectivewashings of upper tract,

urethralbiopsyprostatic

Metastatic orlocal recurrencepostcystectomy

Chemotherapy and/or RTg h

Chemotherapy and/or RTg h

Invasive

Tis, Ta,or T1

Intravesical BCGor cystectomy

Noresponse

Cystectomyb

Cystectomy or salvage chemotherapyif not surgical candidateorRT (if no prior RT)orPalliative TURBT

g

h

�

�

�

�

�

�

Liver function tests,creatinine, electrolytes,chest x-ray every 6-12 modepending on risk ofrecurrence

IVP or Ultrasound atbaseline and every 12 moCT at baseline and at 6mo if high risk

If bladder sparing,cystoscopy + cytologyevery 3 mo x 4, thenincreasing intervals

If cystectomy, urinecytology every 6-12 mo

If cystectomy + cutaneousdiversion, urethral washcytology every 6-12 mo

If cystectomy + continentdiversion,

Vitamin B12 annuallyorthotopic

Muscleinvasive

Metastatic

SALVAGE THERAPY/TREATMENT OF RECURRENCE

Bladder Cancer

b

g

h


See Principles of Chemotherapy Management (BL-C).



BL-7

Guidelines Index

Bladder Cancer TOC



TURBT: Papillary

�

�

Adequate resection with muscle ifpapillary lesion

If incomplete, reresectwhen possible

Repeat biopsy:

� T1, G3

�

�

�

If no muscle in biopsy

Small fragment of T2 insufficient to attribute risk

Repeat TURBT should be considered if firstTURBT does not allow adequate staging orattribution of risk factor for treatment selectionor when using bladder-preserving treatment bychemotherapy and/or RT

�

�

�

Multiple random biopsies

Biopsy adjacent to tumor

Prostate urethral biopsies (in males)

TURBT: CIS

TURBT: Invasive

PRINCIPLES OF SURGICAL MANAGEMENT

Bladder Cancer



RADICAL CYSTECTOMY

� Radical cystectomy should includeregional node resection


BL-A

Guidelines Index

Bladder Cancer TOC





PROBABILITY OF RECURRENCE AND PROGRESSION

Conventional

PathologyProbability ofProgression

Probability ofRecurrence

Minimal

Low

Moderate

Moderate

High

High

Ta, G1

Ta, G1-2

Ta, G3

T1, G1-2

T1, G3

CIS

50%

50%

60%

50%

70%

50%–90%


Bladder Cancer

BL-B

Guidelines Index

Bladder Cancer TOC





Active agents:

�

�

Two-to-three drug combinations base taxanes, andgemcitabine are used for treatment of metastatic disease. Adjuvant orneoadjuvant therapy is also considered for patients at high risk ofrecurrence.

Patients who are poor risk experience high morbidity from the more toxicregimens(e.g. MVAC) and should be treated with combinations of lowertoxicity profiles.These patients are characterized by:

comorbiditylow performance statusvisceral, liver, bone, and lung metastaseshigh alkaline phosphatasehigh LDH

�

�

�

�

�

d on cisplatin,

PRINCIPLES OF CHEMOTHERAPY MANAGEMENT


Bladder Cancer

BL-C

Guidelines Index

Bladder Cancer TOC



Bladder Cancer



PRINCIPLES OF RADIATION THERAPY MANAGEMENTOF INVASIVE DISEASE

�

�

�

�

�

�

Use multiple fields from high-energy linear accelerator beams.

Simulate and treat patients with the bladder empty.

Precede radiation by maximal TUR of the tumor when safely possible.

Combining concurrent chemotherapy with radiation is encouraged for added tumorcytotoxicity. Such therapy is optimally given by dedicated multidisciplinary teams.

External beam radiation is rarely appropriate for patients with recurrent superficialtumors or diffuse CIS.

Treat the whole bladder with 40-55 Gy and then boost the bladder tumor to a total dose of64-66 Gy excluding, if possible, normal areas of the bladder from the high-dose volume.


BL-D

Guidelines Index

Bladder Cancer TOC



NON-TRANSITIONAL CELL CARCINOMA (TCC) BLADDER CANCER

Same as TCC management with the following issues:



Mixed Histology:

with complete responseless likely if bladder sparingconsidered

Cystectomy or RT

Pure Squamous:

�

� Follow Transitional Cell Carcinoma ofthe Bladder

Adenocarcinoma:

�

�

�

�

MVAC ineffectiveCystectomy or partial cystectomyConsider 5-FU-based therapy

Adjuvant or neoadjuvantchemotherapy using small-cellregimens and local treatment(surgery, radiotherapy)

Small-cell:


Bladder Cancer

BL-E

Guidelines Index

Bladder Cancer TOC





Renal

pelvis

�

�

�

�

�

�

�

�

�

IVP

Cytology

Cystoscopy

Retrograde

pyelogram

± Ureteroscopy

± CT

Renal function

tests

Renal scan

(optional)

Chest x-ray,

CBC, chemistry

profile

Bone scan if

abnormal

enzymes or

bone signs

Operable

Nephroureterectomy with

cuff of bladder

Nephron-sparing procedure

or

Endoscopic resection

± postsurgical intra

chemotherapy or BCG

or

pelvic

Nephroureterectomy

with cuff of bladder

Chemotherapy

Metastatic or

serious comorbid

condition

Low grade

High grade, large,

or parenchymal

invasion

PathologicStagingRenal Pelvisand TCC Ureter(UTT-3)

WORKUP PRIMARY TREATMENT

Upper GU Tract Tumors


UTT-1

Guidelines Index

Bladder Cancer TOC



TCC

ureter

Excision and

ureteroureterostomy

or


or

Nephroureterectomy


Nephroureterectomy


Distal ureterectomy

and reimplantation of

ureter (preferred if

clinically feasible)

or


or

Nephroureterectomy


Small,

low grade

Large or

high grade

Upper

Mid

Distal

Nephroureterectomy


or


SeeStaging andFollow-UpRenal Pelvisand TCCUreter(UTT-3)

WORKUP PRIMARY TREATMENT



�

�

�

�

�

�

�

�

�

IVP

Cytology

Cystoscopy

Retrograde

pyelogram

± Ureteroscopy

± CT

Renal function

tests

Renal scan

(optional)

Chest x-ray,

CBC, chemistry

profile

Bone scan if

abnormal

enzymes or

bone signs


UTT-2

Guidelines Index

Bladder Cancer TOC



pT0, pT1, pT2

pT3, pT4, pN+

None

Consider

chemotherapy

for p 3T

Chemotherapy ±

RT for pT4, pN+

�

�

�

�

�

Cystoscopy every 3 mo for 1year, then at increasingintervalsUpper tract imaging 1-2 yrintervals± uteroscopy 3-12 monthintervals± CT scan± Chest x-ray

b

a

b

Follow recommendations for adjuvant chemotherapy after

ensuring that patient is fully staged to rule out metastatic disease.

Imaging may include IVP, CT urography (if available), retrograde pyelogram or MRI urogram.

Same as above

FOLLOW-UP

PATHOLOGIC

STAGING

ADJUVANT

TREATMENT a

Primary TreatmentRenal Pelvisand TCC Ureter




UTT-3


Guidelines Index

Bladder Cancer TOC



WORKUP PATHOLOGY ADDITIONAL

WORKUP

PRIMARY

TREATMENT

�

�

�

�

�

�

Digital rectal examination

Cystoscopy (including

bladder biopsy)

TUR biopsies of prostate

to include stroma

PSA

Needle biopsy

if DRE is abnormal

IVP

or

Retrograde pyelogram

Stromal

invasion

Ductal

+ acini

Prostatic

urethra

Chest x-ray

CT

Chest x-ray

± CT

Cystoprostatectomy

± urethrectomy

Cystoprostatectomy

± urethrectomy

Cystoprostatectomy

± urethrectomy

Cystoprostatectomy

± urethrectomy or

TURP and BCG

TURP + BCG

Consideradjuvantchemotherapy

Recurrence

Recurrence

Transitional Cell Carcinomaof the Prostate



Back to BladderCancer Table ofContents

TCCP-1

Guidelines Index

Bladder Cancer TOC



Staging

Bladder Cancer

ST-1

Table 1

American Joint Committee on Cancer (AJCC)TNM Staging System For Bladder Cancer

TX

T0

Ta

Tis

T1

T2

T2a

T2b

T3

T3a

T3b

T4

T4a

T4b

NX

N0

N1

N2

N3

MX

M0

M1

Stage 0a

Stage 0is

Stage I

Stage II

Stage III

Stage IV

Primary tumor cannot be assessed

No evidence of primary tumor

Noninvasive papillary carcinoma

Carcinoma : “flat tumor”

Tumor invades subepithelial connective tissue

Tumor invades muscle

Tumor invades superficial muscle (inner half)

Tumor invades deep muscle (outer half)

Tumor invades perivesical tissue

Microscopically

Macroscopically (extravesical mass)

Tumor invades any of the following: prostate, uterus, vagina, pelvicwall, abdominal wall

Tumor invades prostate, uterus, vagina

Tumor invades pelvic wall, abdominal wall

Regional lymph nodes are those within the true pelvis; all others are distantlymph nodes.

Regional lymph nodes cannot be assessed

No regional lymph node metastasis

Metastasis in a single lymph node, 2 cm or less in greatest dimension

Metastasis in a single lymph node, more than 2 cm but not more than5 cm in greatest dimension; or multiple lymph nodes, none more than5 cm in greatest dimension

Metastasis in a lymph node more than 5 cm in greatest dimension

Distant metastasis cannot be assessed

No distant metastasis

Distant metastasis

Ta N0 M0

Tis N0 M0

T1 N0 M0

T2a N0 M0

T2b N0 M0

T3a N0 M0

T3b N0 M0

T4a N0 M0

T4b N0 M0

Any T N1 M0

Any T N2 M0

Any T N3 M0

Any T Any N M1

in situ

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastasis (M)

Stage Grouping Histopathologic Type

In Situ

Squamous cell carcinoma

Adenocarcinoma

Undifferentiated carcinoma

Histopathologic Grade (G)

GX

G1

G2

The histolologic types are the following:

PapillaryFlatWith squamous metaplasiaWith glandular metaplasia

With squamous and glandularmetaplasia

The predominant cancer is urothelial(transitional cell) carcinoma.

Grade cannot be assessed

Well differentiated

Moderately differentiated

Used with the permission of the American Joint Committee on Cancer

(AJCC), Chicago, Illinois. The original and primary source for this

information is the AJCC Cancer Staging Manual, Sixth Edition (2002)

published by Springer-Verlag New York. (For more information, visit

) Any citation or quotation of this material must

be credited to the AJCC as its primary source. The inclusion of this

information herein does not authorize any reuse or further distribution

without the expressed, written permission of Springer-Verlag New York,

Inc., on behalf of the AJCC.

www.cancerstaging.net.

G3-4 Poorly differentiated orundifferentiated

http://www.cancerstaging.net

Guidelines Index

Bladder Cancer TOC



Manuscript

NCCN Categories of Consensus

Overview

Category 1

Category 2A

Category 2B

Category 3

All recommendations are category 2A unless otherwise noted.

: There is uniform NCCN consensus, based on high-level

evidence, that the recommendation is appropriate.

: There is uniform NCCN consensus, based on lower-

level evidence including clinical experience, that the

recommendation is appropriate.

: There is nonuniform NCCN consensus (but no major

disagreement), based on lower-level evidence including clinical

experience, that the recommendation is appropriate.

: There is major NCCN disagreement that the

recommendation is appropriate.

In 2003, an estimated 57,400 new cases of urinary bladder cancer

were diagnosed in the United States (42,200 male and 15,200

female), making the disease the fourth most common cancer in men

and the tenth most common neoplasm in women. During that same

time period, some 12,500 deaths (8,600 male and 3,900 female)

from bladder cancer were anticipated. Bladder cancers are rarely

diagnosed in individuals under age 40. Because the median age of

diagnosis is 65, medical comorbidities are a frequent consideration

in patient management.

The clinical spectrum of bladder cancer can be divided into three

categories, which differ in prognosis, management, and therapeutic

aims. The first category consists of noninvasive tumors, for which

treatment is directed at reducing recurrences and progression to a

more advanced stage.

The second group encompasses the invasive lesions. The goal of

therapy for this group is to determine which bladders should be

removed, which can be preserved without compromising survival,

and which, independent of the management of the primary lesion,

have a high risk of distant spread and require systemic approaches

to improve the likelihood of cure.

The critical concern of therapy for the third group, consisting of

metastatic lesions, is how to prolong life. However, even within this

category, the outlook is changing, as numerous agents with different

mechanisms of action have antitumor effects in this disease. The

issue then becomes how to use these agents so as to achieve the

best possible outcome.

More than 90% of urothelial tumors begin in the urinary bladder, 8%

begin in the renal pelvis, and the remaining 2% originate in the

ureter and urethra. Transitional cell carcinomas, the most common

histologic subtype in the United States, may develop anywhere there

is transitional epithelium, from the renal pelvis to the ureter, bladder,

and proximal two-thirds of the urethra. The distal third of the urethra

is dominated by squamous epithelium. The diagnosis of squamous

cell tumors, which constitute 3% of the urinary tumors diagnosed in

the United States, requires the presence of keratinization in the

specimen. In areas where infections with

are endemic (e.g., Egypt), 40% of urothelial tumors are pure

squamous cell carcinomas.

1

1

2

Histology

Schistosoma haematobium

Bladder Cancer

MS-1

Guidelines Index

Bladder Cancer TOC



Of the other histologic subtypes, 2% are adenocarcinomas and 1%

are small-cell tumors (with or without an associated paraneoplastic

syndrome). Adenocarcinomas often occur in the dome of the bladder

in the embryonal remnant of the urachus, in the periurethral

tissues, or with a signet-ring-cell histology. Often, urothelial tumors

have a mixture of histologic subtypes, such as transitional cell and

squamous or transitional cell and adenocarcinoma. These should be

treated as transitional cell tumors.

The systemic chemotherapy regimens used to treat transitional cell

tumors are generally ineffective for tumors with a pure

nontransitional cell (adenocarcinoma or squamous carcinoma)

histology. In some cases with a mixed histology, only the

nontransitional cell component remains after systemic treatment.

The most common presenting symptom in patients with bladder

cancer is microscopic hematuria, although urinary frequency as a

result of irritation or a reduced bladder capacity can also develop.

Less commonly, a urinary tract infection is the presenting symptom,

or, for a more advanced lesion, upper tract obstruction or pain may

occur. Patients who present with these symptoms should be

evaluated by office cystoscopy to determine whether a lesion is

present. If one is documented, the patient should be scheduled for a

transurethral resection of the bladder tumor (TURBT) to confirm the

diagnosis and determine the extent of disease within the bladder.

If the cystoscopic appearance of the tumor is solid (sessile), high-

grade or suggests invasion into muscle, a computed tomographic

(CT) scan of the abdomen and pelvis is recommended before the

TURBT. The results of a CT scan rarely alter the management of

tumors with a purely papillary appearance or cases in which only the

mucosa appears abnormal, suggesting carcinoma in situ (CIS);

thus, a CT scan is not recommended in such situations.

The additional workup for all patients should include evaluation of

the upper tracts with an intravenous pyelogram (IVP), retrograde

pyelogram and urine cytology.

TURBT with a bimanual examination under anesthesia (EUA) is

performed to resect visible tumor and to sample muscle within the

area of the tumor to assess whether invasion has occurred. When a

large papillary lesion is noted, more than one session may be

needed to completely resect the tumor. In the case of CIS, biopsy of

sites adjacent to the tumor, as well as multiple random biopsies,

should be done to assess for a field change. A TUR biopsy of the

prostate may also be considered in these cases. Finally, if an

invasive tumor is noted, it is important to ensure that an adequate

sample of muscle is obtained. A small fragment of tumor with few

muscle fibers is inadequate for assessing the depth of invasion and

guiding treatment recommendations.

Additional diagnostic tests, such as bone scan, should be performed

if clinically indicated. Treatment decisions are then based on

disease extent within the three general categories--noninvasive,

invasive, or metastatic.

In the presence of a positive cytology and a normal cystoscopy, an

evaluation of the upper tracts (and, in males, the prostate) is

required.

Management is based on the pathologic findings of the biopsy

specimen, with attention to histology, grade, and depth of invasion.

These factors are used to estimate the probability of recurrence and

the probability of progression to a more advanced stage. Ploidy,

vascularity, p53 status, and other markers (e.g., NMP-22, BTA, M344)

3,4

5

Clinical Presentation and Workup

Bladder Cancer

MS-2

Guidelines Index

Bladder Cancer TOC



are considered of uncertain clinical benefit and are not used to guide

treatment decisions outside of the experimental protocol setting.

About 70% of newly detected cases are exophytic papillary tumors

confined largely (70%) to the mucosa (Ta) or, less often (30%), to

the submucosa (T1). These tumors tend to be friable and have a

high propensity to bleed. Their natural history is characterized by a

tendency to recur in the same portion or another part of the bladder

over time (a phenomenon termed “polychronotropism”); these

recurrences can be either at the same stage as the initial tumor or at

a more advanced stage.

Papillary tumors confined to the mucosa or submucosa are

generally managed endoscopically by complete resection.

Progression to a more advanced stage may result in local symptoms

or, less commonly, symptoms related to metastatic disease.

It is estimated that 10% to 70% of patients with a tumor confined to

the mucosa will have a recurrence or a new occurrence of a

transitional cell carcinoma within 5 years. These probabilities of

progression vary as a function of the initial stage and grade.

Refining these estimates for the individual patient is an area of

active research.

The most commonly utilized staging system is the tumor, node,

metastasis (TNM) system, as shown in .

Bladder tumors are graded as low (G1), intermediate (G2), or high

(G3). However, the determination of grade has a greater impact on

the management of noninvasive tumors because most invasive

tumors (i.e., greater than T1) are high grade. An alternative grading

system has been proposed but is not universally accepted at this

time.

Papillomas (Ta, G1) are considered to be benign tumors that closely

resemble the normal urothelium. They can be recognized

histologically because they have more than the normal seven

epithelial layers, normal polarity of the nuclei, and minimal

pleomorphism. Papillomas and G1, Ta carcinomas are managed

almost exclusively by endoscopic means because they rarely

progress to a higher, more lethal stage. In contrast, Ta, G3 tumors

have a higher chance of progression to a more advanced stage.

Once stage and grade have been determined, treatment decisions

are based on the depth of invasion and extent of disease.

The treatment of bladder cancer entails the disciplines of urologic

surgical oncology, radiation oncology, and medical oncology. For

many of the complex strategies the involvement of multidisciplinary

teams will optimize results. The general principles for each of these

modalities have been delineated.

Surgery

Chemotherapy

Radiation Therapy

“Superficial” non muscle-invasive tumors are divided into

noninvasive papillomas or carcinomas (Ta), those invading the

lamina propria (T1), and CIS. In some cases, a papillary or T1

Pathology And Natural History

6

7

8

9,10

11

Staging And Grading

Table 1

BL-A

BL-C

BL-D

Treatment

Treatment of Nonmuscle-Invasive Disease

Bladder Cancer

MS-3

Guidelines Index

Bladder Cancer TOC



lesion will be documented as having an associated in situ component

(Tis). The standard treatment in such cases is repeat TUR. However,

depending on the depth of invasion and grade, intravesical therapy

may be recommended. This suggestion is based on the estimated

probability of recurrence (i.e., a new tumor formation within the

bladder) and progression to a more advanced, usually invasive

stage--events that should be considered independently. Cystectomy

is rarely considered for a Ta, G1 or G2 lesion.

Intravesical therapy is used in two general settings: as prophylactic

or adjuvant therapy following a complete endoscopic resection or,

rarely, as therapy aimed at eradicating residual disease that could

not be completely resected. This distinction is important, as most

published data reflect prophylactic or adjuvant use with the aim of

preventing recurrence and/or delaying progression to a higher grade

or stage. In many cases, intravesical therapy is given to patients

who do not require it because the probability of recurrence or

progression in them is low. Management of the different histologic

subtypes of different grades is outlined below.

TUR without intravesical therapy is the standard treatment for Ta,

G1 and Ta, G2 tumors. Since patients diagnosed with these tumors

have a relatively high risk of recurrence, the panel also offers

consideration of a single dose of intravesicle chemotherapy (not

immunotherapy) within 24 hours of resection. Close follow-up is

needed, even though the risk of progression to a more advanced

stage is low. As a result, these patients are advised to undergo a

cystoscopy at 3 months, initially, and then at increasing intervals. If

no recurrences develop during the first year, the interval between

evaluations can be increased. Patients in whom a recurrence is

documented are treated based on the stage and grade of the

recurrent lesion; they are then followed at 3-month intervals.

Intravesical therapy is recommended for patients who have a history

of recurrences.

Tumors staged as Ta, G3 lesions are considered to be high grade

papillary tumors with a relatively high risk of recurrence and

progression towards more invasiveness. For this reason, they are

treated in the same manner as T1, G1-2 tumors with intravesicle

BCG being the preferred option for post-operative treatment.

Primary Tis is a high-grade lesion that is believed to be a precursor

of invasive bladder cancer. Standard therapy for this lesion is a

complete endoscopic resection followed by intravesical therapy with

bacillus Calmette-Guérin (BCG). This is generally given once a

week for 6 weeks, followed by a 6-week rest period, with a full

reevaluation at week 12 (i.e., 3 months) after the start of therapy.

Patients with Tis who have recurrent/persistent disease at the 12-

week (3-month) evaluation can be given a second course of BCG

induction therapy, although some urologists advise a cystectomy at

this point. If a second course of BCG is given and there is residual

disease at the second 12-week (3-month) follow-up, a cystectomy

should be strongly considered. Depending upon prior treatment, the

extent of the disease, and the frequency of recurrences, intravesical

therapy with mitomycin, or less commonly valrubicin, or alpha-

interferon is an alternative to cystectomy. In some centers, however,

these patients might still be candidates for investigational therapies.

For patients with no disease at the follow-up cystoscopy, whether one

or two courses of induction therapy were administered, maintenance

therapy is advised, although this recommendation is not universal.

Papilloma/TA, G1 or G2

TA, G3 Disease

Superficial Tis

Bladder Cancer

MS-4

Guidelines Index

Bladder Cancer TOC



Regardless of whether or not maintenance therapy is administered,

patients with Tis should be followed at 3-month intervals with a

urinary cytology and cystoscopy for the first 2 years, and if no

recurrences are documented, every 6 months in the third and fourth

years and then annually. If progression to an invasive lesion is

documented at any point during follow-up, a radical cystectomy is

recommended. Although controversial, patients who present with

recurrent superficial tumors prior to the documentation of a muscle-

invading lesion are generally not considered to be candidates for

bladder-sparing approaches.

T1 lesions are considered to be invasive (invading the lamina

propria) and have a high risk of both recurrence and progression.

These tumors may occur as solitary lesions or as multifocal tumors,

with or without an associated in situ component. They, too, are

treated with a complete endoscopic resection followed by intravesical

therapy (this is optional for G1 or G2 lesions). Within the category of

T1 disease, two risk strata can be identified: low-risk (G1, G2, or

solitary) and high-risk (G3 or multifocal lesions, tumors associated

with vascular invasion, or lesions that recur after BCG treatment).

Patients with low-risk disease are advised to

undergo a repeat cystoscopy 6 to 12 weeks after the initial diagnosis

to ensure that there is no invasion into the muscularis propria (T2),

in which case a radical cystectomy would be the treatment of choice.

If no tumor is documented or if there is no further invasion,

intravesical therapy is optional.

Follow-up is similar to that previously outlined above for Ta, G1 or

G2 disease, with a urinary cytology and cystoscopy recommended

at 3-month intervals for the first 2 years and repeated at increasing

intervals over the next 4 years. Recurrent disease is treated as

appropriate for the stage documented at the time of relapse.

Patients with high-risk disease (T1, G3) can be

treated with a course of BCG (category 1) or mitomycin, but evolving

data suggest that the preferred approach may be early cystectomy,

due to the high risk of progression to a more advanced stage. A

fourth option is to perform a repeat resection at 4 to 8 weeks. If it is

negative, maintenance BCG therapy may be continued; if it is

positive, consider a cystectomy or BCG. If high-risk disease is

managed conservatively and does not respond to BCG, a

cystectomy should be performed.

The standard treatment for a T2 or T3 muscle-invading tumor is

surgical removal of the bladder by radical cystectomy. In recent

years, radiation therapy (RT) and chemotherapy have been used in

a few centers in the primary treatment of bladder cancer so that now

several options, including sparing of the bladder, may be available

depending on the stage of the tumor.

Before any treatment is advised, the patient should be assessed for

the presence of regional and/or distant metastases. This evaluation

should include a cystoscopy, EUA/TURBT, chest x-ray, and evaluation

of the upper tracts with a CT or MRI scan of the abdomen and pelvis.

Some physicians advocate performing magnetic resonance imaging

(MRI) to determine the depth of invasion within the bladder and, in

particular, to ascertain whether a tumor has reached the perivesical

fat (T3b). Unfortunately, CT scans, ultrasound, or MRI cannot

accurately predict the true depth of invasion.

If distant disease is documented, the initial management should be

systemic. Comorbidities, such as cardiac or pulmonary disease and

T1 Disease

Treatment of Muscle Invasive Disease

Low-risk Disease:

High-risk Disease:

12

13,14

Bladder Cancer

MS-5

Guidelines Index

Bladder Cancer TOC



renal or hepatic dysfunction, which may influence the ability to

undergo a major operation, must also be evaluated and factored into

any treatment recommendations.

Assuming that the metastatic workup is negative and the patient

does not have medical comorbidities that preclude surgery, the

treatment may proceed directly with surgery. An exploratory

laparotomy with pelvic lymph node dissection is performed. If

extensive disease is found in the lymph nodes or elsewhere in the

pelvis, the cystectomy is generally not completed, and the patient is

referred for systemic therapy. If there is minimal or no gross disease

in the lymph nodes, the cystectomy is completed. If the bladder

cannot be removed or metastatic disease is found in the pelvic lymph

nodes, omentum, or liver, a decision is made as to whether a urinary

diversion is required, and the patient is closed. After recovery from

surgery, the patient should be evaluated for systemic chemotherapy

or a combination of radiation and chemotherapy, as appropriate.

The appropriate surgical procedure involves a cystoprostatectomy in

males or a cystectomy and hysterectomy in females, followed by the

formation of a urinary diversion. Forms of urinary diversion include

an ileal conduit or directing urine to an internal urinary reservoir,

with drainage to the abdominal wall or to the urethra. Relative

contraindications to urethral drainage include CIS in the prostatic

urethra or outlet obstruction. Orthotopic diversion or a neobladder

provides bladder function similar to that of a native bladder with

some increased risk of nighttime incontinence or urinary retention

requiring intermittent self-catheritization.

Depending upon the pathologic findings, adjuvant chemotherapy

may or may not be recommended. Patients with nontransitional cell

invasive disease are generally managed by cystectomy, although

those with certain urachal tumors may be appropriately treated with

partial cystectomy. In patients with nontransitional cell tumors of any

stage, there are no data to support the use of adjuvant

chemotherapy, even though the risk of relapse may be high.

Two critical issues in the management and prognosis of patients

with muscle-invasive disease are (1) whether or not a palpable mass

is appreciated at the time of the EUA and (2) whether or not the

tumor has extended through the bladder wall.

Tumors that are organ-confined (T2) have a better prognosis than

those that have extended through the bladder wall to the perivesical

fat (T3) and beyond. Treatment options include radical cystectomy

with consideration of neoadjuvant chemotherapy, segmental

cystectomy in highly selected cases, and a variety of bladder-

sparing approaches.

Unfortunately, the accuracy of the staging

cystoscopy and biopsy is modest in making these distinctions, with

both understaging and overstaging encountered frequently.

Consequently, most physicians advise a radical cystectomy when

muscle-invasive disease is documented and defer the decision

about whether to administer postoperative treatment until the

pathologic findings have been evaluated.

Follow-up after a cystectomy should include urine cytology and

serum chemistries every 6 to 12 months and then at increasing

intervals. Patients should be monitored for vitamin B deficiency if a

continent diversion was created. A urethral wash is optional,

depending on whether there was involvement of the urethra by CIS

or diffuse CIS within the bladder. A postoperative CT scan is advised

to define the revised anatomy of the pelvis and should be repeated

Organ-Confined (t2) Disease in Surgical Candidates

Surgical Approaches and Postoperative Adjuvant Therapy

Radical Cystectomy:

12

Bladder Cancer

MS-6

Guidelines Index

Bladder Cancer TOC



in 6 months if the risk of recurrence is high An IVP or ultrasound

scan at baseline and then every 12 months is also advised.

In approximately 5% of cases or fewer, an

initial invasive tumor will develop in an area of the bladder where an

adequate margin (minimum of 2 cm) of noninvolved urothelium can

be removed along with the tumor without compromising continence

or significantly reducing bladder capacity. Partial cystectomy is most

frequently recommended for lesions that develop on the dome of the

bladder and that have no associated CIS in other areas of the

urothelium. Relative contraindications to this procedure are lesions

that occur in the trigone or bladder neck. The requirement for a

ureteral reimplantation, however, is not an absolute contraindication.

As is the case with radical cystectomy, partial cystectomy begins

with a laparotomy and evaluation of the pelvic lymph nodes prior to

making the decision to remove the affected portion of the bladder. If

the intraoperative findings preclude a partial cystectomy, a radical

cystectomy is performed. The decision to recommend adjuvant

therapy is based on the pathologic stage, as is the case in patients

who undergo a radical cystectomy.

Follow-up after a partial cystectomy is similar to that outlined above

for a radical cystectomy, with the addition of monitoring for relapse

in the bladder, as well as for systemic recurrence, with serial

cytologic examinations and cystoscopies at 3-month intervals. A

local recurrence within the preserved bladder should be evaluated

as a new cancer. Patients with a superficial recurrence (Tis, Ta, or

T1) may be considered for intravesical BCG treatment; if BCG elicits

no response, salvage cystectomy is a possible option. Those with an

invasive recurrence should undergo cystectomy or, if they are not

surgical candidates, RT or chemotherapy, or both.

If a positive cytology is documented in a patient with a normal

bladder, an evaluation of the upper tracts with selective washings

and a prostatic urethral biopsy is recommended. Pending these

findings, management is the same as that for upper tract or prostatic

urethral disease, as described below.

Data are conflicting as to the role of

adjuvant systemic chemotherapy in invasive bladder cancer

because no randomized comparisons of adequate sample size have

definitively shown a survival benefit of such therapy. Many of the

trials demonstrating a survival benefit were not randomized, raising

the question of selection bias in the analysis of outcomes.

Two trials, one from the University of California and a second from

Germany, did show a survival advantage afforded by therapy with

CAP (cyclophosphamide, doxorubicin, and cisplatin) in the

California study and with M-VAC (methotrexate, vinblastine,

doxorubicin, and cisplatin) or M-VEC (methotrexate, vinblastine,

epirubicin, and cisplatin) in the German trial, but methodological

issues have raised questions as to the applicability of both studies

to all patients with urothelial tumors. With respect to the latter trial,

patients who relapsed in the control arm did not receive

chemotherapy, which is not typical of more contemporary series.

Nevertheless, the results of currently available trials do show that

adjuvant chemotherapy can delay recurrences, which, for most

patients, is benefit enough to justify the routine administration of

chemotherapy in those at a high risk for relapse. A minimum of four

cycles of a cisplatin-based combination such as M-VAC should be used

when adjuvant therapy is given. No data support the use of adjuvant

chemotherapy for nontransitional cell tumors, regardless of stage.

.

Partial Cystectomy:

Adjuvant Chemotherapy:

15

Bladder Cancer

MS-7

Guidelines Index

Bladder Cancer TOC



Patients with tumors that are pathologic stage T2 or less and have

no nodal involvement are considered to be at low risk and do not

necessarily require adjuvant chemotherapy. They should be

monitored with urinary cytology. T2 tumors with nodal involvement or

other high-risk pathological features, such as high-grade histology,

transmural invasion, or vascular invasion should be considered for

adjuvant chemotherapy, or less commonly, radiotherapy. Some

groups are beginning to stratify patients on the basis of the p53

status of the tumor, as tumors with more than 20% of positive cells

appear to have a higher risk of systemic relapse. Determination of

the p53 status of the tumor is still considered an experimental

procedure, however, and is not part of routine management.

Because of the higher risk of relapse, an IVP or ultrasound

examination at baseline and repeated every 12 months is advised,

as is a CT scan at baseline and at 6 months for patients at high risk.

If a relapse is documented, salvage chemotherapy is advised with a

regimen to which the patient has not been previously exposed.

Within the category of T2 transitional cell tumors, selected patients

may be considered for bladder-sparing approaches (Category 2B).

The options include aggressive endoscopic resection alone,

endoscopic resection followed by chemotherapy alone, RT alone, or

a combination of chemotherapy and RT. There is not uniform

consensus about the applicability of these approaches to the

management of T2 tumors.

The decision as to whether or not to use a bladder-sparing approach

is based, in part, on the location of the lesion, the depth of invasion,

the size of the tumor, the status of the “noninvolved” urothelium, and

the status of the patient. Bladder-preserving approaches are

reasonable alternatives to cystectomy for patients who are medically

unfit for surgery and for patients who seek an alternative. Patients

with hydronephrosis are poor candidates for bladder-sparing

procedures. The antecedent history of the bladder with respect to

prior superficial disease, risk of new tumor formation, and bladder

capacity should also be considered. In addition, metastatic disease

must be excluded.

With any of the nonsurgical approaches, a concern exists over the

ability to determine with certainty which bladders that appear to be

endoscopically free of tumor (T0), based on a clinical assessment

that includes a repeat TURBT, are, in fact, pathologically free of

tumor (PT0). Depending upon the series, upward of 30% to 40% of

bladders believed to be free of disease preoperatively after

chemotherapy were found to have residual disease at cystectomy.

The frequency of residual disease is lower for patients who present

with T2 disease but, nevertheless, must be considered when

proposing a bladder-sparing approach. When possible, bladder-

sparing options should be chosen in the context of clinical trials and

not considered to be standard approaches, because of the

suggestion in some series that survival may be compromised and

because this treatment is best done by dedicated multidisciplinary

teams. The guidelines indicate that following maximal TUR

chemotherapy and radiation therapy, chemotherapy alone, or

radiation therapy alone are appropriate treatment options.

Patients in whom a bladder-sparing approach is being considered

generally undergo a repeat TURBT within 4 to 6 weeks of the

original procedure to determine whether all disease has been

resected. In cases in which it has, observation, chemotherapy with

or without radiation may be advised, depending on the treatment

16

17

Bladder-Sparing Options

Bladder Cancer

MS-8

Guidelines Index

Bladder Cancer TOC



policy of the institution. In cases in which all disease has not been

resected, radical cystectomy is recommended.

All of these approaches are based on the principle that an

immediate cystectomy need not be performed in all cases--and that

the decision to remove the bladder can be deferred until the

response to therapy (be it chemotherapy alone or chemotherapy

and RT) is assessed. If, after 2 to 3 months of induction therapy, no

disease is documented at the repeat TURBT, the patient may be

observed or the response consolidated with chemotherapy and/or

RT. If there is residual disease, a cystectomy is generally advised,

or, if the disease is unresectable, salvage therapy is recommended.

To date, these approaches have been shown to be beneficial in

selected cases, but few of these therapeutic strategies have been

formally evaluated in prospective randomized comparisons and

must, therefore, still be considered investigational.

It must also be remembered that management of the bladder tumor

is only one part of the overall management of patients with T2

disease, as these individuals remain at risk for recurrence in both

the bladder and other sections of the urothelial tract, as well as for

systemic disease. Continued monitoring of the urothelium, with

urinary cytologies at 3-month intervals, along with serial

cystoscopies, is a routine part of the management of all cases in

which the bladder is preserved. Imaging studies should also be

performed, as outlined under postcystectomy follow-up.

TUR, by itself, may be curative in selected cases in

which the lesion is solitary, less than 2 cm in size, and has minimally

invaded the muscle. There should be no associated in situ

component, palpable mass, or associated hydronephrosis.

If considered for TURBT alone, patients should undergo an aggressive

re-resection of the site within 4 weeks of the primary procedure to

ensure that there is no residual disease. If the repeat TURBT is

negative for residual tumor, the patient can be managed conservatively

with repeat endoscopic evaluations and cytologies every 3 months

until a relapse is documented. At that point, management would

depend on the stage of the lesion documented at relapse.

Without a complete TURBT, radiation alone is not

considered standard treatment for patients with an invasive bladder

tumor. It is only indicated for those who cannot tolerate a cystectomy

due to the presence of medical comorbidities. Even in these cases,

combinations of chemotherapy and RT are considered to be

superior to RT alone with respect to control of disease within the

bladder. The results of RT alone are also considered to be inferior to

those of radical surgery, and the irradiated patient remains at risk for

new tumor formation or persistence of disease within the bladder.

These approaches entail the use

of induction therapy with deferred management of the bladder

pending the assessment of response in the primary tumor.

The use of chemotherapy alone is not

considered adequate without additional treatment to the bladder.

This view is based on reported series showing that the complete

pathologic response proportions in the bladder using neoadjuvant

chemotherapy alone were only 20% to 30%. A higher proportion of

bladders can be rendered tumor-free and, as such, preserved when

chemotherapy is followed by a partial cystectomy or is combined

with RT in a sequential or concurrent manner.

When chemotherapy alone is used, two cycles of therapy are

generally administered, and a reassessment that includes a

TUR Alone:

RT Alone:

Combined-Modality Strategies:

Chemotherapy Alone:

18

Bladder Cancer

MS-9

Guidelines Index

Bladder Cancer TOC



cystoscopy and biopsy is advised. This evaluation is performed to

exclude progression or a negative response, which would warrant

an immediate cystectomy.

Patients who respond to two cycles of chemotherapy are advised to

complete an additional two to four cycles followed by a cystoscopy

and biopsy, at which point, management of the bladder is determined.

In general, if residual disease is documented after four cycles of

chemotherapy, a cystectomy should be performed. Even when no

disease is documented (T0), the possibility of occult residual disease

in the bladder must be factored into the therapeutic recommendations.

Only 5% of

invasive tumors present initially in a location that is amenable to

curative resection by partial cystectomy. In one series, 27% of

tumors that were originally felt to require radical cystectomy for

control could be removed by partial cystectomy following M-VAC

chemotherapy. Such an approach is not widely utilized. This

procedure has the advantages of surgically removing the diseased

portion of the bladder and allowing for definitive lymph node staging.

Follow-up is the same as outlined above for partial cystectomy.

Several groups have investigated the

combination of concurrent or sequential chemotherapy and RT after

TURBT. First, an endoscopic resection that is as complete as

possible is performed. This is followed by one of three general

approaches, which, based on single-arm studies, appears to provide

the highest proportion of tumor-free bladders: (1) MCV induction

chemotherapy for two cycles, followed by concurrent cisplatin and

RT; (2) concurrent cisplatin and RT without MCV (methotrexate,

cisplatin, vinblastine) induction; or (3) concurrent cisplatin, 5-

fluorouracil (5-FU), and RT.

Two cycles of MCV chemotherapy are administered, following which

a repeat cystoscopy and TURBT are performed. If progression is

documented, a cystectomy is advised. If a response is noted, 40 Gy

of external-beam RT is administered via a four-field technique, and

two doses of concurrent cisplatin are given on days 1 and 22.

Following this, an endoscopic reevaluation is performed. If residual

disease is noted, a cystectomy is advised. If there is no visible

disease, and the cytology and biopsy are negative (T0), an

additional 25 Gy of external-beam RT is administered, along with

one additional dose of cisplatin. The patient is then followed with

serial urinary cytologies and cystoscopies, as outlined previously,

because the Radiation Therapy Oncology Group (RTOG) reported

no benefit with MCV induction prior to concurrent cisplatin and

radiation. MCV induction is being used less frequently.

In prospective, single- and multi-institution series, upward of 70% of

patients who completed this regimen were rendered tumor-free in

the bladder. However, during follow-up, about one-fourth of these

individuals developed a new superficial or invasive lesion requiring

additional therapy. These patients must also be monitored for

possible systemic relapses, as described previously.

Following a complete TURBT,

patients are treated with cisplatin and 5-FU on days 1 to 3 and again

on days 15 to 17. RT is delivered to a total dose of 45 Gy, and the

patient is reevaluated with cystoscopy, biopsy, and urinary cytology.

If these evaluations are negative, RT is continued to a total dose of

64.8 Gy, along with one additional course of cisplatin. The follow-up

schema is the same as outlined previously, beginning with a

cystoscopy and cytology 3 months after therapy is completed.

Chemotherapy Followed by Partial Cystectomy:

Chemotherapy and RT:

Concurrent Cisplatin Plus RT, With or Without MCV Induction:

Concurrent Cisplatin/5-FU Plus RT:

19

20,21

Bladder Cancer

MS-10

Guidelines Index

Bladder Cancer TOC



Relapses in the Bladder After Bladder-Sparing Approaches:

Treatment of relapses is based on the extent of disease at the time

of relapse, with consideration given to the prior treatment that a

patient has received.

Tis, Ta, or T1 tumors are generally managed with intravesical BCG

therapy. If there is no response, a cystectomy is advised. A positive

cytology with no evidence of disease in the bladder should prompt

selective washings of the upper tracts and an evaluation of the

urethra. If the selective cytologies are positive, patients are

managed as described below under treatment of upper tract tumors.

Invasive disease is generally managed by radical cystectomy; a

second attempt at bladder preservation is not advisable.

All patients who relapse after bladder-sparing therapy and are being

considered for radical cystectomy should be evaluated for medical

comorbidities and undergo a full restaging evaluation to ensure that

there is no metastatic disease. As is the case with primary

cystectomy, an exploratory laparotomy is performed first to ensure

that there is no involvement of the lymph nodes, omentum, or other

organ sites. Even in patients who have no extravesical spread, the

morbidity of radical cystectomy can be significant, although the

operative mortality is low (1% to 3%).

Although cystectomy is the preferred approach, it may not be

possible for a patient who has received a full course (greater than

65 Gy) of external-beam RT and has bulky residual disease. For

these patients, salvage chemotherapy is advised, generally with a

regimen that is non-cross-resistant to the one that the patient has

previously received. Those treated with single-agent cisplatin can be

considered for a standard three- or four-drug regimen, whereas

those who have already received a three-drug (e.g., CMV) or four-

drug (e.g., M-VAC) regimen may be considered for therapy with

paclitaxel, gemcitabine, or ifosfamide, as outlined below under

salvage chemotherapy. If the patient has not received RT, a course

of RT may also be considered.

Metastatic disease is managed with salvage chemotherapy using a

regimen to which the patient has not been previously exposed.

The primary treatment for a tumor that has extended beyond the

confines of the bladder wall and that is still considered resectable,

based on the mobility of the bladder, is radical cystectomy, as

outlined previously. Except in highly selected cases (see below),

bladder preservation is not an option in such patients, as the

proportion rendered tumor-free using chemotherapy alone is

generally less than 10%. Tumors that are pathologic stage T3 or T4

with nodal involvement or vascular invasion have a high risk (greater

than 50%) of systemic relapse and, therefore, may be considered for

treatment with adjuvant chemotherapy) or radiotherapy. The follow-

up schema is the same as that previously outlined for high-risk

patients in the section on adjuvant chemotherapy.

Owing to the high risk of systemic relapse in this group, based on

historical series using surgery alone, a number of groups are also

investigating combined-modality approaches using neoadjuvant

chemotherapy followed by surgery or neoadjuvant chemotherapy

and radiation followed by surgery. If possible, these patients should

be placed on clinical trials.

Bladder preservation can be considered in selected cases in which

there is no palpable mass on EUA and no hydronephrosis. This

approach should also be used in the context of an investigational

protocol. Bladder preservation may also be considered for patients who

are deemed unsuitable for surgery based on medical comorbidities.

Non-Organ-Confined Disease (T3/T4A)

Bladder Cancer

MS-11

Guidelines Index

Bladder Cancer TOC



The general approach to this bladder-sparing strategy for these

patients is similar to that outlined previously under combined-

modality, bladder-sparing strategies in patients with organ-confined

disease. Patients are treated with a course of induction therapy

(e.g., neoadjuvant chemotherapy alone or neoadjuvant

chemotherapy plus RT with or without concurrent chemotherapy),

with a deferred decision on management of the primary lesion.

Patients with unresectable disease, defined as a fixed bladder

mass, or those with positive nodes prior to laparotomy are

considered for chemotherapy alone or chemotherapy with RT. An

initial stratification is based on the results of transaxial imaging. For

patients who show no nodal disease on CT scans, the treatment

recommendation is for two to three courses of chemotherapy

followed by cystoscopy and CT scan. If the tumor has responded,

options include consolidation chemotherapy, RT or surgery. If no

response is noted, chemotherapy/RT or a new chemotherapy

regimen can be used.

If pelvic lymph nodes greater than 2 cm are documented, a biopsy is

advised to exclude nodal spread. Baseline renal function, the

presence or absence of cardiac disease, and overall performance

status must also be considered when making a treatment

recommendation. Patients with a good performance status and no

significant comorbid disease may be considered for chemotherapy

with or without RT if their nodes are positive. If complete response is

obtained, surgery may be contemplated.

Chemotherapy options are discussed below under metastatic

disease, whereas combined-modality approaches using

chemotherapy and RT are discussed above. For patients who

cannot tolerate multidrug combinations with radiotherapy, an

alternative is to use RT with a radiation sensitizer, such as cisplatin,

administered starting on day 1 and day 21, or 5-FU with a variety of

schedules. Patients are initially treated with 45 Gy of radiation to the

pelvis and bladder, with a boost of approximately 20 Gy to sites of

disease within the bladder.

In highly selected patients with metastatic disease who have a

complete systemic response to chemotherapy, salvage surgery may

be performed to render the patient disease-free. Data from several

groups show that this aggressive approach can result in long-term

survival.

Prior to exploratory surgery, metastatic disease must be excluded

with appropriate imaging studies. If the exploration is negative for

metastases within the abdomen, salvage surgery can be performed.

Patients who have residual invasive disease in the bladder or nodal

spread after combined-modality therapy have a high risk of local and

systemic relapse and should be followed as outlined above, under

high-risk adjuvant therapy. If there is no response, a change in

chemotherapy is recommended or, depending on the patient's

symptoms from the primary lesion, palliative radiotherapy may be

considered.

Patients who present with unresectable or metastatic disease or

who subsequently develop metastatic disease are generally treated

with systemic chemotherapy ( ) or radiotherapy. These

patients should undergo a staging evaluation that includes a chest

x-ray, transaxial imaging of the abdomen and pelvis, and

determination of creatinine clearance.

T4B Disease

Metastatic Disease

Table 2

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The specific chemotherapy regimen recommended depends, in part,

on the presence or absence of medical comorbidities, such as

cardiac disease and renal dysfunction, along with the risk

classification of the patient based on disease extent. In general,

long-term survival with combination chemotherapy alone has been

reported only in good-risk patients, defined as those with good

performance status, no visceral (liver, lung) or bone disease, and

normal alkaline phosphatase or lactic dehydrogenase (LDH) levels.

Poor-risk patients, defined as those with a poor performance status

or visceral disease, have consistently demonstrated very poor

tolerance to multiagent combination programs and few complete

remissions--a prerequisite for cure.

Currently there are three active drug types that are active in the

management of advanced bladder cancer: cisplatin, the taxanes,

and gemcitabine. Various two or three drug combinations of these

agents have demonstrated clinical benefit. A commonly used

combination in good-risk patients is a multidrug cisplatin-based

regimen, such as M-VAC or CMV. An alternative is cisplatin and

gemcitabine, based on a direct comparison to M-VAC.

More recently, the taxanes have been shown to be active as both

front-line and salvage therapies, and gemcitabine and ifosfamide

have shown utility as salvage therapy. Based on these results, a

number of groups are exploring two- and three-drug combinations

using these agents, with and without cisplatin, as initial therapy. A

major determinant of the regimen to be used is the performance

status of the patient, with the use of regimens with lower toxicity

profiles in patients with compromised liver or renal status or serious

co-morbid conditions.

The regimens effective for transitional cell histologies have limited

efficacy for patients with nontransitional cell tumors. These

individuals are often treated on the basis of the histology identified,

(e.g., adenocarcinomas with regimens typically used for colon

cancers, and squamous tumors with regimens typically used for

tumors originating in the head and neck). However, overall

experience with chemotherapy in nontransitional cell tumors is

limited.

Independent of the specific regimen used, patients with metastatic

disease are reevaluated after two to three cycles of chemotherapy,

and treatment is continued for two more cycles in patients whose

disease responds or remains stable. Salvage surgery may be

considered in patients who show a major partial response in an

unresectable primary tumor or who have a solitary site of residual

disease that is resectable after chemotherapy. In selected series,

this approach has been shown to afford a survival benefit. If disease

is completely resected, consideration can be given to two additional

cycles of chemotherapy, depending on patient tolerance. Those in

whom surgery is not considered are generally treated with

chemotherapy for a maximum of six cycles, depending on their

response.

If there is no response after two cycles or if significant morbidities

are encountered, a change in therapy is advised. The change

should take into account the patient's current performance status,

extent of disease, and the specific prior therapy that has been

administered. The same would apply for patients who have relapsed

systemically after adjuvant chemotherapy. Patients who cannot

tolerate cisplatin-based therapy because of medical comorbidities

may be considered for a carboplatin-based regimen or, alternatively,

paclitaxel or gemcitabine as a single agent. For salvage therapy,

paclitaxel (if it has not been used earlier), gemcitabine, or ifosfamide

is advised, depending upon the patient's current status ( ).

22

23,24

Table 3

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Upper Tract Tumors

Upper tract tumors include those that originate in the renal pelvis or

in the ureter.

Tumors that develop in the renal pelvis may be identified during

evaluation of hematuria or a renal mass. (In the latter case, renal

pelvic tumors must be distinguished from the more typical

adenocarcinomas that originate in the renal parenchyma.) Such

tumors may also be detected during an assessment aimed at

pinpointing the source of a positive cytology in the setting of a

negative cystoscopy with a retrograde pyelogram.

The evaluation of a patient with a suspected renal pelvic

tumor should include an IVP and a retrograde pyelogram, with or

without ureteroscopy. A CT scan is useful to determine the location

of the mass and whether there is any nodal spread, and a chest x-

ray can help evaluate for possible metastatic disease and assess

any comorbid diseases that may be present. Hematologic, renal,

and hepatic function should also be evaluated. Additional imaging

studies may be needed if indicated by the results of these tests or by

the presence of specific symptoms.

In general, the primary form of treatment for renal pelvic

tumors is surgery. If metastatic disease is documented or if there are

associated comorbid conditions, treatment should include systemic

chemotherapy with regimens similar to those used for transitional

cell bladder tumors.

Well-differentiated tumors may be managed with a

nephroureterectomy with a cuff of bladder or a nephron-sparing

procedure via a transureteroscopic approach or a percutaneous

approach to nephroscopy, with or without postsurgical intra-pelvic

chemotherapy or BCG. High-grade tumors or those that are large

and invade the renal parenchyma are managed via

nephroureterectomy with a cuff of bladder.

Subsequent management is dictated by the extent of

disease at surgery. Tumors that are pathologic stage pT0, pT1 or

pT2 should be followed with serial cystoscopies at 3-month intervals

for the first year and, if negative, every 6 months thereafter. Such

tumors should also be followed with an IVP at 3- to 6-month

intervals if a nephron-sparing procedure was performed or every 12

months if more extensive surgery was done.

Patients with pT3, pT4, or nodal disease should be considered for

adjuvant chemotherapy, as discussed above under high-risk disease

originating in the bladder. RT is an option in pT4 patients. Serial

evaluations of the urothelial tract, along with imaging studies to

exclude metastatic disease, should also be performed.

Ureteral tumors may develop de novo or in patients who have

undergone successful treatment for superficial tumors that originate

in the bladder. The presentation varies as a function of disease

extent; most commonly, ureteral tumors are identified in patients

who have a positive cytology with a negative cystoscopy in whom

selective catheterization of the ureters is performed. More extensive

lesions may result in pain or obstruction.

The evaluation is similar to that outlined for tumors that

originate in the renal pelvis.

For ureteral tumors that are resectable, the primary

management is surgical. The specific procedure required varies

Renal Pelvis

Ureteral Tumors

Workup:

Treatment:

Follow-up:

Workup:

Treatment:

Bladder Cancer

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depending on where in the ureter the tumor began (upper, mid, or

distal location) and on disease extent.

Tumors that originate in the upper ureter are treated by

nephroureterectomy or endoscopic resection; a portion of the

bladder is removed due to the difficulty in following the remaining

ureteral stump, which is also at risk for developing disease. Tumors

that originate in the mid portion can be divided by grade and size.

Small, low-grade tumors can be managed by excision and

ureteroureterostomy or, alternatively, by endoscopic resection or

nephroureterectomy. Larger, high-grade lesions are managed by

nephroureterectomy. Distal ureteral tumors may be managed by a

distal ureterectomy and reimplantation of the ureter or by

endoscopic resection; in some cases, a nephroureterectomy is also

required.

The final pathologic stage is used to guide subsequent

management, as is the case for tumors that originate in other sites.

No adjuvant therapy is advised for lesions that are PT2 or less, but

serial follow-up of the urothelial tracts or remaining unit (as

previously described under renal pelvic lesions) is recommended.

Patients with more extensive disease are advised to undergo

systemic adjuvant treatment with chemotherapy with or without RT

for PT4 tumors, depending upon the anticipated tolerance of the

patient to the regimen based on comorbidities. The justification for

considering adjuvant therapy is similar to that used for tumors that

originate in the bladder.

Transitional cell tumors of the prostate represent a distinct entity

with a unique staging system. They should be distinguished from

transitional cell tumors of bladder origin that invade the prostate.

Transitional cell tumors of the prostate may occur de novo or, more

typically, concurrently or after treatment of a bladder cancer. As is

the case with tumors originating in other sites of the urothelium,

management of transitional cell prostate tumors is based on extent

of disease, with particular reference to the urethra, ductal acini, and

stroma.

The evaluation of a suspected transitional cell carcinoma of the

prostate includes a digital rectal examination (DRE), cystoscopy,

muscle biopsy, and a TUR that includes the prostatic stroma.

Multiple stromal biopsies are also advised and, if the DRE is

abnormal, determination of the prostate-specific antigen level and

additional needle biopsies are required to exclude primary

adenocarcinoma of the prostate.

Pending histologic confirmation, tumors that are limited to the

prostatic urethra with no acinar or stromal invasion can be managed

with BCG and transurethral resection of the prostate (TURP), with

follow-up similar to that outlined under superficial disease of the

bladder. Patients with tumors that invade the ductal acini should

undergo an additional workup to exclude metastatic disease,

following which a cystoprostatectomy, with or without a

urethrectomy, should be performed or, alternatively, TUR and BCG

may be offered. Patients with documented stromal invasion are

treated with a cystoprostatectomy, with or without urethrectomy and

adjuvant therapy may be advised. Recurrences in patients

undergoing TURP and BCG therapy are treated with

cystoprostatectomy with or without urethrectomy.

Follow-up:

Assessment

Management

Transitional Cell Tumors of the Prostate

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Nontransitional Cell Carcinoma Bladder Cancers

Summary

Infrequently, the histology of the bladder tumor differs from

transitional cell carcinoma. These pathologic entities include mixed

histology, pure squamous, adenocarcinoma, and small cell tumors.

The general principles of management applicable to transitional cell

carcinomas are appropriate with some minor variations. These

variations are documented on page .

Urothelial tumors represent a spectrum of diseases with a range of

prognoses. Once a diagnosis is established at any point within the

urothelial tract, the patient remains at risk for developing a new

lesion at a different or the same location and at a similar or more

advanced stage. Continued monitoring for recurrence is an essential

part of management, as most recurrences are superficial and can be

managed by endoscopic means. Within each category of disease,

more refined methods to determine prognosis and guide

management, based on molecular staging, are under development.

These methods are aimed at optimizing the individual patient's

likelihood of cure and chance for organ preservation.

For patients with more extensive disease, newer treatments typically

involve combined-modality approaches, using recently developed

surgical procedures, or three-dimensional treatment planning for

more precise delivery of radiation therapy. While these are not

appropriate in all cases, they do offer the promise of an improved

quality of life and prolonged survival.

Finally, within the category of metastatic disease, a number of new

agents have been identified that appear to be superior to those

currently considered to be standard therapies. It is thought,

therefore, that the treatment of urothelial tumors will evolve rapidly

over the next few years, with improved outcomes for patients at all

stages of disease.

BL-E

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Table 2:

Table 3

Combination Chemotherapy Regimens

Relapse or Noncomplete Response

Second-Line Chemotherapy

Regimen DosageM-VAC

MCV

GEMCITABINE/CISPLATIN

Methotrexate 30 mg/m on days 1, 15, 22Vinblastine 3 mg/m on days 2, 15, 22Doxorubicin 30 mg/m on day 2Cisplatin 70 mg/m on day 2

Methotrexate 30 mg/m on days 1, 8Vinblastine 3 mg/m on days 1, 8Cisplatin 100 mg/m on day 2

Gemcitabine 1,000 mg/m on days 1, 8, 15 of 28 day cycleCisplatin 70 mg/m on day 2

IfosfamideGemcitabinePaclitaxel (if no prior paclitaxel)

2

2

2

2

2

2

2

2

2

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nd

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