NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Bladder Cancer
Version 3.2020 — January 17, 2020

NCCN.org

NCCN Guidelines for Patients®

For important information
regarding the BCG shortage
see MS-11. Also see the AUA
Continue BCG Shortage Notice.

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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

*Thomas W. Flaig, MD †/Chair *Harry W. Herr, MD ϖ Anthony Patterson, MD ϖ

University of Colorado Cancer Center Memorial Sloan Kettering Cancer Center St. Jude Children’s Research Hospital/
*Philippe E. Spiess, MD, MS ¶ ϖ/Vice Chair Jean Hoffman-Censits, MD † The University of Tennessee
Moffitt Cancer Center The Sidney Kimmel Comprehensive Cancer Health Science Center

Neeraj Agarwal, MD ‡ † Center at Johns Hopkins Elizabeth R. Plimack, MD, MS † Þ

Huntsman Cancer Institute *Christopher Hoimes, MD † Fox Chase Cancer Center
at the University of Utah Case Comprehensive Cancer Center/University Kamal S. Pohar, MD ¶ ϖ
Rick Bangs, MBA Hospitals Seidman Cancer Center and Cleveland The Ohio State University Comprehensive
Patient Advocate Clinic Taussig Cancer Institute Cancer Center - James Cancer Hospital
*Brant A. Inman, MD, MSc ¶ ϖ and Solove Research Institute
*Stephen A. Boorjian, MD ϖ
Mayo Clinic Cancer Center Duke Cancer Institute Mark A. Preston, MD, MPH ϖ
Masahito Jimbo, MD, PhD, MPH Þ Dana-Farber/Brigham and Women’s
Mark K. Buyyounouski, MD, MS § Cancer Center
Stanford Cancer Institute University of Michigan Rogel Cancer Center
A. Karim Kader, MD, PhD ¶ ϖ *Wade J. Sexton, MD ϖ
Sam Chang, MD, MBA ¶ Moffitt Cancer Center
Vanderbilt-Ingram Cancer Center UC San Diego Moores Cancer Center
Subodh M. Lele, MD ≠ *Arlene O. Siefker-Radtke, MD †
Tracy M. Downs, MD ϖ The University of Texas
University of Wisconsin Carbone Cancer Center Fred & Pamela Buffett Cancer Center
MD Anderson Cancer Center
Jason A. Efstathiou, MD, DPhil § Jeff Michalski, MD, MBA §
Siteman Cancer Center at Barnes- Jonathan Tward, MD, PhD §
Massachusetts General Hospital Cancer Center Huntsman Cancer Institute
Jewish Hospital and Washington
Terence Friedlander, MD † University School of Medicine at the University of Utah
UCSF Helen Diller Family Jonathan L. Wright, MD ϖ
Comprehensive Cancer Center Jeffrey S. Montgomery, MD, MHSA ϖ
University of Michigan Rogel Cancer Center Fred Hutchinson Cancer Research Center/
*Richard E. Greenberg, MD ϖ Seattle Cancer Care Alliance
Fox Chase Cancer Center Lakshminarayanan Nandagopal, MD †
O'Neal Comprehensive Cancer Center at UAB NCCN
Khurshid A. Guru, MD ϖ Lisa Gurski, PhD
Roswell Park Comprehensive Cancer Center *Lance C. Pagliaro, MD † Alyse Johnson-Chilla, MS
Mayo Clinic Cancer Center
Thomas Guzzo, MD, MPH ϖ
Abramson Cancer Center at the Sumanta K. Pal, MD †
University of Pennsylvania City of Hope National Medical Center
‡ Hematology/Hematology § Radiotherapy/Radiation
oncology oncology
Þ Internal medicine ¶ Surgery/Surgical Oncology
NCCN Guidelines Panel Disclosures Continue † Medical oncology ϖ Urology
≠ Pathology * Discussion writing
committee member

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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

NCCN Bladder Cancer Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Introduction with cancer is in a clinical trial.
Bladder Cancer Participation in clinical trials is
• Clinical Presentation and Initial Evaluation (BL-1) especially encouraged.
• Non-Muscle Invasive or Tis, Primary Evaluation/Surgical Treatment (BL-1) To find clinical trials online at NCCN
Secondary Surgical Treatment, Adjuvant Intravesical Treatment, Follow-up (BL-2) Member Institutions, click here:
Posttreatment cTa, cT1, Tis Recurrent or Persistent Cancer (BL-3) nccn.org/clinical_trials/member_
• Muscle Invasive or Metastatic, Primary Evaluation/Surgical Treatment, Additional Workup (BL-1) institutions.aspx.
Stage II (cT2, N0) Primary and Adjuvant Treatment (BL-5)
NCCN Categories of Evidence and
Stage IIIA (cT3, N0; cT4a, N0; cT1-cT4a, N1) Primary and Adjuvant Treatment (BL-7)
Consensus: All recommendations
Stage IIIB (cT1-cT4a, N2,3) Primary and Subsequent Treatment (BL-8)
are category 2A unless otherwise
Stage IVA (cT4b, Any N, M0; Any T, Any N, M1a) Primary and Subsequent Treatment (BL-9)
indicated.
Metastatic Disease, Additional Workup, Primary Treatment (BL-10)
See NCCN Categories of Evidence
Follow-up, Recurrent or Persistent Disease (BL-11)
and Consensus.
• Principles of Imaging for Bladder/Urothelial Cancer (BL-A)
• Principles of Surgical Management (BL-B) NCCN Categories of Preference:
• Principles of Pathology Management (BL-C) All recommendations are considered
• Bladder Cancer: Non-Urothelial and Urothelial with Variant Histology (BL-D) appropriate.
• Follow-up (BL-E) See NCCN Categories of Preference.
• Principles of Intravesical Treatment (BL-F)
• Principles of Systemic Therapy (BL-G)
• Principles of Radiation Management of Invasive Disease (BL-H)
Upper GU Tract Tumors:
• Renal Pelvis (UTT-1)
• Urothelial Carcinoma of the Ureter (UTT-2)
• Urothelial Carcinoma of the Prostate (UCP-1)
• Primary Carcinoma of the Urethra (PCU-1)
Staging (ST-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2020.
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

Updates in Version 3.2020 of the NCCN Guidelines for Bladder Cancer from Version 2.2020 include:
BL-3 BL-4
• Pembrolizumab was added as a treatment option in select patients. • Bladder positive pathway: "If BCG-unresponsive" options are new.
Also for BL-4. MS-1
Footnote q is new: "Pembrolizumab is indicated for the treatment • The discussion section was updated to reflect the changes in the
of patients with BCG-unresponsive, high-risk, non-muscle invasive algorithm.
bladder cancer with Tis with or without papillary tumors who are
ineligible for or have elected not to undergo cystectomy."
Updates in Version 2.2020 of the NCCN Guidelines for Bladder Cancer from Version 1.2020 include:
Principles of Systemic Therapy
BL-G (4 of 7)
• Enfortumab vedotin was added as a preferred treatment option.
Updates in Version 1.2020 of the NCCN Guidelines for Bladder Cancer from Version 4.2019 include:
Bladder Cancer BL-2
Global Changes • Clinical Staging: "Low grade" and "High grade" were removed from
• "FDG" was added at each mention of "PET/CT" throughout the cT1
Guidelines. • Adjuvant Intravesical Treatment, cTa, low grade: "Intravesical
BL-1 chemotherapy" changed to "Intravesical therapy"
• Initial Evaluation • Footnote l is new: "Intravesical chemotherapy is preferred, although
Imaging bullets were combined into the 4th bullet: "Abdominal/ BCG may be considered when not in shortage."
pelvic CT or MRI imaging that includes imaging of upper urinary • Footnote n was updated: "Cystectomy is generally reserved
tract collecting system before transurethral resection of bladder for residual T1, high-grade, and muscle-invasive disease at re-
tumor (TURBT)" resection, and variant histology associated with adverse outcomes."
The last bullet is new: "Screen for smoking (See NCCN Guidelines • "low grade" was added to footnote o.
for Smoking Cessation)" BL-3
• Primary Evaluation/Surgical Treatment • Treatment
"especially in bladder preservation" was removed from the 4th "high grade" was removed from "cTa, cT1 or Tis"
bullet "T2 or higher" pathway is new.
"Consider transurethral biopsy of prostate" was removed as a sub • Footnote d was updated: "Immediate intravesical chemotherapy
bullet reduces the recurrence rate by 35%. Most efficacious in patients
• Presumptive Clinical Stage "Non-muscle invasive" was updated with low grade, low-volume Ta urothelial cancer. See Principles of
• Additional Staging Workup, Muscle invasive: "Bone scan" changed Intravesical Treatment (BL-F)."
to "Bone imaging" BL-4
• Footnote a is new: "For tools to aid optimal assessment and • Evaluation: The last bullet is new, "Consider enhanced cystoscopy
management of older adults with cancer, see NCCN Guidelines for (if available)"
Older Adult Oncology." • Treatment of Bladder Positive
"Complete response" was changed to "NED"
"Incomplete response" was changed to "Persistent or recurrent
disease" Continued
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Bladder Cancer from Version 4.2019 include:
BL-5 BL-10
• Adjuvant Treatment of Cystectomy candidates was updated (also for • "Molecular/genomic testing" was added to Additional Workup
BL-7): • "and/or Palliative RT" was added to Primary Treatment
"Based on pathologic risk (pT3-4 or positive nodes or positive • "Consider" was removed from footnote cc.
margins)..." • Footnote dd is new: "For patients with borderline GFR, consider
"Consider adjuvant RT" is now a category 2B recommendation timed urine collection which may more accurately determine
BL-6 eligibility for cisplatin."
• Primary Treatment BL-11
"Concurrent chemoradiotherapy" is now a preferred, category 1 • "Muscle invasive or and selected metastatic disease treated with
recommendation. Also for BL-7 curative intent" was updated.
"and consider intravesical BCG" was removed from TURBT • "Muscle" was added to "Invasive" after local recurrence or
• Adjuvant Treatment persistent disease...
"No tumor" pathway: "If prior BCG, maintenance BCG" was • Treatment of Recurrent or Persistent Disease
removed "Systemic therapy" was added as an option for muscle invasive.
"Tumor pathway" Recommendations for Tis, Ta, or T1 were updated:
◊◊"or RT alone" was added to "Concurrent chemoradiotherapy" Consider intravesical therapy BCG
◊◊"Palliative" was removed from TURBT. (Also for BL-7) or Cystectomy
BL-7 or TURBT
• Primary Treatment: "Cystectomy alone for those not eligible to Principles of Imaging for Bladder/Urothelial Cancer
receive cisplatin-based chemotherapy" is new. BL-A (1 of 5)
• Footnote x was updated: "Cystectomy alone is appropriate for those • Abdominal and Pelvic Imaging: "Ureteroscopy" was removed as a
not eligible to receive cisplatin-based chemotherapy. Patients with sub bullet from Staging.
cN1 disease do better have better outcomes if there is a response to BL-A (2 of 5)
they are given neoadjuvant chemotherapy and have than if there is a • The following bullet was removed from chest imaging: "Chest
response to surgery alone." imaging may be performed with plain film radiography with
BL-8 posteroanterior (PA) and lateral views in early-stage disease. If an
• Additional Workup: "Consider" was added to the last bullet. abnormality is seen, then CT of the chest may then be performed."
BL-9 • Staging
• M1a disease: "or" was removed from the first sub bullet. Also for Follow-up
"Concurrent chemoradiotherapy" was moved from Primary with or without cystectomy and Follow-up of T4b and metastatic
Treatment to Subsequent Treatment as an option for CR disease.
"Boost with RT" was removed from subsequent treatment. 2nd sub bullet was updated: "CT of the chest with or without
• Subsequent Treatment contrast (preferred) Chest CT with IV contrast could be considered
No tumor pathway: "Completion of definitive RT" was removed. in patients undergoing concurrent imaging of the abdomen and
Tumor present pathway pelvis."
◊◊"Change systemic therapy" was removed • Follow-up with or without cystectomy, 2nd sub bullet was updated:
◊◊"and/or Cystectomy" was updated. "Chest CT with or without IV contrast (preferred)" Also for Follow-up
Stable Disease or Progression was updated: "See Treatment of of T4b and metastatic disease.
Recurrent or Persistent Disease Treat as metastatic disease" BL-A (4 of 5) Continued
• Follow-up, Low risk: "1-to-2-year follow-up" was removed. UPDATES
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Bladder Cancer from Version 4.2019 include:
Principles of Surgical Management Principles of Systemic Therapy
BL-B (1 of 4) BL-G (1 of 7)
• TURBT for Staging, last bullet: "and visibly complete resection" was • 3rd bullet was updated: "Meta-analysis suggests a overall
added. survival benefit to with adjuvant cisplatin-based chemotherapy for
BL-B (2 of 4) pathologic T3, T4 or N+ disease at cystectomy, if it was not given as
• TUR of the Urethral Tumor, last bullet was updated: "Consider neoadjuvant."
postsurgical intraurethral therapy is recommended" • 7th bullet was updated: "For gemcitabine/cisplatin, both a 21-day
• Partial Cystectomy, last bullet was updated: " Bilateral pelvic cycle is preferred. and 28-day regimens are acceptable. Better
lymphadenectomy should be performed and include at a minimum dose..."
common..." Also for Radical Cystectomy/Cystoprostatectomy. • "Consider timed urine collection which may more accurately
BL-B (3 of 4) determine eligibility for cisplatin." was added to the last bullet
• Regional Lymphadenectomy BL-G (2 of 7)
2nd bullet, first sub bullet was updated: "Regional • "SP142 assay" added to footnote a.
lymphadenectomy should include at a minimum the paraaortic..." • "22C3 antibody assay" added to footnote b.
3rd bullet, first sub bullet was updated: "Regional BL-G (3 of 7)
lymphadenectomy should include at a minimum the paracaval • Title of both tables was changed from "Subsequent" to "Second-
lymph nodes from the renal hilum to the aortic IVC bifurcation." line"
4th bullet, first sub bullet was updated: "Regional • The following regimens were removed from this page: albumin-
lymphadenectomy should be performed and include at a minimum bound paclitaxel, pemetrexed, ifosfamide, and methotrexate
the common..." • Erdafitinib was added as an Other Recommended treatment option
in the bottom table.
BL-C • Footnote c was updated: "If PFS >12 months after platinum (eg,
• This page was extensively revised. cisplatin or carboplatin) more than 12 months ago, consider..."
• References 20, 25, and 26 are new.
BL-D (1 of 2) BL-G (4 of 7)
• Any Small-Cell Component (or neuroendocrine features), first bullet: • The subsequent-line systemic therapy for locally advanced or
"Concurrent chemoradiotherapy or" was added. metastatic disease (Stage IV) table is new.
• Footnote e is new: "Patient should have already received platinum
Principles of Intravesical Treatment and a checkpoint inhibitor, if eligible."
BL-F (2 of 3) BL-G (5 of 7)
• "Intrapelvic" was removed from "Postsurgical Therapy for Upper • Title of bottom table was updated: "Radiosensitizing chemotherapy
Tract Tumors heading. given concurrently with conventionally fractionated radiation
"intrapelvic therapy" was added to the first bullet and subsequent for with palliative intent for regional disease of metastases or
sub bullets recurrence"
The 2nd bullet is new: "Perioperative intravesical chemotherapy • Reference 29 is new.
with mitomycin or gemcitabine may be given following
nephroureterectomy with cuff of bladder resection." Principles of Radiation Management of Invasive Disease
BL-H
• 13th bullet, postoperative adjuvant pelvic RT is now a Continued
category 2B recommendation. UPDATES
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

Updates in Version 1.2020 of the NCCN Guidelines for Bladder Cancer from Version 4.2019 include:
Upper GU Tract Tumors
UTT-1
• Workup: "(<60 y at presentation, personal history of colon/endometrial cancer)" was added to the last bullet.
UTT-3
• Follow-up, pT0, pT1
"and consider cytology for high grade" was added to the first bullet.
2nd bullet was updated: "If nephron-sparing surgery endoscopic resection..." Also for pT2, pT3, pT4, pN+.
pT2, pT3, pT4, pN+: "and cytology" was added to the first bullet.

Primary Carcinoma of the Urethra

PCU-2
• "with cystoscopy" was added to Follow-up imaging throughout
• Male
Pendulous urethra: "Negative margin" pathway was added.
Bulbar urethra: "pT1/pT2 and pN0" pathway was added.
• Primary Treatment for T2, female: "Distal urethrectomy (depending on tumor location)" was added.
PCU-3
• cN0, Primary Treatment
"(if urothelial carcinoma)" added to Neoadjuvant chemotherapy.
"Consolidative surgery alone for non-urothelial histology" was added.

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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

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Bladder Cancer Discussion

INTRODUCTION

NCCN and the NCCN Bladder Cancer Panel

believes that the best management for any
patient with cancer is in a clinical trial.
Participation in clinical trials is especially
encouraged.

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INTRO
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Bladder Cancer Discussion

CLINICAL INITIAL PRIMARY EVALUATION/ PRESUMPTIVE ADDITIONAL STAGING WORKUP

PRESENTATION EVALUATIONa SURGICAL TREATMENT CLINICAL
STAGE

cTae
• H&P
• Examination under
• Office cystoscopy
anesthesia (EUA)
• Consider cytology Non-muscle invasive cT1e See BL-2
(bimanual)
• Abdominal/pelvic
• TURBTc
imagingb that
• Single-dose intravesical Tis
includes imaging
chemotherapy within 24
of upper urinary
hours of TURBTd
tract collecting Stage II
Suspicion Gemcitabine (preferred) See BL-5
of bladder
system before
(category 1) or (cT2, N0)e
transurethral
cancer Mitomycin (category 1)
resection of Stage IIIA
• If sessile, suspicious for • Complete blood
bladder tumor (cT3, N0;
high grade or Tis: count (CBC) See BL-7
(TURBT) cT4a, N0;
Consider selected • Chemistry profile,
• Screen for cT1-T4a, N1)e
mapping biopsies including alkaline
smoking (See
• Imaginga of upper tract Muscle phosphatase Stage IIIB
NCCN Guidelines See BL-8
collecting system, if not invasive • Chest imaging (cT1-T4a, N2,3)e
for Smoking
previously done • Bone imagingb if
Cessation) Stage IVA
clinical suspicion or (cT4b, Any N, M0; See BL-9
symptoms of bone Any T, Any N, M1a)e
metastases
Metastatic
(Stage IVB See BL-10
Any T, Any N, M1b)

a For tools to aid optimal assessment and management of older adults with cancer, see NCCN Guidelines for Older Adult Oncology.
b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
c See Principles of Surgical Management (BL-B).
d Immediate intravesical chemotherapy reduces the recurrence rate by 35%. See Principles of Intravesical Treatment (BL-F).
e The modifier “c” refers to clinical staging based on bimanual examination under anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging
studies. The modifier “p” refers to pathologic staging based on cystectomy and lymph node dissection.

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

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

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BL-1
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Non-Muscle Invasive Bladder Cancer Discussion

CLINICAL SECONDARY ADJUVANT INTRAVESICAL TREATMENTi,j FOLLOW-UPb

STAGINGe,f,g SURGICAL TREATMENT

Observation
cTa,
or See Follow-up (BL-E)
low grade
Intravesical therapyj,k,l

• If incomplete resection, BCG (preferred)

repeat TURBT or See Recurrent
cTa,
• If no muscle in specimen, Intravesical chemotherapyk or
high grade
strongly consider repeat or Persistent
TURBT Observation Disease (BL-3)

BCG (category 1) See Follow-up (BL-E)

Residual
or If prior BCG,
disease
Strongly advise Cystectomyc,m,n maintenance BCG
repeat TURBT (preferred)
or BCG (preferred) (category 1)
cT1 No or
Consider
cystectomyc,h residual Intravesical chemotherapyk
for high-grade disease or
Observation in highly selected caseso
Any Tis BCG
i Indications for adjuvant induction therapy: Based on probability of recurrence and
progression to muscle-invasive disease, such as size, number, and grade.
b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). j See Principles of Intravesical Treatment (BL-F).
c See Principles of Surgical Management (BL-B). k The most commonly used options for intravesical chemotherapy are gemcitabine
e The modifier “c” refers to clinical staging based on bimanual examination under (preferred) and mitomycin.
anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging l Intravesical chemotherapy is preferred, although BCG may be considered when
studies. The modifier “p” refers to pathologic staging based on cystectomy and not in shortage.
lymph node dissection. m If not a cystectomy candidate, consider concurrent chemoradiotherapy (category
f Montironi R, Lopez-Beltran A. The 2004 WHO classification of bladder tumors: A 2B) or a clinical trial. See Principles of Systemic Therapy (BL-G 5 of 7).
summary and commentary. Int J Surg Pathol 2005;13:143-153. n Cystectomy is generally reserved for residual T1, high-grade, muscle-invasive
See Principles of Pathology Management (BL-C). disease at re-resection, and variant histology associated with adverse outcomes.
g See Bladder Cancer: Non-Urothelial and Urothelial with Variant Histology (BL-D). o Highly
 selected cases with low grade, small-volume tumors with limited lamina
h See Follow-Up (BL-E). propria invasion and no CIS.

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

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

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BL-2
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NCCN Guidelines Version 3.2020 NCCN Guidelines Index

Table of Contents
Non-Muscle Invasive Bladder Cancer Discussion

RECURRENT OR FOLLOW-UP RESULTS EVALUATION TREATMENT

PERSISTENT
DISEASE Based on tumor stage
• TURBTc and grade:
• Single-dose intravesical • Adjuvant intravesical
chemotherapy within 24 therapyi
Cystoscopy Follow-up at 3 mo, then at
hours of TURBTd or
positive longer intervalsh
Gemcitabine (preferred, • Cystectomyp
category 1) or or
Mitomycin (category 1) • Pembrolizumab (in
Posttreatment select patients)q
cTa, cT1, Tis • Cytology positive
recurrent or • Imaging negative See BL-4
persistent • Cystoscopy negative
cancer If prior BCG, maintenance
No residual disease
BCG (preferred)

• TURBTc
Cystoscopy • Single-dose intravesical
Cystectomyc,h,p (preferred for cT1)
suspicious for chemotherapy within 24
or
recurrence post- hours of TURBTd
cTa, cT1 or Tis Pembrolizumab (in select patients)q
intravesical therapy; Gemcitabine (preferred,
or
no more than 2 category 1)
Change intravesical agentj,r
consecutive cycles or
Mitomycin (category 1)
• Stage II, see BL-5
• Stage IIIA, see BL-7
T2 or higher • Stage IIIB, see BL-8
• Stage IVA, see BL-9
• Stage IVB (metastatic), see BL-10
c See Principles of Surgical Management (BL-B). p If not a cystectomy candidate, and recurrence is cTa or cT1, consider concurrent
d Most efficacious in patients with low grade, low-volume Ta urothelial cancer. See chemoradiotherapy (category 2B for cTa, category 2A for cT1) or a clinical trial.
Principles of Intravesical Treatment (BL-F). See Principles of Systemic Therapy (BL-G 5 of 7).
h See Follow-Up (BL-E). q Pembrolizumab is indicated for the treatment of patients with BCG-unresponsive,
i Indications for adjuvant induction therapy: Based on probability of recurrence and high-risk, non-muscle invasive bladder cancer with Tis with or without papillary
progression to muscle-invasive disease, such as size, number, and grade. tumors who are ineligible for or have elected not to undergo cystectomy.
j See Principles of Intravesical Treatment (BL-F). r Valrubicin is approved for BCG-refractory carcinoma in situ.

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

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

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BL-3
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Non-Muscle Invasive Bladder Cancer Discussion

RECURRENT OR EVALUATION TREATMENT Follow-up at 3 mo, then at

PERSISTENT longer intervalsh
DISEASE FOLLOW-UP Bladder, prostate, and
or
RESULTS upper tract negative
If prior BCG, maintenance
BCG (optional)
No evidence
of disease Maintenance BCG (preferred)
(NED)
BCG Cystectomyc,h,p
• Selected mapping or
biopsies including Persistent Pembrolizumab (in select patients)q
transurethral biopsy Bladder or recurrent or
of prostatec Cystectomyc,h,p
positive disease Change
and Incomplete or
intravesical response Pembrolizumab
• Cytology positive • Cytology of upper agent j,r
• Imaging negative tract (in select patients)q
If BCG-unresponsive:
• Cystoscopy and
• Cystectomyc,h,p
negative • Consider
or
ureteroscopy
• Pembrolizumab (in select patients)q
and
• Consider enhanced Prostate
See Urothelial Carcinoma of the Prostate (UCP-1)
cystoscopyc (if positive
available)

Upper tract
See Upper GU Tract Tumors (UTT-1)
positive
c See Principles of Surgical Management (BL-B).
h See Follow-Up (BL-E).
j See Principles of Intravesical Treatment (BL-F).
p If not a cystectomy candidate, and recurrence is cTa or cT1, consider concurrent chemoradiotherapy (category 2B for cTa, category 2A for cT1) or a clinical trial. See
Principles of Systemic Therapy (BL-G 5 of 7).
q Pembrolizumab is indicated for the treatment of patients with BCG-unresponsive, high-risk, non-muscle invasive bladder cancer with Tis with or without papillary
tumors who are ineligible for or have elected not to undergo cystectomy.
r Valrubicin is approved for BCG-refractory carcinoma in situ.

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

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

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CLINICAL ADDITIONAL WORKUPb PRIMARY TREATMENT ADJUVANT TREATMENT

STAGINGe
Neoadjuvant cisplatin-based
combination chemotherapyt followed
by radical cystectomyc (category 1)
or
Neoadjuvant cisplatin-based Based on pathologic risk (pT3-4 or
combination chemotherapyt followed positive nodes or positive margins),
by partial cystectomyc (highly consider adjuvant cisplatin-
selected patients with solitary lesion based chemotherapyt or consider
in a suitable location; no Tis) adjuvant RTv (category 2B) if no
Cystectomy neoadjuvant treatment given
or
candidates
Cystectomy alone for those not
• Abdominal/
eligible to receive cisplatin-based
pelvic CT or
chemotherapy
MRIb,s if not No See
previously Observation Follow-up
or tumor
done (BL-E)
Reassess
Stage II • Chest imaging
Concurrent tumor status If Tis, Ta, or T1,
(cT2, N0) • Bone scanb
chemoradiotherapyu,v,w,x 2–3 months consider intravesical
if clinical
(category 1) after full BCGj
suspicion or
treatmentv or
symptoms
of bone Tumor Surgical
metastases consolidationc
or
Non-cystectomy Treat as metastatic
See BL-6
candidates disease (BL-10)

u See Principles of Systemic Therapy (BL-G 5 of 7).

b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). v See Principles of Radiation Management of Invasive Disease (BL-H).
c See Principles of Surgical Management (BL-B). w There are data to support equivalent survival rates. Not all institutions
have
e The modifier “c” refers to clinical staging based on bimanual examination under experience with these multidisciplinary treatment approaches, which require a
anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging dedicated team.
studies. The modifier “p” refers to pathologic staging based on cystectomy and x Optimal
 candidates for bladder preservation with chemoradiotherapy include
lymph node dissection. patients with tumors that present without hydronephrosis, are without concurrent
j See Principles of Intravesical Treatment (BL-F). extensive or multifocal Tis, and are <6 cm. Ideally, tumors should allow a
s Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). visually complete or maximally debulking TURBT. See Principles of Radiation
t See Principles of Systemic Therapy (BL-G 1 of 7). Management of Invasive Disease (BL-H).
See Recurrent
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
or Persistent
Disease (BL-11)
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PRIMARY TREATMENT ADJUVANT TREATMENT

No
Observation
tumor

Concurrent
chemoradiotherapyu,v
Stage II Reassess
(preferred, category 1)
(cT2, N0) tumor status
or
Non-cystectomy 2–3 months
RTv See
candidates after treatmentv
or Follow-up
TURBTc Systemic therapyt (BL-E)
or
Concurrent chemoradiotherapy
Tumor or RT alone (if no prior RT)u,v
or
TURBT
and
Best supportive care

c See Principles of Surgical Management (BL-B).

t See Principles of Systemic Therapy (BL-G 2 of 7). See Recurrent
u See Principles of Systemic Therapy (BL-G 5 of 7). or Persistent
v See Principles of Radiation Management of Invasive Disease (BL-H). Disease (BL-11)
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

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CLINICAL ADDITIONAL PRIMARY TREATMENT ADJUVANT TREATMENT

STAGINGe WORKUPb
Neoadjuvant cisplatin-based Based on pathologic risk (pT3-4
combination chemotherapyt followed or positive nodes or positive
by radical cystectomyc,y (category 1) margins), consider adjuvant
or cisplatin-based chemotherapyt
Cystectomy alone for those not or consider adjuvant RTv
eligible to receive cisplatin-based (category 2B) if no neoadjuvant
• Abdominal/ chemotherapyy treatment given
pelvic CT or No
or Observation
MRIb,s if not Reassess tumor
previously Concurrent tumor
Stage IIIA If Tis, Ta, or T1, consider
done chemoradiotherapyu,v,w,x status 2–3
(cT3, N0; intravesical BCGj
• Chest imaging (category 1) months after See
cT4a, N0;
• Bone scanb treatmentv Tumor
or Follow-up
cT1-T4a, Surgical consolidationc
if clinical (BL-E)
N1) or
suspicion or or
symptoms Treat as metastatic disease (BL-10)
of bone No
metastases Non-cystectomy Observation
tumor
candidates: Reassess
• Concurrent tumor
chemoradiotherapy status 2–3 Systemic therapyt
(preferred, category 1)u,v months after or
or treatmentv TURBT
Tumor
• RTv and
Best supportive care
v See Principles of Radiation Management of Invasive Disease (BL-H).
b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). w There are data to support equivalent survival rates. Not all institutions
have
c See Principles of Surgical Management (BL-B). experience with these multidisciplinary treatment approaches, which require a
e The modifier “c” refers to clinical staging based on bimanual examination under dedicated team.
anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging x Optimal
 candidates for bladder preservation with chemoradiotherapy include
studies. The modifier “p” refers to pathologic staging based on cystectomy and patients with tumors that present without hydronephrosis, are without concurrent
lymph node dissection. extensive or multifocal Tis, and are <6 cm. Ideally, tumors should allow a
j See Principles of Intravesical Treatment (BL-F). visually complete or maximally debulking TURBT. See Principles of Radiation
s Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). Management of Invasive Disease (BL-H).
t See Principles of Systemic Therapy (BL-G). y Patients with cN1 disease have better outcomes they are given neoadjuvant
u See Principles of Systemic Therapy (BL-G 5 of 7). chemotherapy and have a response.
See Recurrent
Note: All recommendations are category 2A unless otherwise indicated. or Persistent
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Disease (BL-11)
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CLINICAL ADDITIONAL PRIMARY SUBSEQUENT TREATMENT

STAGINGe WORKUPb TREATMENT
Consolidation cystectomyc
or
Complete
Consolidation chemoradiotherapyu,v
response See
or
Observation Follow-up
Reassess (BL-E)
Cystectomyc
tumor
or
• Abdominal/ Downstaging status 2–3 Partial
Chemoradiotherapyu,v
pelvic CT or systemic therapyt months response
or
MRIb,s if not after
Treat as metastatic disease (See BL-10)
previously treatmentaa
done
• Chest imaging
• Bone scanb Progression Treat as metastatic disease (See BL-10)
Stage IIIB
if clinical
(cT1-T4a, or
suspicion or
N2,3) Complete
symptoms
of bone response See
metastases Follow-up
• Consider If Tis, Ta, or T1, consider (BL-E)
molecular/ Reassess intravesical BCGj
genomic tumor or
Concurrent Partial
testingz status 2–3 Surgical consolidationc
chemoradiotherapyu,v response
months after or
treatmentv,aa Treat as metastatic disease
(See BL-10)

Progression Treat as metastatic disease (See BL-10)

b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). t See Principles of Systemic Therapy (BL-G 2 of 7).
c See Principles of Surgical Management (BL-B). u See Principles of Systemic Therapy (BL-G 5 of 7).
e The modifier “c” refers to clinical staging based on bimanual examination under v See Principles of Radiation Management of Invasive Disease (BL-H).
anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging z Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ
studies. The modifier “p” refers to pathologic staging based on cystectomy and RT-PCR for FGFR3 or FGFR2 genetic alterations. See Discussion.
lymph node dissection. aa Imaging with CT of chest/abdomen/pelvis with contrast. If there is no evidence
j See Principles of Intravesical Treatment (BL-F). of distant disease on imaging reassessment, further cystoscopic assessment of
s Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). tumor response in the bladder is recommended.
See Recurrent
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
or Persistent
Disease (BL-11)
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CLINICAL ADDITIONAL WORKUPb PRIMARY TREATMENT SUBSEQUENT TREATMENT

STAGINGe
Consider
consolidation
systemic therapyt
or
No
Chemoradio-
tumor
After 2–3 cycles, therapyu,v (if no
reassess with previous RT)
cystoscopy, and/or
Systemic therapyt EUA, TURBT, Cystectomyc
and imaging of
abdomen/pelvisb See
• Abdominal/ M0 disease or
Follow-up
pelvic CT or (BL-E)
MRIb,s if not Reassess tumor Systemic therapyt,cc
previously Concurrent status 2–3 months or
done chemoradiotherapyu,v after treatmentv Chemoradio-
Tumor
Stage IVA • Chest imaging therapyu,v (if no
(cT4b, • Bone scanb present
previous RT)
Any N, M0; if clinical and/or
Any T, suspicion or Cystectomyc
Any N, M1a) symptoms
of bone
metastases Concurrent chemoradiotherapyu,v
• Molecular/ Evaluate with
cystoscopy, CR or
genomic Cystectomyc
testingz M1a disease Systemic therapyt EUA, TURBT,
and imaging of
Stable
abdomen/pelvisb Treat as metastatic disease
diseasebb or
(BL-10)
progression
b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). t See Principles of Systemic Therapy (BL-G 2 of 7).
c See Principles of Surgical Management (BL-B). u See Principles of Systemic Therapy (BL-G 5 of 7).
e The modifier “c” refers to clinical staging based on bimanual examinationunder v See Principles of Radiation Management of Invasive Disease (BL-H).
anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging z Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ
studies. The modifier “p” refers to pathologic staging based on cystectomy and RT-PCR for FGFR3 or FGFR2 genetic alterations. See Discussion.
lymph node dissection. bb Non-bulky disease and no significant clinical progression.
s Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). cc See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
See Recurrent
Note: All recommendations are category 2A unless otherwise indicated. or Persistent
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Disease (BL-11)

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CLINICAL STAGINGe ADDITIONAL WORKUPb PRIMARY TREATMENT

• Bone scanb if clinical suspicion or

symptoms of bone metastases
Metastaticz • Chest CT
Systemic therapyt,cc
(Stage IVB • Consider CNS imagingb
and/or
Any T, Any • Estimate GFR to assess eligibility for
Palliative RTv
N, M1b) cisplatindd
• Consider biopsy if technically feasible
• Molecular/genomic testingz

b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

e The modifier “c” refers to clinical staging based on bimanual examination under anesthesia, endoscopic surgery (biopsy or transurethral resection), and imaging
studies. The modifier “p” refers to pathologic staging based on cystectomy and lymph node dissection.
t See Principles of Systemic Therapy (BL-G 2 of 7).
v See Principles of Radiation Management of Invasive Disease (BL-H).
z Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ RT-PCR for FGFR3 or FGFR2 genetic alterations. See Discussion.
cc See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
dd For patients with borderline GFR, consider timed urine collection which may more accurately determine eligibility for cisplatin.

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

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

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FOLLOW-UPb RECURRENT OR TREATMENT OF RECURRENT OR

PERSISTENT DISEASE PERSISTENT DISEASE
Cystectomyc,h
or
Chemoradiotherapy (if no prior RT)u,v
Muscle
or
invasive
Systemic therapyt,cc
or
Local recurrence or Palliative TURBT and best supportive care
persistent disease;
Preserved bladder Consider intravesical No
Cystectomyc,h,ee
therapyj response
Tis, Ta, or
or T1 Cystectomyc,h
or
TURBT
If upper See Upper GU
Additional evaluation: tract Tract Tumors
Cytology positive;
Muscle invasive or • Retrograde selective positive (UTT-1)
Preserved bladder;
selected metastatic See Follow-up washings of upper
Cystoscopy, EUA,
disease treated (BL-E) tract
selected mapping
with curative intent • Prostatic urethral
biopsy negative If prostate See Urothelial
biopsy
urethral Carcinoma of the
positive Prostate (UCP-1)

Systemic therapyt,cc
Metastatic or or
local recurrence Chemoradiotherapyu,v (if no previous RT)
postcystectomy or
Radiotherapyv
b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). u See Principles of Systemic Therapy (BL-G 5 of 7).
c See Principles of Surgical Management (BL-B). v See Principles of Radiation Management of Invasive Disease (BL-H).
h See Follow-Up (BL-E). cc See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
j See Principles of Intravesical Treatment (BL-F). ee If not a cystectomy candidate, consider concurrent chemoradiotherapy (See
t See Principles of Systemic Therapy (BL-G 2 of 7). BL-G 5 of 7) (if no prior RT), change in intravesical agent, or a clinical trial.

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

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

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PRINCIPLES OF IMAGING FOR BLADDER/UROTHELIAL CANCER

No single follow-up plan is appropriate for all patients. Follow-up frequency and duration should be individualized based on patient
requirements, and may be extended beyond 5 years after shared decision-making between the patient and physician.

Non-Muscle-Invasive Bladder Cancer (NMIBC)

Chest Imaging
• Staging:
Chest imaging may not be necessary in initial staging of noninvasive disease.
• Follow-up of NMIBC:
Routine chest imaging is not recommended.1

Abdominal and Pelvic Imaging

• Staging:
CT urography (CTU) (CT of the abdomen and pelvis without and with IV contrast with excretory imaging).
MR urography (MRU) may be appropriate in patients with poor renal function or iodinated contrast allergy but with GFR >30 and no acute
renal failure. May be performed without gadolinium-based contrast utilizing T2 imaging and native image contrast to evaluate upper tracts.
Will have decreased sensitivity to plaque-like or non-obstructive lesions and metastasis.
Renal ultrasound (US) or CT without contrast may be utilized in conjunction with retrograde ureteropyelography in patients who cannot
receive either iodinated or gadolinium-based contrast material.
Consider: In sessile or high-grade tumors, MRI of the pelvis without and with IV contrast for local staging.
◊◊May be performed in addition to CTU.
◊◊Can be performed without contrast if renal function does not allow for contrast administration, as early data suggest T2 and diffusion-
weighted images may help with local staging.2,3
• Follow-up of NMIBC: (See BL-E)
Upper tract (CTU, MRU, or retrograde ureteropyelography with CT or US) and abdominal/pelvic imaging at baseline. For high-risk patients,
UT imaging also should be performed at 12 mo and every 1–2 years thereafter up to 10 years.

Evaluation for Suspected Bone Metastasis

• Bone imaging not generally recommended as bone metastasis is unlikely.

Neurologic/Brain Imaging4,5
• Staging
Brain MRI not generally recommended.

Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
BL-A
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Bladder Cancer Discussion

PRINCIPLES OF IMAGING FOR BLADDER/UROTHELIAL CANCER

No single follow-up plan is appropriate for all patients. Follow-up frequency and duration should be individualized based on patient
requirements, and may be extended beyond 5 years after shared decision-making between the patient and physician.

Muscle-Invasive Bladder Cancer

Chest Imaging
• Staging:4
PA and lateral chest x-ray
CT of the chest with or without contrast (preferred)6
FDG-PET/CT (category 2B) may be beneficial in selected patients with T2 (muscle-invasive disease) and in patients with ≥cT3 disease. This
will also include abdomen and pelvis if performed.7-10 FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.

• Follow-up with or without cystectomy: (See BL-E)

PA and lateral chest x-ray
Chest CT with or without IV contrast (preferred)
◊◊May be performed without contrast if IV contrast cannot be given.
◊◊Consider performing with the abdomen and pelvis for a single exam in patients who also need imaging of the abdomen and pelvis.
FDG-PET/CT (category 2B) may be performed if not previously done or if metastasis is suspected in selected patients. This examination
will also include abdomen and pelvis. FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.

• Follow-up of cT4b (See BL-E) and metastatic disease:

PA and lateral chest x-ray
Chest CT with or without IV contrast (preferred)
◊◊May be performed without contrast if IV contrast cannot be given.
◊◊Consider performing with the abdomen and pelvis for a single exam in patients who also need imaging of the abdomen and pelvis.
FDG-PET/CT (category 2B) may be performed if not previously done or in high-risk patients in whom metastatic disease is suspected. This
could also be used to guide biopsy in certain patients. FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.

Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
BL-A
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PRINCIPLES OF IMAGING FOR BLADDER/UROTHELIAL CANCER

Muscle-Invasive Bladder Cancer (continued)
Abdominal and Pelvic Imaging
• Staging:
CTU (CT of the abdomen and pelvis without and with IV contrast with excretory imaging).11
MRU may be appropriate in patients with poor renal function or iodinated contrast allergy but with GFR >30 and no acute renal failure.
Renal US and CT without contrast (particularly when FDG-PET/CT is not utilized) may be utilized in conjunction with retrograde evaluation
in patients who cannot receive either iodinated or gadolinium-based contrast material.
Ureteroscopy if suspected upper tract lesions.
FDG-PET/CT (category 2B) may be useful in selected patients with ≥cT2 disease and may change management in patients with ≥cT3
disease.1 FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.
CT or MRI of the abdomen and pelvis with IV contrast if not performed with initial evaluation.
MRI of the pelvis without and with IV contrast for local staging.
◊◊May be performed in addition to CTU.
◊◊May also be performed without contrast if there is a contraindication to contrast.1
• Follow-up (See BL-E):
Upper-tract and abdominal/pelvic imaging as defined previously at 3- to 6-month intervals for 2 years, then abdominal/pelvic imaging
annually for up to 5 y and as indicated thereafter.
FDG-PET/CT (category 2B) may be performed if not previously done or in high-risk patients in whom metastatic disease is suspected. This
could also be used to guide biopsy in certain patients. FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.

Evaluation for Suspected Bone Metastasis

• Symptomatic, or high-risk patients, or those with laboratory indicators of bone metastasis may be imaged with MRI, FDG-PET/CT (category
2B), or bone scan. FDG-PET/CT (category 2B) may also be considered in cases when additional sites of extraosseous metastatic disease are
suspected or previously documented.

Neurologic/Brain Imaging4,5
• Staging
Brain MRI without and with IV contrast is recommended only in symptomatic or selected “high-risk” (eg, small cell histology) patients.
CT with IV contrast is considered only when symptomatic patients cannot undergo MRI (ie, non-MRI–compatible cardiac pacer, implant or
foreign body, end-stage renal disease).

Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
BL-A
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PRINCIPLES OF IMAGING FOR BLADDER/UROTHELIAL CANCER

Upper Tract (renal pelvis and urothelial carcinoma of the ureter)12
• Staging and follow-up of ≤T1 disease (see recommendations for NMIBC bladder cancer).
• Staging and follow-up of ≥T2 disease (see recommendations for MIBC bladder cancer).

Urothelial Carcinoma of the Prostate/Primary Carcinoma of the Urethra

• Staging:
PA and lateral chest x-ray or chest CT.
Consider abdominal CT or MRI in high-risk T1 disease or patients with ≥T2 disease.13
MRI of the pelvis without and with IV contrast for local staging.

• Additional staging if urothelial carcinoma of prostate:

Imaging of upper tracts and collecting system.
CTU (CT of the abdomen and pelvis without and with IV contrast with excretory imaging).
MRU may be appropriate in patients with poor renal function or iodinated contrast allergy but with GFR >30 and no acute renal failure.
Ureteroscopy
Renal US or CT without contrast may be utilized in conjunction with retrograde evaluation in patients who cannot receive either iodinated
or gadolinium-based contrast material.

• Additional staging if primary carcinoma of non-prostatic male urethra or female urethra:

In the setting of palpable inguinal lymph nodes:
◊◊Biopsy of palpable nodes.
◊◊CT of the chest, abdomen, and pelvis for additional staging, if not yet performed.

• Follow-up:
Low-risk T1 or <T1 disease:
◊◊MRI or CT of pelvis with and without IV contrast.
High-risk T1 or ≥T2:
◊◊May consider more extensive follow-up based on risk factors; 3–6 months for 2 years and then yearly.
––Chest imaging with x-ray and/or CT as previously discussed.
––Imaging of abdomen and pelvis with MRI or CT with and without contrast.

References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF IMAGING FOR BLADDER/UROTHELIAL CANCER

REFERENCES
1 Leyendecker JR, Clingan MJ, Eberhardt SC, et al; Expert Panel on Urologic Imaging. ACR Appropriateness Criteria® post-treatment surveillance of bladder cancer
[online publication]. Reston, VA: American College of Radiology (ACR); 2014.
2 Tekes A, Kamel I, Imam K, et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am J Roentgenol 2005;184:121–127.
3 Wu LM, Chen XX, Xu JR, et al. Clinical value of T2-weighted imaging combined with diffusion-weighted imaging in preoperative T staging of urinary bladder cancer: a
large-scale, multiobserver prospective study on 3.0-T MRI. Acad Radiol 2013;20:939–946.
4 Shinagare AB, Ramaiya RH, Jagannathan JP, et al. Metastatic pattern of bladder cancer: correlation with the characteristics of the primary tumor. AJR Am J
Roentgenol 2011;196:117-122.
5 Anderson TS, Regine WF, Kryscio R, et al. Neurologic complications of bladder carcinoma: A review of 359 cases. Cancer 2003;97:2267-2272.
6 Witjes JA, Compérat E, Cowan NC, et al. EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol 2014;65:778-
792.
7 Kollberg P, Almquist H, Bläckberg M, et al. [18F]Fluorodeoxyglucose – positron emission tomography/computed tomography improves staging in patients with high-risk
muscle-invasive bladder cancer scheduled for radical cystectomy. Scand J Urol 2015;49:1-6.
8 Goodfellow H, Viney Z, Hughes P, et al. Role of fluorodeoxyglucose positron emission tomography (FDG PET)-computed tomography (CT) in the staging of bladder
cancer. BJU Int 2014;114:389-395.
9 Lu YY, Chen JH, Liang JA, et al. Clinical value of FDG PET or PET/CT in urinary bladder cancer: A systematic review and meta-analysis. Eur J of Radiol
2012;81:2411–2416.
10 Kibel AS, Dehdashti F, Katz MD, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-
invasive bladder carcinoma. J Clin Oncol 2009;27:4314-4320.
11 Zhang J, Gerst S, Lefkowitz RA, et al. Imaging of bladder cancer. Radiol Clin North Am 2007;45:183-205.
12 Rouprêt M, Babjuk M, Compérat E, et al. European guidelines on upper tract urothelial carcinomas: 2013 update. Eur Urol 2013;63:1059-1071.
13 Gakis G, Witjes JA, Compérat E, et al. EAU guidelines on primary urethral carcinoma. Eur Urol 2013;64:823-830.

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

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

Transurethral Resection of the Bladder Tumor (TURBT) for Staging
• Adequate resection with muscle in specimen
Muscle may be omitted in cases of documented low-grade Ta disease
In cases of suspected or known carcinoma in situ:
◊◊Biopsy adjacent to papillary tumor
◊◊Consider prostate urethral biopsy
Papillary appearing tumor (likely non-muscle invasive)
◊◊Early repeat TURBT (within 6 weeks) if:
–– Incomplete initial resection
–– No muscle in original specimen for high-grade disease
–– Large (≥3 cm) or multi-focal lesions
––Any T1 lesion
Transurethral resection for sessile or invasive appearing tumor (likely muscle invasive)
◊◊Repeat TURBT if:
––Prior resection did not include muscle in the setting of high-grade disease
––Any T1 lesion
––First resection does not allow adequate staging/attribution of risk for treatment selection
––Incomplete resection and considering tri-modality bladder preservation therapy
• Enhanced (blue light and narrow-band imaging) cystoscopy may be helpful in identifying lesions not visible using white light cystoscopy.
• Immediate postoperative intravesical chemotherapy within 24 hours is recommended if NMIBC and if no concern for bladder perforation and
visibly complete resection.
Gemcitabine (preferred) (category 1) and mitomycin (category 1) are the most commonly used options for intravesical chemotherapy.

TURBT/Maximal TURBT for Treatment

• Bladder preservation with maximally complete and safe TURBT and concurrent chemoradiotherapy is most suitable for patients with solitary
tumors, negative nodes, no extensive or multifocal carcinoma in situ, no tumor-related hydronephrosis, and good pre-treatment bladder
function.
• TURBT alone can be considered for non-cystectomy candidates.
• A visually complete TURBT is associated with improved patient outcomes in non-metastatic settings.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Transurethral Resection of the Prostate (TURP)
• Primary treatment option for urothelial carcinoma of the prostate with ductal/acini or prostatic urethral pathology.
• Postsurgical intravesical BCG is recommended [see Principles of Intravesical Treatment (BL-F)].

Transurethral Resection (TUR) of the Urethral Tumor

• Primary treatment of Tis, Ta, T1 primary carcinoma of the urethra.
• Patients with a prior radical cystectomy and a cutaneous diversion should consider a total urethrectomy.
• Consider postsurgical intraurethral therapy [see Principles of Intravesical Treatment (BL-F)].

Partial Cystectomy
• May be used for cT2 muscle-invasive disease with solitary lesion in location amenable to segmental resection with adequate margins. May
also be appropriate in other select situations including cancer in a bladder diverticulum.
• No carcinoma in situ as determined by random biopsies.
• Should be given with neoadjuvant cisplatin-based combination chemotherapy.
• Bilateral pelvic lymphadenectomy should be performed and include common, internal iliac, external iliac, and obturator nodes.

Radical Cystectomy/Cystoprostatectomy
• In non-muscle-invasive disease, radical cystectomy is generally reserved for residual high-grade cT1.
• Cystectomy should be done within 3 months of diagnosis if no therapy is given.
• Primary treatment option for cT2, cT3, and cT4a disease. Highly select patients with cT4b disease that responds to primary treatment may be
eligible for cystectomy.
• Should be given with neoadjuvant cisplatin-based combination chemotherapy for patients with cT2-cT4a disease. For patients who cannot
receive neoadjuvant chemotherapy, radical cystectomy alone is an option.
• Bilateral pelvic lymphadenectomy should be performed and include common, internal iliac, external iliac, and obturator nodes.

Radical Nephroureterectomy with Cuff of Bladder

• Primary treatment option for non-metastatic high-grade upper GU tract tumors.
• For upper GU tract urothelial carcinoma, strongly consider single-dose immediate postoperative intravesical chemotherapy, as randomized
trials have shown a decrease in intravesical recurrence. The most commonly used option for intravesical chemotherapy is mitomycin;
gemcitabine is being utilized in select patients.
• Neoadjuvant chemotherapy should be considered in select patients with high-grade disease.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SURGICAL MANAGEMENT

Urethrectomy
• Neoadjuvant chemotherapy (category 2B) or chemoradiation should be considered.
• Distal urethrectomy may include inguinal lymph node dissection in selected cases.
• Total urethrectomy may include inguinal lymphadenectomy in selected cases.
• Male patients with T2 primary carcinoma of the urethra in the bulbar urethra may be treated with a urethrectomy with or without a
cystoprostatectomy.
• Male patients with T2 primary carcinoma of the urethra in the pendulous urethra may receive a distal urethrectomy. Alternatively, a partial
penectomy can be considered. A total penectomy may be necessary in cases of recurrence.
• Female patients with T2 primary carcinoma of the urethra may be treated with urethrectomy and cystectomy.

Regional Lymphadenectomy
• Recommended for patients with high-grade upper GU tract tumors.
• Left-sided renal pelvic, upper ureteral, and midureteral tumors:
Regional lymphadenectomy should include the paraaortic lymph nodes from the renal hilum to the aortic bifurcation.
Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
• Right-sided renal pelvic, upper ureteral, and midureteral tumors:
Regional lymphadenectomy should include the paracaval lymph nodes from the renal hilum to the IVC bifurcation.
Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
• Distal ureteral tumors:
Regional lymphadenectomy should be performed and include the common iliac, external iliac, obturator, and hypogastric lymph nodes.

Pelvic Exenteration (category 2B)

• Therapy for recurrence in female patients with ≥T2 primary carcinoma of the urethra.
• Ilioinguinal lymphadenectomy and/or chemoradiotherapy can be considered in patients with ≥T3 disease.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SURGICAL MANAGEMENT

Endoscopic Management of Upper Tract Urothelial Cancer (UTUC)
• Favorable clinical and pathologic criteria for nephron preservation:
Low-grade tumor based on cytology and biopsy
Papillary architecture
Tumor size <1.5 cm
Unifocal tumor
Cross-sectional imaging showing no concern for invasive disease
• For favorable tumors - ureteroscopic and percutaneous management provide similar survival outcomes compared to nephroureterectomy
• Less favorable clinical and pathologic criteria for nephron preservation:
Multifocal tumors
Flat or sessile tumor architecture
Tumor size >1.5 cm
High-grade tumors
cT2-T4 tumors
Mid and proximal ureteral tumor due to technical challenges
Tumor crossing in fundibulum or ureteropelvic junction
• Imperative indications for conservative therapy of UTUC
Bilateral renal pelvis and/or urothelial carcinoma of the ureter
Solitary or solitary functioning kidney
Chronic kidney disease/renal insufficiency
Hereditary predisposition (eg, hereditary nonpolyposis colon cancer [HNPCC])
• Percutaneous or ureteroscopic surgical procedures
Tumor fulguration/cautery
Tumor resection incorporating electrical energy, baskets, or cold cup devices with fulguration of the tumor bed
Laser therapies (Nd:YAG – penetration 4–6 mm; Ho:YAG – shallow penetration <0.5 mm)
• Extirpative surgical procedures
Segmental ureterectomy ± ureteral reimplantation for distal ureteral tumors
Complete ureterectomy with ileal ureter replacement (proximal/mid ureteral tumors)
• Topical immunotherapy and chemotherapy management
BCG, mitomycin
Route of administration might include percutaneous antegrade (preferred) or retrograde ureteral catheters
Induction and maintenance therapy regimens, similar to intravesical therapy, can be used
• Patients with renal pelvis and urothelial carcinoma of the ureter managed with nephron-preserving procedures and adjunctive therapies
require long-term surveillance, including cross-sectional urography or endoscopic visualization. Treatment can be associated with patient
anxiety, tumor seeding, and the need for multiple procedures and ultimate nephroureterectomy with bladder cuff. Clinical/pathologic
understaging is problematic. Recurrence or tumor persistence might be life-threatening due to disease progression.
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF PATHOLOGY MANAGEMENT

2016 WHO Classification of Tumors of the Urothelial Tract1,2
Urothelial tumors Squamous Cell Neoplasms Mesenchymal Tumors
• Infiltrating urothelial carcinoma • Pure squamous cell carcinoma • Rhabdomyosarcoma
Infiltrating urothelial carcinoma • Verrucous carcinoma • Leiomyosarcoma
Infiltrating urothelial carcinoma with • Squamous cell papilloma • Angiosarcoma
divergent differentiation • Inflammatory myofibroblastic tumor
◊◊Squamous differentiation Glandular neoplasms • Perivascular epithelioid cell tumor
◊◊Glandular differentiation • Adenocarcinoma, NOS Benign
◊◊Trophoblastic differentiation Enteric Malignant
◊◊Müllerian differentiation Mucinous • Solitary fibrous tumour
Infiltrating urothelial carcinoma, variants: Mixed • Leiomyoma
◊◊Nested, including large nested • Villous adenoma • Haemangioma
◊◊Microcystic • Granular cell tumour
◊◊Micropapillary Urachal carcinoma • Neurofibroma
◊◊Lymphoepithelioma-like
◊◊Plasmacytoid/ signet ring cell/diffuse Tumors of Müllerian Type Urothelial Tract Haematopoietic and
◊◊Sarcomatoid • Clear cell carcinoma Lymphoid tumors
◊◊Giant cell • Endometrioid carcinoma
◊◊Poorly-differentiated Miscellaneous tumors
◊◊Lipid-rich Neuroendocrine Tumors • Carcinoma of Skene, Cowper, and Littre
◊◊Clear cell • Small Cell neuroendocrine carcinoma glands
• Non-Invasive urothelial neoplasms • Large cell neuroendocrine carcinoma • Metastatic tumors and tumors extending
Urothelial carcinoma in situ • Well-differentiated neuroendocrine tumor from other organs
Non-invasive papillary urothelial • Paraganglioma • Epithelial tumors of the upper urinary tract
carcinoma, low grade • Tumors arising in a bladder diverticulum
Non-Invasive papillary urothelial Melanocytic tumors • Urothelial tumors of the urethra
carcinoma, high-grade • Malignant melanoma
Papillary urothelial neoplasm of low • Naevus
malignant potential • Melanosis
Urothelial papilloma
Inverted urothelial papilloma References
Urothelial proliferation of uncertain 1 Moch H, Cubilla AL, Humphrey PA, et al. The 2016 WHO Classification of
malignant potential Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile,
Urothelial dysplasiaa and Testicular Tumours. Eur Urol. 2016;70:93-105.
2 Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of
a The term “urothelial dysplasia” is very rarely used. Its morphologic features are Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and
poorly defined and interobserver reproducibility of this diagnosis is very low. Bladder Tumours. Eur Urol. 2016;70:106-119.
Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF PATHOLOGY MANAGEMENT

• The pathology report on biopsy/TURBT specimens should specify:
If muscularis propria (detrusor muscle) is present and if present whether it is invaded by tumor
Presence or absence of lamina propria invasion
Presence or absence of lymphovascular space invasion
Presence or absence of adjacent urothelial carcinoma in-situ
• Urothelial tumors with an inverted growth pattern should be graded similar to the system for papillary tumors as described above

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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BLADDER CANCER: NON-UROTHELIAL AND UROTHELIAL WITH VARIANT HISTOLOGY

Mixed Histology: Any Small-Cell Component (or neuroendocrine features):
• Urothelial carcinoma plus squamous, adenocarcinoma, micropapillary, • Concurrent chemoradiotherapy or neoadjuvant
nested, plasmacytoid, and sarcomatoid should be identified because of the chemotherapy followed by local treatment (cystectomy or
potential to have a more aggressive natural history. radiotherapy) is recommended for any patient with small-cell
• These are usually treated in a similar manner to pure urothelial carcinoma of component histology with localized disease regardless of
the bladder. stage.
• Micropapillary,1,2 plasmacytoid,3 and sarcomatoid histologies are generally • Neoadjuvant chemotherapy
at higher risk for progression to muscle-invasive disease and a more Standard cisplatin eligible
aggressive approach should be considered. ◊◊Etoposide + cisplatin7
◊◊Alternating ifosfamide + doxorubicin with etoposide +
Pure Squamous: cisplatin8-10
• No proven role for neoadjuvant/adjuvant chemotherapy for pure squamous Standard cisplatin ineligible
cell carcinoma of the bladder. ◊◊Etoposide + carboplatin11
• Local control with surgery or RT and best supportive care recommended. • Metastatic chemotherapy
• For advanced disease, clinical trial preferred. For selected patients, Standard cisplatin eligible
combination chemotherapy with paclitaxel, ifosfamide, and cisplatin may be ◊◊Etoposide + cisplatin7
considered.4 Standard cisplatin ineligible
• Consider postoperative RT in selected cases (positive margins).5 ◊◊Etoposide + carboplatin11
Alternate regimen for select patients
Pure Adenocarcinoma Including Urachal: ◊◊Alternating ifosfamide + doxorubicin with etoposide +
• No proven role for neoadjuvant/adjuvant chemotherapy for pure cisplatin8-10
adenocarcinomas of the bladder including urachal carcinoma.
• Local control with surgery or RT and best supportive care recommended. Primary Bladder Sarcoma:
• For urachal carcinoma with localized disease, a partial or complete • Treatment as per NCCN Guidelines for Soft Tissue Sarcoma.
cystectomy with en bloc resection of the urachal ligament with umbilicus and
lymph node dissection is recommended.
• For node-positive disease, consider chemotherapy with colorectal regimen
(FOLFOX [oxaliplatin, leucovorin, and 5-FU] or GemFLP [5-FU, leucovorin,
gemcitabine, and cisplatin]). Consider post-chemotherapy surgical
consolidation in responding disease.
• For advanced disease, clinical trial preferred. For selected patients,
combination chemotherapy with a 5-FU–based regimen (FOLFOX or GemFLP)
or ITP (paclitaxel, ifosfamide, and cisplatin). Alternatively, combination
paclitaxel and platinum may be considered.4,6
• For non-urachal pure adenocarcinoma, consider additional metastatic
workup. See NCCN Guidelines for Occult Primary.
References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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BLADDER CANCER: NON-UROTHELIAL AND UROTHELIAL WITH VARIANT HISTOLOGY

REFERENCES
1 Meeks JJ, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int 2013;111:E325-30.
2 Siefker-Radtke AO, Dinney CP, Shen Y, et al. A phase 2 clinical trial of sequential neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine followed by
cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial cancer: Final results. Cancer 2013;119:540-547.
3 Dayyani F, Czerniak BA, Sircar K, et al. Plasmacytoid urothelial carcinoma, a chemosensitive cancer with poor prognosis, and peritoneal carcinomatosis. J Urol
2013;189:1656-1661.
4 Galsky M, Iasonos A, Mironov S, et al. Prospective trial of ifosfamide, paclitaxel, and cisplatin in patients with advanced non-transitional cell carcinoma of the urothelial
tract. Urology 2007;69:255-259.
5 Zaghloul MS, Awwad HK, Akoush HH, et al. Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local
control. Int J Radiat Oncol Biol Phys 1992;23:511-517.
6 Siefker-Radtke A, Gee J, Shen Y, et al. Multimodality management of urachal carcinoma: The M. D. Anderson Cancer Center experience. J Urol 2003;169:1295-1298.
7 Roth BJ, Johnson DH, Einhorn LH, et al. Randomized study of cyclophosphamide, doxorubicin, and vincristine versus etoposide and cisplatin versus alternation of
these two regimens in extensive small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group. J Clin Oncol 1992;10:282-291.
8 Siefker-Radtke AO, Kamat AM, Grossman HB, et al. Phase II clinical trial of neoadjuvant alternating doublet chemotherapy with ifosfamide/doxorubicin and etoposide/
cisplatin in small-cell urothelial cancer. J Clin Oncol 2009; 27:2592-2597.
9 Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: Results from a
retrospective study at the MD Anderson Cancer Center. Eur Urol 2013;64:307-313.
10 Siefker-Radtke AO, Dinney CP, Abrahams NA, et al. Evidence supporting preoperative chemotherapy for small cell carcinoma of the bladder: A retrospective review of
the M. D. Anderson cancer experience. J Urol 2004;172:481-484.
11 Okamoto
 H, Watanabe K, Nishiwaki Y, et al. Phase II study of area under the plasma-concentration-versus-time curve-based carboplatin plus standard-dose
intravenous etoposide in elderly patients with small-cell lung cancer. J Clin Oncol 1999;17:3540-3545.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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FOLLOW-UP
No single follow-up plan is appropriate for all patients. The follow-up tables are to provide guidance, and should be modified for the individual patient based on sites
of disease, biology of disease, and length of time on treatment. Reassessment of disease activity should be performed in patients with new or worsening signs or
symptoms of disease, regardless of the time interval from previous studies. Further study is required to define optimal follow-up duration.
Table 1: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer*
Low Risk Intermediate Risk High Risk
• Low grade (LG) solitary Ta ≤3 cm • Recurrence within 1 year, LG Ta • HG T1
• Papillary urothelial neoplasm of low • Solitary LG Ta >3 cm • Any recurrent, HG Ta
malignant potential • LG Ta, multifocal • HG Ta, >3 cm (or multifocal)
• High grade (HG) Ta, ≤3 cm • Any carcinoma in situ (CIS)
• LG T1 • Any BCG failure in HG patient
• Any variant histology
• Any lymphovascular invasion
• Any HG prostatic urethral involvement
*Reproduced with permission from Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 2016;196:1021.

Table 2: Low-Risk,1 Non-Muscle-Invasive Bladder Cancer

Test Year
1 2 3 4 5 5–10 >10
Cystoscopy 3, 12 Annually As clinically indicated
Upper tract 2
Baseline
and abdominal/ As clinically indicated
imaging
pelvic3 imaging4
Blood tests N/A
Urine tests N/A

Intermediate Risk, Non-Muscle-Invasive (BL-E 2 of 5) Post-Cystectomy Muscle-Invasive Bladder Cancer (BL-E 4 of 5)

High-Risk, Non-Muscle Invasive (BL-E 2 of 5) Post-Bladder Sparing (BL-E 5 of 5)
Post-Cystectomy Non-Muscle-Invasive Bladder Cancer (BL-E 3 of 5) See Recurrent or Persistent Disease (BL-11)
1 See Table 1: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer definitions on BL-E (1 of 5).
2 Upper tract imaging includes CTU, MRU, intravenous pyelogram (IVP), retrograde pyelography, or ureteroscopy.
3 Abdominal/pelvic imaging includes CT or MRI.
4 See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
5 Urine cytology should be done at time of cystoscopy if bladder in situ.
See NCCN Guidelines
Note: All recommendations are category 2A unless otherwise indicated. for Survivorship
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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FOLLOW-UP
No single follow-up plan is appropriate for all patients. The follow-up tables are to provide guidance, and should be modified for the individual patient based on sites
of disease, biology of disease, and length of time on treatment. Reassessment of disease activity should be performed in patients with new or worsening signs or
symptoms of disease, regardless of the time interval from previous studies. Further study is required to define optimal follow-up duration.
Table 3: Intermediate Risk,1 Non-Muscle-Invasive Bladder Cancer
Test Year
1 2 3 4 5 5–10 >10
Cystoscopy 3, 6, 12 Every 6 mo Annually As clinically indicated
Upper tract 2
Baseline
and abdominal/ As clinically indicated
imaging
pelvic3 imaging4
Blood tests N/A
Urine cytology5 Urine cytology Annually As clinically indicated
Urine tests
3, 6, 12 every 6 mo
Table 4: High-Risk,1 Non-Muscle-Invasive Bladder Cancer
Test Year
1 2 3 4 5 5–10 >10
As clinically
Cystoscopy Every 3 mo Every 6 mo Annually
indicated
Baseline
Upper tract2 As clinically
imaging, and at Every 1–2 y
imaging4 indicated
12 mo
Abdominal/ Baseline
As clinically indicated
pelvic3 imaging4 imaging
Blood tests N/A
• Urine cytology5 every 3 mo
As clinically
Urine tests • Consider urinary urothelial Urine cytology every 6 mo Annually
indicated
tumor markers (category 2B)

1 See Table 1: AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer 3 Abdominal/pelvic imaging includes CT, MRI, or FDG PET/CT (category 2B) (PET/
definitions on BL-E (1 of 5). CT not recommended for NMIBC).
2 Upper tract imaging includes CTU, MRU, intravenous pyelogram (IVP), retrograde 4 See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
pyelography, or ureteroscopy. 5 Urine cytology should be done at time of cystoscopy if bladder in situ.

See NCCN Guidelines

Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. for Survivorship
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FOLLOW-UP
No single follow-up plan is appropriate for all patients. The follow-up tables are to provide guidance, and should be modified for the individual patient based on sites
of disease, biology of disease, and length of time on treatment. Reassessment of disease activity should be performed in patients with new or worsening signs or
symptoms of disease, regardless of the time interval from previous studies. Further study is required to define optimal follow-up duration.
Table 5: Post-Cystectomy Non-Muscle-Invasive Bladder Cancer
Test Year
1 2 3 4 5 5–10 >10
Cystoscopy N/A
CTU or MRU
(image upper
tracts + axial CTU or MRU (image upper tracts + axial imaging of abdomen/pelvis) Renal US As clinically
Imaging4
imaging of annually annually6 indicated
abdomen/pelvis)
at 3 and 12 mo
• Renal function
testing
(electrolytes
and creatinine)
every 3–6 mo • Renal function testing (electrolytes and creatinine) annually
Blood tests • LFT7 every 3–6 • LFT7 annually B12 annually
mo • B12 annually
• CBC, CMP
every 3–6 mo
if received
chemotherapy
• Urine cytology5 every 6–12 mo
Urine cytology as clinically indicated
Urine tests • Consider urethral wash cytology
Urethral wash cytology as clinically indicated
every 6–12 mo8

Post-Cystectomy MIBC (BL-E 4 of 5) Post-Bladder Sparing (BL-E 5 of 5) See Recurrent or Persistent Disease (BL-11)
7 Liver function testing includes AST, ALT, bilirubin, and alkaline phosphatase.
4 See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). 8 Urethral wash cytology is reserved for patients with high-risk disease. High-risk
5 Urine cytology should be done at time of cystoscopy if bladder in situ. disease includes: positive urethral margin, multifocal CIS, and prostatic urethral
6 Renal US to look for hydronephrosis. invasion.
See NCCN Guidelines
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. for Survivorship
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FOLLOW-UP
No single follow-up plan is appropriate for all patients. The follow-up tables are to provide guidance, and should be modified for the individual patient based on sites
of disease, biology of disease, and length of time on treatment. Reassessment of disease activity should be performed in patients with new or worsening signs or
symptoms of disease, regardless of the time interval from previous studies. Further study is required to define optimal follow-up duration.
Table 6: Post-Cystectomy Muscle-Invasive Bladder Cancer
Test Year
1 2 3 4 5 5–10 >10
Cystoscopy N/A
• CTU or MRU (image upper tracts +
axial imaging of abdomen/pelvis)
• Abdominal/pelvic CT or MRI annually
every 3–6 mo
• Chest x-ray or CT chest annually
• Chest x-ray or CT chest every 3–6 Renal US As clinically
Imaging4 or
mo annually6 indicated
• FDG PET/CT (category 2B) only if metastatic
or
disease suspected
• FDG PET/CT (category 2B) only if
metastatic disease suspected
• Renal function
testing
(electrolytes and
creatinine) every • Renal function testing (electrolytes and creatinine) annually
Blood tests 3–6 mo • LFT7 annually B12 annually
7
• LFT every 3–6 mo • B12 annually
• CBC, CMP every
3–6 mo if received
chemotherapy
• Urine cytology5 every 6–12 mo
Urine cytology as clinically indicated
Urine tests • Consider urethral wash cytology
8 Urethral wash cytology as clinically indicated
every 6–12 mo

Post-Bladder Sparing (BL-E 5 of 5)

See Recurrent or Persistent Disease (BL-11)
7 Liver function testing includes AST, ALT, bilirubin, and alkaline phosphatase.
4 See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). 8 Urethral wash cytology is reserved for patients with high-risk disease. High-risk
5 Urine cytology should be done at time of cystoscopy if bladder in situ. disease includes: positive urethral margin, multifocal CIS, and prostatic urethral
6 Renal US to look for hydronephrosis. invasion.
See NCCN Guidelines
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. for Survivorship
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FOLLOW-UP
No single follow-up plan is appropriate for all patients. The follow-up tables are to provide guidance, and should be modified for the individual patient based on sites
of disease, biology of disease, and length of time on treatment. Reassessment of disease activity should be performed in patients with new or worsening signs or
symptoms of disease, regardless of the time interval from previous studies. Further study is required to define optimal follow-up duration.
Table 7: Post-Bladder Sparing (ie, Partial Cystectomy or Chemoradiation)
Test Year
1 2 3 4 5 5–10 >10
As clinically
Cystoscopy Every 3 mo Every 6 mo Annually
indicated
• CTU or MRU (image upper tracts + axial
imaging of abdomen/pelvis) every 3–6 mo
• Abdominal/pelvic CT or MRI annually
for MIBC
• Chest x-ray or CT chest annually
• Chest x-ray or CT chest every 3–6 mo for
Imaging4 or As clinically indicated
MIBC
• FDG PET/CT (category 2B) only if metastatic
or
disease suspected9
• FDG PET/CT (category 2B) only if metastatic
disease suspected
• Renal function testing
(electrolytes and
creatinine) every 3–6 mo
• Renal function testing (electrolytes and creatinine) as clinically indicated
Blood tests • LFT6 every 3–6 mo
• LFT6 as clinically indicated
• CBC, CMP every
3–6 mo if received
chemotherapy
Urine tests Urine cytology4 every 6–12 mo Urine cytology as clinically indicated

4 See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

9 PET/CT not recommended for NMIBC.

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

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

Indications: Based on probability of recurrence and progression to muscle-invasive disease, such as size, number, and grade.
Intravesical Therapy for Bladder Cancer
Immediate Postoperative Intravesical Chemotherapy
• See Clinical Presentation and Initial Evaluation (BL-1)
• A single instillation of chemotherapy is administered within 24 hours of surgery (ideally within 6 hours).
• Gemcitabine (preferred) (category 1)1 and mitomycin (category 1)2 are the most commonly used agents in the United States for intravesical
chemotherapy. Thiotepa does not appear to be effective.3
• Immediate postoperative intravesical chemotherapy reduces the 5-year recurrence rate by approximately 35% and has a number needed to
treat to prevent a recurrence of 7. However, it does not reduce the risk of progression or the risk of cancer mortality.3
• It is not effective in patients with an elevated EORTC recurrence risk score (≥5). This includes patients with ≥8 tumors and those with
≥1 recurrence per year.
• Contraindications include: bladder perforation, known drug allergy
Induction (Adjuvant) Intravesical Chemotherapy or BCG
• Treatment option for NMIBC (See BL-2, BL-3, and BL-10).
• The most commonly used agents are BCG, mitomycin, and gemcitabine.
• In the event of a BCG shortage, BCG should be prioritized for induction of high-risk patients (eg, high-grade T1 and CIS). Preferable
alternatives to BCG include mitomycin or gemcitabine.
Other options include: epirubicin, valrubicin, docetaxel, or sequential gemcitabine/docetaxel or gemcitabine/mitomycin.
If feasible, the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage.
• Initiated 3–4 weeks after TURBT with or without maintenance.
• Weekly instillations during induction are given for approximately 6 weeks.
• Maximum of 2 consecutive cycle inductions without complete response.
• Withhold if traumatic catheterization, bacteriuria, persistent gross hematuria, persistent severe local symptoms, or systemic symptoms.
Maintenance Intravesical BCG
• Although there is no standard regimen for maintenance BCG, many NCCN Member Institutions follow the SWOG regimen consisting of a
6-week induction course of BCG followed by maintenance with 3 weekly instillations at months 3, 6, 12, 18, 24, 30, and 36.4
• In the event of a BCG shortage, BCG should be prioritized for high-risk patients (eg, high-grade T1 and CIS), especially in the early
maintenance period (ie, 3 and 6 months post-induction).
If feasible, the dose of BCG may be split (1/3 or 1/2 dose) so that multiple patients may be treated with a single vial in the event of a shortage.
• Ideally maintenance should be given for 1 year for intermediate-risk and 3 years for high-risk NMIBC.
• BCG would be withheld if traumatic catheterization, bacteriuria, persistent gross hematuria, persistent severe local symptoms, or systemic
symptoms.
• Dose reduction is encouraged if there are substantial local symptoms during maintenance therapy.
• Data suggest the benefit of maintenance BCG therapy through a decreased rate of recurrence for NMIBC.4
Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF INTRAVESICAL TREATMENT

Indications: Based on probability of recurrence and progression to muscle-invasive disease, such as size, number, and grade.
Topical or Percutaneous Administration of Chemotherapy or BCG
• Although the target site differs, the principles of this treatment are similar to intravesical therapy. Topical chemotherapeutic agents are
delivered by instillation. Administration can be percutaneous or through a retrograde approach using a catheter. There is no standard
regimen and patients should be referred to an institution with experience in this treatment or a clinical trial.

Postsurgical Intraprostatic BCG for Urothelial Carcinoma of the Prostate

• Treatment for patients with ductal + acini, or prostatic urethra involvement. See Urothelial Carcinoma of the Prostate (UCP-1)
• Induction (adjuvant) therapy should be initiated 3–4 weeks after TURP
• Induction BCG should be followed with maintenance BCG
• Data indicate a reduction in recurrence in the prostate in patients with superficial disease5-11

Postsurgical Intraurethral Therapy for Primary Carcinoma of the Urethra

• Consider as primary treatment for select patients with Tis, Ta, or T1 disease. See Primary Carcinoma of the Urethra (PCU-2)
• Induction (adjuvant) therapy should be initiated 3–4 weeks after TUR.
• The most commonly used agents are BCG, mitomycin, and gemcitabine.
• Role of maintenance in this context is uncertain.
• Efficacy of this treatment in primary carcinoma of the urethra has not been established.

Postsurgical Therapy for Upper Tract Tumors

• Consider intrapelvic therapy for patients with non-metastatic, low-grade tumors of the renal pelvis. See Upper GU Tract Tumors: Renal Pelvis
(UTT-1)
Intrapelvic induction (adjuvant) therapy should be initiated 3–4 weeks after endoscopic resection.
The most commonly used agents for intrapelvic therapy are BCG, mitomycin C, and gemcitabine.
Role of maintenance following intrapelvic therapy in this context is uncertain.
Efficacy of intrapelvic therapy in upper urinary tract cancer has not been established.12-14
• Perioperative intravesical chemotherapy with mitomycin or gemcitabine may be given following nephroureterectomy with cuff of bladder
resection.

References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF INTRAVESICAL TREATMENT

REFERENCES
1 Messing E, Tangen C, Lerner S, et al. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-
invasive bladder cancer on tumor recurrence. JAMA 2018;319:1880-1888.
2 Bosschieter J, Nieuwenhuijzen JA, van Ginkel T, et al. Value of an immediate intravesical instillation of mitomycin C in patients with non-muscle-invasive bladder
cancer: A prospective multicentre randomised study in 2243 patients. Eur Urol 2018;73:226-232.
3 Sylvester RJ, Oosterlinck W, Holmang S, et al. Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate
instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa-pT1 urothelial carcinoma of the bladder: Which
patients benefit from the instillation? Eur Urol 2016;69:231-244.
4 Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell
carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000;163:1124-1129.
5 Hillyard RW, Jr., Ladaga L, Schellhammer PF. Superficial transitional cell carcinoma of the bladder associated with mucosal involvement of the prostatic urethra: results
of treatment with intravesical bacillus Calmette-Guerin. J Urol 1988;139:290-293.
6 Canda AE, Tuzel E, Mungan MU, et al. Conservative management of mucosal prostatic urethral involvement in patients with superficial transitional cell carcinoma of
the bladder. Eur Urol 2004;45:465-469; discussion 469-470.
7 Palou J, Xavier B, Laguna P, et al. In situ transitional cell carcinoma involvement of prostatic urethra: bacillus Calmette-Guerin therapy without previous transurethral
resection of the prostate. Urology 1996;47:482-484.
8 Schellhammer PF, Ladaga LE, Moriarty RP. Intravesical bacillus Calmette-Guerin for the treatment of superficial transitional cell carcinoma of the prostatic urethra in
association with carcinoma of the bladder. J Urol 1995;153:53-56.
9 Bretton PR, Herr HW, Whitmore WF, Jr., et al. Intravesical bacillus Calmette-Guerin therapy for in situ transitional cell carcinoma involving the prostatic urethra. J Urol
1989;141:853-856.
10 Orihuela E, Herr HW, Whitmore WF, Jr. Conservative treatment of superficial transitional cell carcinoma of prostatic urethra with intravesical BCG. Urology
1989;34:231-237.
11 Solsona E, Iborra I, Ricos JV, et al. Recurrence of superficial bladder tumors in prostatic urethra. Eur Urol 1991;19:89-92.
12 Cutress ML, Stewart GD, Zakikhani P, et al. Ureteroscopic and percutaneous management of upper tract urothelial carcinoma (UTUC): systematic review. BJU Int
2012;110:614-628.
13 Hayashida Y, Nomata K, Noguchi M, et al. Long-term effects of bacille Calmette-Guerin perfusion therapy for treatment of transitional cell carcinoma in situ of upper
urinary tract. Urology 2004;63:1084-1088.
14 Audenet F, Traxer O, Bensalah K, Roupret M. Upper urinary tract instillations in the treatment of urothelial carcinomas: a review of technical constraints and
outcomes. World J Urol 2013;31:45-52.

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

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

Perioperative chemotherapy (neoadjuvant or adjuvant)

Preferred regimens
• DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support for 3 or 4 cycles1,2
• Gemcitabine and cisplatin for 4 cycles3,4
Other recommended regimens
• CMV (cisplatin, methotrexate, and vinblastine) for 3 cycles5

• For patients who are not candidates for cisplatin, there are no data to support a recommendation for perioperative chemotherapy.
• Randomized trials and meta-analyses show a survival benefit for cisplatin-based neoadjuvant chemotherapy (3 or 4 cycles) in patients with
muscle-invasive bladder cancer.1,6,7
• Meta-analysis suggests overall survival benefit with adjuvant cisplatin-based chemotherapy for pathologic T3, T4 or N+ disease at
cystectomy, if it was not given as neoadjuvant.7
• Neoadjuvant chemotherapy is preferred over adjuvant-based chemotherapy on a higher level of evidence data.
• DDMVAC is preferred over standard MVAC based on category 1 evidence for metastatic disease showing DDMVAC to be better tolerated
and more effective than conventional MVAC in advanced disease.2,8 Based on these data, the traditional dose and schedule for MVAC is no
longer recommended.
• Perioperative gemcitabine and cisplatin is a reasonable alternative to DDMVAC based on category 1 evidence for metastatic disease showing
equivalence to conventional MVAC in the setting of advanced disease.4,9
• For gemcitabine/cisplatin, a 21-day cycle is preferred. Better dose compliance may be achieved with fewer delays in dosing using the 21-day
schedule.10
• Neoadjuvant chemotherapy may be considered for select patients with UTUC, particularly for higher stage and/or grade tumors, as renal
function will decline after nephroureterectomy and may preclude adjuvant therapy.
• Carboplatin should not be substituted for cisplatin in the perioperative setting.
For patients with borderline renal function or minimal dysfunction, a split-dose administration of cisplatin may be considered
(such as 35 mg/m2 on days 1 and 2 or days 1 and 8) (category 2B). While safer, the relative efficacy of the cisplatin-containing combination
administered with such modifications remains undefined.
• For patients with borderline renal function, estimate GFR to assess eligibility for cisplatin. Consider timed urine collection which may more
accurately determine eligibilty for cisplatin.

Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SYSTEMIC THERAPY

First-line systemic therapy for locally advanced or metastatic disease (Stage IV)
Preferred regimens
Cisplatin eligible • Gemcitabine and cisplatin4 (category 1)
• DDMVAC with growth factor support (category 1)2,8
Preferred regimens
Cisplatin ineligible • Gemcitabine and carboplatin11
• Atezolizumab12 (only for patients whose tumors express PD-L1a or who are not eligible for any
platinum-containing chemotherapy regardless of PD-L1 expression)
• Pembrolizumab13 (only for patients whose tumors express PD-L1b or who are not eligible for any
platinum-containing chemotherapy regardless of PD-L1 expression)

Other recommended regimens

• Gemcitabine14
• Gemcitabine and paclitaxel15

Useful under certain circumstances

• Ifosfamide, doxorubicin, and gemcitabine16 (for patients with good kidney function and good PS)

• The presence of both non-nodal metastases and ECOG performance score ≥2 strongly predict poor outcome with chemotherapy. Patients
without these adverse prognostic factors have the greatest benefit from chemotherapy. The impact of these factors in relation to immune
checkpoint inhibition is not fully defined, but they remain poor prognostic indicators in general.
• For most patients, the risks of adding paclitaxel to gemcitabine and cisplatin outweigh the limited benefit seen in the randomized trial.17
• A substantial proportion of patients cannot receive cisplatin-based chemotherapy due to renal impairment or other comorbidities.
Participation in clinical trials of new or more tolerable therapy is recommended.

a Atezolizumab: SP142 assay, PD-L1–stained tumor-infiltrating immune cells covering ≥5% of the tumor area.
b Pembrolizumab: 22C3 antibody assay, Combined Positive Score (CPS) ≥10.
Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SYSTEMIC THERAPY

Second-line systemic therapy for locally advanced or metastatic disease (Stage IV) (post-platinum)c
Participation in clinical trials of new agents is recommended.
Preferred regimen Other recommended regimens
• Pembrolizumab (category 1)18 • Paclitaxel26 or docetaxel27
• Gemcitabine14
Alternative preferred regimens Useful in certain circumstances based on prior medical therapy
• Immune checkpoint inhibitor • Ifosfamide, doxorubicin, and gemcitabine16
Atezolizumab 19,20 • Gemcitabine and paclitaxel15
Nivolumab 21 • Gemcitabine and cisplatin4
Durvalumab 22 • DDMVAC with growth factor support2
Avelumab 23,24
• Erdafitinibd,25

Second-line systemic therapy for locally advanced or metastatic disease (Stage IV) (post-checkpoint inhibitor)
Participation in clinical trials of new agents is recommended.
Preferred regimen for cisplatin ineligible, Other recommended regimens
chemotherapy naïve • Erdafitinibd,25
• Gemcitabine/carboplatin • Paclitaxel or docetaxel27
• Gemcitabine14
Preferred regimens for cisplatin eligible, Useful in certain circumstances based on prior medical therapy
chemotherapy naïve • Ifosfamide, doxorubicin, and gemcitabine16
• Gemcitabine and cisplatin4 • Gemcitabine and paclitaxel15
• DDMVAC with growth factor support 2

c If PFS >12 months after platinum (eg, cisplatin or carboplatin), consider re-treatment with platinum if the patient is still platinum eligible.
d Only for patients with susceptible FGFR3 or FGFR2 genetic alterations.
Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SYSTEMIC THERAPY

Subsequent-line systemic therapy for locally advanced or metastatic disease (Stage IV)e
Participation in clinical trials of new agents is recommended.
Preferred regimen Other recommended regimens
• Enfortumab vedotin28 • Gemcitabine14
• Erdafitinibd • Paclitaxel26 or docetaxel27
• Ifosfamide, doxorubicin, and gemcitabine16
• Gemcitabine and paclitaxel15
• Gemcitabine and cisplatin4
• DDMVAC with growth factor support2

d Only for patients with susceptible FGFR3 or FGFR2 genetic alterations.

e Patient should have already received platinum and a checkpoint inhibitor, if eligible.
Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SYSTEMIC THERAPY

Radiosensitizing chemotherapy regimens for organ-preserving chemoradiation

Preferred regimens (doublet chemotherapy is preferred when feasible)
• Cisplatinf and 5-FU29,30
• Cisplatinf and paclitaxel29,31
• 5-FU and mitomycin32
• Cisplatinf alone33
Other recommended regimen
• Low-dose gemcitabine30,34,35 (category 2B)

Radiosensitizing chemotherapy given concurrently with conventionally

fractionated radiation with palliative intent for regional disease
Preferred regimen
• Cisplatinf
Other recommended regimens
• Taxane (docetaxel or paclitaxel) (category 2B)
• 5-FU (category 2B)
• 5-FU and mitomycin (category 2B)
• Low-dose gemcitabine30 (category 2B)
• Capecitabine (category 3)

f Carboplatinis not an effective radiation sensitizer and should not be substituted for cisplatin with radiation. (Rödel C, Grabenbauer GG, Kühn R, et al. Combined-
modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002; 20:3061.)
References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Bladder Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

1 Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus 10 Soto Parra H, Cavina R, Latteri F, et al. Three-week versus four-week schedule
cystectomy compared with cystectomy alone for locally advanced bladder cancer. of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol
N Engl J Med 2003;349:859-866. 2002;13:1080-1086.
2 Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of 11 De
 Santis M, Bellmunt J, Mead G, et al: Randomized phase II/III trial assessing
high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients
chemotherapy and recombinant human granulocyte colony-stimulating factor with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy:
versus classic MVAC in advanced urothelial tract tumors: European Organization EORTC study 30986. J Clinl Oncol 2012;30:191-199.
for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol 12 Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment
2001;19:2638-2646. in cisplatin-ineligible patients with locally advanced and metastatic urothelial
3 Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine plus carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389:67-76.
cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective 13 Balar AV, Castellano DE, O’Donnell PH, et al. Pembrolizumab as first-line
experience. Cancer 2008;113:2471-2477. therapy in cisplatin-ineligible advanced urothelial cancer: Results from the total
4 Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin KEYNOTE-052 study population [abstract]. J Clin Oncol 2018;6S:Abstract 284.
versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced 14 Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine
or metastatic bladder cancer: results of a large, randomized, multinational, in previously untreated patients with metastatic urothelial cancer. J Clin Oncol
multicenter, phase III study. J Clin Oncol 2000;18:3068-3077. 1997;15:3394-3398.
5 Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing 15 Calabro
 F, Lorusso V, Rosati G, et al: Gemcitabine and paclitaxel every 2
neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle- weeks in patients with previously untreated urothelial carcinoma. Cancer
invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2009;115:2652-2659.
2011;29:2171-2177. 16 Siefker-Radtke AO, Dinney CP, Shen Y, et al: A phase 2 clinical trial of sequential
6 Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine
chemotherapy in invasive bladder cancer: update of a systematic review and followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial
meta-analysis of individual patient data advanced bladder cancer (ABC) meta- cancer: final results. Cancer 2013;119:540-547.
analysis collaboration. Eur Urol 2005;48:202-205; discussion 205-206. 17 Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study
7 Advanced Bladder Cancer Meta-analysis Collaboration. Adjuvant chemotherapy comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients
in invasive bladder cancer: a systematic review and meta-analysis of individual with locally advanced or metastatic urothelial cancer without prior systemic
patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30:1107-1113.
Urol 2005;48:189-199; discussion 199-201. 18 Bellmunt, de Wit R, Vaughn D, et al. Pembrolizumab as second-line therapy for
8 Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an advanced urothelial carcinoma. N Engl J Med 2018;376:1015-1026.
EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF 19 Rosenberg JE, Hoffman-Censits J, Powles T et al. Atezolizumab in patients with
versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer locally advanced and metastatic urothelial carcinoma who have progressed
2006;42:50-54. following treatment with platinum-based chemotherapy: A single-arm,
9 von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of multicentre, phase 2 trial. Lancet 2018; 387:1909-1920.
a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, 20 Sternberg CN, Loriot Y, James N, et al. Primary results from SAUL, a
vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin multinational single-arm safety study of atezolizumab therapy for locally
Oncol 2005;23:4602-4608. advanced or metastatic urothelial or nonurothelial carcinoma of the urinary tract.
Eur Oncol. 2019;76:73-81.

Continued
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF SYSTEMIC THERAPY - REFERENCES

21 Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2
trial. Lancet Oncol 2018.
22 Powles T, et al. Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma [abstract]. J Clin Oncol 2018;35: Abstract 286.
23 Apolo AB, Infante JR, Patel MR, et al. Avelumab, an anti-programmed death-ligand 1 antibody, in patients with refractory metastatic urothelial carcinoma: Results from
a multicenter, phase Ib study. J Clin Oncol 2018; Apr 4.
24 Patel M, Ellerton J, Infante J, et al. Avelumab in patients with metastatic urothelial carcinoma: Pooled results from two cohorts of the phase 1b JAVELIN Solid Tumor
trial [abstract]. J Clin Oncol 2018;6S:Abstract 330.
25 Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338-348.
26 Sideris S, Auon F, Zanaty M, et al. Efficacy of weekly paclitaxel treatment as a single agent chemotherapy following first-line cisplatin treatment in urothelial bladder
cancer. Mol Clin Oncol. 2016;4:1063-1067.
27 McCaffrey JA, Hilton S, Mazumdar M, et al: Phase II trial of docetaxel in patients with advanced or metastatic transitional-cell carcinoma. J Clin Oncol 1997;15:1853-
1857.
28 Rosenberg JE, O-Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed
Death Ligand 1 Therapy. J Clin Oncol. 2019;37:2592-2600.
29 Mitin T, Hunt D, Shipley W, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation
and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomized multicentre phase 2 trial. Lancet Oncol 2013;14:863-872.
30 Coen JJ, Zhang P, Saylor PJ, et al. Bladder Preservation With Twice-a-Day Radiation Plus Fluorouracil/Cisplatin or Once Daily Radiation Plus Gemcitabine for
Muscle-Invasive Bladder Cancer: NRG/RTOG 0712-A Randomized Phase II Trial. J Clin Oncol. 2019;37:44-51.
31 Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: The
MGH experience. Eur Urol 2012; 61:705-711.
32 James ND, Hussain SA, Hall E, et al; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med
2012;366:1477-1488.
33 Tester W, Caplan R, Heaney J, et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation
Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14:119-126.
34 Kent E et al. Combined-modality therapy with gemcitabine and radiotherapy as a bladder preservation strategy: results of a phase I trial. J Clin Oncol 2004;22:2540-
2545.
35 Choudhury A, Swindell R, Logue JP, et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle-invasive bladder cancer.
J Clin Oncol 2011; 29:733-738.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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PRINCIPLES OF RADIATION MANAGEMENT OF INVASIVE DISEASE

Carcinoma of the Bladder: Unless otherwise stated, doses are 1.8–2.0 Gy daily fractionation.
• Precede radiation therapy (RT) alone or concurrent chemoradiotherapy by maximal TUR of the tumor when safely possible.
• Simulating and treating patients when they have an empty bladder is preferred for daily reproducibility (bladder full for tumor boosts is acceptable with
image guidance).
• Use multiple fields from high-energy linear accelerator beams.
• For invasive tumors, consider low-dose preoperative RT prior to segmental cystectomy (category 2B).
• Concurrent chemoradiotherapy or RT alone is most successful for patients without hydronephrosis and without extensive carcinoma in situ associated
with their muscle-invading tumor.
• For patients with stage Ta, T1, or Tis, external beam RT (EBRT) alone is rarely appropriate. For patients with recurrent Ta-T1 disease usually following
BCG therapy but without extensive Tis who are not candidates for cystectomy, concurrent chemoradiotherapy may be considered as a potentially curative
alternative to radical cystectomy, which is the standard treatment by NCCN Guidelines.
• Treat the whole bladder with or without pelvic nodal radiotherapy 39.6–50.4 Gy using conventional or accelerated hyperfractionation. Elective treatment to
the lymph nodes is optional and should take into account patient comorbidities and the risks of toxicity to adjacent critical structures. Then boost either
the whole or partial bladder between 60–66 Gy. For node-positive disease, consider boosting grossly involved nodes to the highest achievable dose that
does not violate DVH parameters based on the clinical scenario. Reasonable alternatives to conventional fractionation include taking the whole bladder to
55 Gy in 20 fractions, or using simultaneous integrated boosts to sites of gross disease.
• When irradiating the bladder only or bladder tumor boost, consider daily image guidance.
• Concurrent chemoradiotherapy is recommended for added tumor cytotoxicity, and can be given without significant increased toxicity over RT alone.
Concurrent 5-FU and mitomycin C or low-dose gemcitabine can be used instead of cisplatin-containing regimens in patients with low or moderate renal
function. Such therapy is optimally given by dedicated multidisciplinary teams.
• Concurrent chemoradiotherapy or RT alone should be considered as potentially curative therapy for medically inoperable patients or for local palliation in
patients with metastatic disease.
• When giving palliative radiation for metastatic bladder cancer or for recurrent pelvic tumor, combining radiation with radiosensitizing chemotherapy
should be considered. See BL-G 5 of 7 for agents. Chemotherapy should not be used concurrently with high-dose (>3 Gy per fraction) palliative radiation.
• Treatment field should include whole bladder and all sites of gross disease plus or minus uninvolved regional lymph nodes. Regional lymph nodes include
the hypogastric, obturator, internal and external iliac, perivesical, sacral, and presacral nodes. For involved nodal disease, the common iliac nodes are a
site of secondary involvement.
• For patients with pT3/pT4 pN0-2 urothelial (pure urothelial or primary urothelial mixed with other subtypes) bladder cancer following radical cystectomy
with ileal conduit, consider postoperative adjuvant pelvic RT (category 2B). Treatment field should encompass areas at risk for harboring residual
microscopic disease based on pathologic findings at resection and may include cystectomy bed and pelvic lymph nodes with doses in the range of 45 to
50.4 Gy. Involved resection margins and areas of extranodal extension could be boosted to 54–60 Gy if feasible based on normal tissue constraints.
• Tumor status assessment after completion of full-dose primary chemoradiotherapy: After 2–3 months, imaging with CT of chest/abdomen/pelvis with
contrast ± bone scan. Cystoscopic surveillance and biopsy are also recommended as follow-up after completion of full-dose chemoradiotherapy.
• In highly selected T4b tumor cases, may consider intraoperative RT.

Continued
Note: All recommendations are category 2A unless otherwise indicated. References
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
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Bladder Cancer Discussion

PRINCIPLES OF RADIATION MANAGEMENT OF INVASIVE DISEASE

Carcinoma of the Urethra: Unless otherwise stated, doses are 1.8–2.0 Gy daily fractionation.
• Data support the use of RT for urothelial carcinoma and squamous cell carcinoma of the urethra (case series and experience treating these
carcinomas arising from other disease sites); radiation can also be considered for adenocarcinomas of the urethra.
• Definitive Radiation Therapy (organ preservation)
cT2 cN0
◊◊66–70 Gy EBRT delivered to gross disease with a margin to encompass areas of potential microscopic spread. Concurrent chemotherapy
with regimens used for bladder cancer is encouraged for added tumor cytotoxicity.
◊◊Strongly consider prophylactic radiation treatment of regional-nodal basins (inguinal and low pelvic nodes for female and distal male
tumors; pelvic lymph nodes for proximal male tumors).

cT3-T4, or lymph node positive

◊◊45–50.4 Gy EBRT delivered to gross disease with a margin to encompass areas of microscopic spread and to regional-nodal basins
(inguinal and low pelvic nodes for female and distal male tumors; pelvic lymph nodes for proximal male tumors). Boost gross primary
disease to 66–70 Gy and gross nodal disease to 54–66 Gy, if feasible. Dose delivered to gross nodal disease may be limited secondary to
normal tissue dose constraints. Concurrent chemotherapy should be administered for added tumor cytotoxicity.

Postoperative adjuvant radiation therapy

◊◊Treatment field should encompass areas at risk for harboring residual microscopic disease based on pathologic findings at resection
and may include resection bed, inguinal lymph nodes, and pelvic lymph nodes. Areas at risk for harboring residual microscopic
disease should receive 45–50.4 Gy EBRT. Involved resection margins and areas of extranodal extension should be boosted to 54–60 Gy if
feasible based on normal tissue constraints. Areas of gross residual disease should be boosted to 66–70 Gy, if feasible based on normal
tissue constraints. Concurrent chemotherapy with regimens used for bladder cancer should be considered for added tumor cytotoxicity.
Recurrent disease
◊◊Clinical target volume (CTV) should include gross disease in any suspected areas of spread at 66–74 Gy (higher dose up to 74 Gy for
larger tumor and non-urothelial histology) and consideration can be given to elective regional-nodal basins (45–50.4 Gy) as discussed
above, if feasible based on normal tissue constraints.

References
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
BL-H
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PRINCIPLES OF RADIATION MANAGEMENT OF INVASIVE DISEASE

REFERENCES
Baumann BC, Bosch WR, Bahl A, et al. Development and validation of consensus contouring guidelines for adjuvant radiation therapy for bladder cancer after Radical
cystectomy. Int J Radiat Oncol Biol Phys 2018;96:78-86.
Baumann BC, He J, Hwang WT, et al. Validating a local failure risk stratification for use in prospective studies of adjuvant radiation therapy for bladder cancer. Int J
Radiat Oncol Biol Phys 2018;95:703-706.
Coen JJ, Zhang P, Saylor PJ, et al. Selective bladder preservation with twice-daily radiation plus 5-flourouracil/cisplatin (FCT) or daily radiation plus gemcitabine (GD) for
patients with muscle invasive bladder cancer: Primary results of NRG/RTOG 0712—A randomized phase 2 multicenter trial [Abstract]. J Clin Oncol 2018;36:6_suppl,
408.
Efstathiou JA, Spiegel DY, Shipley WU, et al. Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH
experience. Eur Urol 2012;61:705-711.
Efstathiou JA, Zietman AL. Bladder Cancer. In Gunderson & Tepper, editors. Clinical Radiation Oncology. Churchill Livingstone Elsevier 2015.
James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366:1477-1488.
Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet 2016;338:2796-2810.
Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy:
A pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol 2014;32:3801-3809.
Mitin T, Hunt D, Shipley WU, et al. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and
adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): A randomised multicentre phase 2 trial. Lancet Oncol 2013;14:863-872.
Ploussard G, Daneshmand S, Efstathiou JA, et al. Critical analysis of bladder sparing with trimodal therapy in muscle-invasive bladder cancer: a systematic review. Eur
Urol 2014; 66:120-137.
Rödel C, Grabenbauer GG, Kühn R, et al. Combined-modality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol
2002; 20:3061-3071.
Shipley WU, Prout GR, Kaufman SD, Perrone TL. Invasive bladder carcinoma. The importance of initial transurethral surgery and other significant prognostic factors for
improved survival with full-dose irradiation. Cancer 1987;60:514-520.
Weiss C, Wolze C, Engehausen DG, Ott OJ, et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: An alternative to intravesical therapy
or early cystectomy? J Clin Oncol 2006;24:2318-2324.
Zaghloul MS, Christodouleas JP, Smith A, et al. Adjuvant sandwich chemotherapy plus radiotherapy vs adjuvant chemotherapy alone for locally advanced bladder
cancer after radical cystectomy: A randomized phase 2 trial. JAMA Surg. 2018;153:e174591. Epub 2018 Jan 17.

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

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
BL-H
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Upper GU Tract Tumors Discussion

WORKUP PRIMARY TREATMENTd

Nephroureterectomy with
cuff of bladder ±
perioperative intravesical
chemotherapye
Low gradec
or
Endoscopic resection
• Imaging of upper tract ± postsurgical intrapelvic
collecting systema chemotherapy or BCG
Non- See Adjuvant
• Cytology
metastatic Treatment and
• Cystoscopy
Nephroureterectomy Follow-up
• Ureteroscopy and biopsy
with cuff of bladder + (UTT-3)
and/or selective washings
regional lymphadenectomy
• Renal function tests
High grade,c large, ± perioperative intravesical
• Chest x-ray
or parenchymal chemotherapye
• CBC, chemistry profile
invasion and
• Nuclear medicine renal
Renal consider neoadjuvant
scan (optional)
pelvis chemotherapyf in selected
• Bone scana if clinical
patients
suspicion or symptoms of
bone metastases
• Family history; for those
at high risk, consider
evaluation for Lynch
syndrome (<60 y at Metastatic Systemic therapyg
presentation, personal
history of colon/
endometrial cancer)b

a See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

b See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal.
c Montironi R, Lopez-Beltran A. The 2004 WHO classification of bladder tumors: A summary and commentary. Int J Surg Pathol 2005;13:143-153.
See Principles of Pathology Management (BL-C).
d See Principles of Surgical Management (BL-B).
e See Principles of Intravesical Treatment (BL-F).
f See Principles of Systemic Therapy (BL-G 1 of 7).
g See Principles of Systemic Therapy (BL-G 2 of 7, 3 of 7 and 4 of 7).

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

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

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Upper GU Tract Tumors Discussion

WORKUP PRIMARY TREATMENTd

Nephroureterectomy with cuff of
bladder and regional lymphadenectomy
if high grade and consider neoadjuvant
Upper chemotherapyf in selected patients
or
• Imaging of upper tract Endoscopic resection
collecting systema
• Cytology Endoscopic resection
• Cystoscopy or
• Ureteroscopy and biopsy Nephroureterectomy with cuff of
and/or selective washings Low gradec bladder
• Renal function tests or
Urothelial • Nuclear medicine renal scan Excision and ureteroureterostomy/ileal
carcinoma (optional) Mid ureter in highly selected patients
of the ureter • Chest x-ray See
• CBC, chemistry profile Nephroureterectomy with cuff of
Adjuvant
• Bone scana if clinical suspicion bladder and regional lymphadenectomy
High gradec and consider neoadjuvant
Treatment
or symptoms of bone and Follow-
metastases chemotherapyf in selected patients
up (UTT-3)
• Family history; for those at high Distal ureterectomy and regional
risk, consider evaluation for lymphadenectomy if high grade and
Lynch syndromeb reimplantation of ureter (preferred if
clinically feasible) and consider
neoadjuvant chemotherapyf in selected
patients
or
Distal Endoscopic resection (low grade)
a See Principles of Imaging for Bladder/Urothelial Cancer (BL-A). or
b See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Nephroureterectomy with cuff of
Colorectal. bladder
c Montironi R, Lopez-Beltran A. The 2004 WHO classification of and regional lymphadenectomy if high
bladder tumors: A summary and commentary. Int J Surg Pathol grade and consider neoadjuvant
2005;13:143-153. See Principles of Pathology Management (BL-C). chemotherapyf in selected patients
d See Principles of Surgical Management (BL-B).
f See Principles of Systemic Therapy (BL-G 1 of 7). Metastatic Systemic therapyg
g See Principles of Systemic Therapy (BL-G 2 of 7, 3 of 7 and 4 of 7).

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

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

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Upper GU Tract Tumors Discussion

PATHOLOGIC STAGINGh ADJUVANT TREATMENT FOLLOW-UP

• Cystoscopy and consider cytology for

high grade every 3 months for 1 year,
then at longer intervals
• If nephron-sparing surgery, imaging
pT0, pT1 None of upper tract collecting systema
or ureteroscopy at 3- to 12-month
intervals ± abdominal/pelvic CT or MRI
with and without contrast
Adjuvant treatment for
renal pelvis
and
urothelial carcinoma • Cystoscopy and cytology every 3
of the ureter months for 1 year, then at longer
intervals
• If nephron-sparing surgery, imaging
pT2, pT3, Consider adjuvant of upper tract collecting systema
pT4, pN+ chemotherapyf,i or ureteroscopy at 3- to 12-month
intervals + abdominal/pelvic CT or
MRI with and without contrast + chest
imaging

a See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

f See Principles of Systemic Therapy (BL-G 1 of 7).
h The modifier “p” refers to pathologic staging based on surgical resection and lymph node dissection.
i Follow recommendations for adjuvant chemotherapy after ensuring that patient is fully staged to rule out metastatic disease.

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

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

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Urothelial Carcinoma of the Prostate Discussion

WORKUP PATHOLOGY ADDITIONAL PRIMARY TREATMENTb THERAPY FOR

WORKUP RECURRENCE

Mucosal
Follow-up Local Cystoprostatectomy
prostatic TURP and BCG
imaginga recurrence ± urethrectomy
urethra

• Digital rectal examination

(DRE) Chest Cystoprostatectomy
• Cystoscopy (including Ductal x-ray ± ± urethrectomy
bladder biopsy) + acini abdominal/ or
Follow-up Local Cystoprostatectomy
Urothelial • TUR biopsies of prostate pelvic CT TURP and BCG
imaginga recurrence ± urethrectomy
carcinoma to include stroma
of the • PSA
prostate • Needle biopsy if DRE is Cystoprostatectomy Consider adjuvant
Chest x-ray/
abnormal (in selected Stromal ± urethrectomy chemotherapy (if
abdominal/
patients) invasion ± neoadjuvant neoadjuvant not
pelvic CT
• Imaging of upper tract chemotherapyc given)c
collecting systema

Metastatic Systemic therapyd

a See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

b See Principles of Surgical Management (BL-B).
c See Principles of Systemic Therapy (BL-G 1 of 7).
d See Principles of Systemic Therapy (BL-G 2 of 7, 3 of 7 and 4 of 7).

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

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

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Primary Carcinoma of the Urethra Discussion

WORKUPa DIAGNOSIS

Urothelial carcinoma of prostate See UCP-1

• Cystourethroscopy
EUA
Suspicion of carcinoma TUR or transvaginal biopsy
of the urethra • Chest x-ray
• MRI of pelvis with and without
contrastb Tis, Ta, T1
See PCU-2
T2

Primary carcinoma of
non-prostatic male urethra T3, T4
or female urethra
Palpable
inguinal See PCU-3
lymph nodes
Distant
metastasis

a Referral to a specialized center is recommended.

b See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

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

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

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CLINICAL ADDITIONAL PRIMARY TREATMENTc ADJUVANT TREATMENT THERAPY FOR

STAGING WORKUP RECURRENCE
Repeat TURd
Tis, Ta, T1
• Followed by intraurethral chemotherapy or BCGe (selected cases)
Additional surgery
or
Positive Chemoradiotherapyg,h
margin (preferred) Systemic therapyj,l,m
Distal Follow-up and/or
Pendulous urethrectomyf or
RTh imaging with Recurrence Total penectomyn
urethra or cystoscopyk and/or
Partial penectomy Negative margin RTh,n
Male
pT1/pT2 and pN0
Bulbar Urethrectomyf ± Follow-up Systemic therapyj,l,m
urethra cystoprostatectomy Consider imaging with Recurrence and/or
pT3/pT4 cystoscopyk RTh,n
chemotherapyi,j
T2 or
or
pN1/pN2
Chemoradiotherapyg,h
Systemic therapyj,l,m
Chemoradiotherapyg,h
or
or
Chemoradiotherapyg,h
Urethrectomyf + cystectomy Follow-up imaging
Female Recurrence (if no prior RT)
or with cystoscopyk
or
Distal urethrectomyf
Pelvic exenteration
(depending on tumor location)
(category 2B)
c See Principles of Surgical Management (BL-B). j Chemotherapy regimen based on histology. (Dayyani F, Pettaway C, Kamat
d In patients with a prior radical cystectomy and a cutaneous diversion, consider a A, et al. Retrospective analysis of survival outcomes and the role of cisplatin-
total urethrectomy. based chemotherapy in patients with urethral carcinomas referred to medical
e See Principles of Intravesical Treatment (BL-F). oncologists. Urol Oncol 2013;31:1171-1177.) Also see Non-Urothelial Cell and
f Consider neoadjuvant chemotherapy (category 2B) or chemoradiation. Urothelial with Variant Histology (BL-D).
g See Principles of Systemic Therapy (BL-G 5 of 7). k See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
h See Principles of Radiation Management of Invasive Disease-Carcinoma of the l See Principles of Systemic Therapy (BL-G 2 of 7).
Urethra (BL-H 2 of 3). m See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
i See Principles of Systemic Therapy (BL-G 1 of 7). n Consider for local recurrence (± chemotherapy).

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

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

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CLINICAL ADDITIONAL PRIMARY TREATMENTc THERAPY FOR

STAGING WORKUP RECURRENCE
Chemoradiotherapyg,h (preferred)
± consolidative surgery
or
Neoadjuvant chemotherapyi,o (if urothelial
carcinoma) and consolidation with surgery
cN0 or RTh Pelvic exenteration
T3, T4 or (category 2B)
RTh ± ilioinguinal
• Chest/ or
Palpable abdominal/ lymphadenectomy
Consolidative surgery alone for non- Follow-up
inguinal pelvic CT Recurrence and/or
urothelial histology imagingk
lymph with contrast Chemoradiotherapyg,h
nodes • Lymph node or
RT preferably with chemotherapy Systemic therapyj,l,m
biopsy
(preferred for squamous cell carcinoma)g,h (category 2B)
or
cN1/
Systemic therapyl,j ± consolidative surgery
cN2
or
Chemoradiotherapyg,h ± consolidative
surgery

Distant
See Metastatic Disease (BL-10)
metastasis

c See Principles of Surgical Management (BL-B).

g See Principles of Systemic Therapy (BL-G 5 of 7).
h See Principles of Radiation Management of Invasive Disease-Carcinoma of the Urethra (BL-H 2 of 3).
i See Principles of Systemic Therapy (BL-G 1 of 7).
j Chemotherapy regimen based on histology. (Dayyani F, Pettaway C, Kamat A, et al. Retrospective analysis of survival outcomes and the role of cisplatin-based
chemotherapy in patients with urethral carcinomas referred to medical oncologists. Urol Oncol 2013;31:1171-1177.) Also see Non-Urothelial Cell and Urothelial with
Variant Histology (BL-D).
k See Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
l See Principles of Systemic Therapy (BL-G 2 of 7).
m See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
o Data support neoadjuvant chemotherapy only for urothelial carcinoma.

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

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

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Table 1. American Joint Committee on Cancer (AJCC)

TNM Staging System for Bladder Cancer 8th ed., 2017)
T Primary Tumor M Distant Metastasis
TX Primary tumor cannot be assessed M0 No distant metastasis
T0 No evidence of primary tumor M1 Distant metastasis
Ta Noninvasive papillary carcinoma M1a Distant metastasis limited to lymph nodes beyond the common
iliacs
Tis Urothelial carcinoma in situ: “flat tumor”
M1b Non-lymph-node distant metastases
T1 Tumor invades lamina propria (subepithelial connective tissue)
Histologic Grade (G)
T2 Tumor invades muscularis propria For urothelial histologies, a low- and high-grade designation is used to
pT2a Tumor invades superficial muscularis propria (inner half) match the current World Health Organization/International Society of
Urological Pathology (WHO/ISUP) recommended grading system:
pT2b Tumor invades deep muscularis propria (outer half)
LG Low-grade
T3 Tumor invades perivesical tissue
HG High-grade
pT3a Microscopically
pT3b Macroscopically (extravesical mass) For squamous cell carcinoma and adenocarcinoma, the following grading
T4 Extravesical tumor directly invades any of the following: schema is recommended:
prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, GX Grade cannot be assessed
abdominal wall
G1 Well differentiated
T4a Extravesical tumor invades prostatic stroma, seminal vesicles,
uterus, vagina G2 Moderately differentiated
T4b Extravesical tumor invades pelvic wall, abdominal wall G3 Poorly differentiated
Table 2. AJCC Prognostic Groups
N Regional Lymph Nodes T N M T N M
NX Lymph nodes cannot be assessed Stage 0a Ta N0 M0 Stage IIIB T1-T4a N2,N3 M0
N0 No lymph node metastasis Stage 0is Tis N0 M0 Stage IVA T4b Any N M0
N1 Single regional lymph node metastasis in the true pelvis Stage I T1 N0 M0 Any T Any N M1a
(perivesical, obturator, internal and external iliac, or sacral lymph
node) Stage II T2a N0 M0 Stage IVB Any T Any N M1b
N2 Multiple regional lymph node metastasis in the true pelvis T2b N0 M0
(perivesical, obturator, internal and external iliac, or sacral lymph Stage IIIA T3a N0 M0
node metastasis)
T3b N0 M0
N3 Lymph node metastasis to the common iliac lymph nodes
T4a N0 M0 Continued
T1-T4a N1 M0
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual,
Eighth Edition (2017) published by Springer International Publishing.
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Table 3 American Joint Committee on Cancer (AJCC)

TNM Staging System for Renal Pelvis and Ureter Cancer (8th ed., 2017)
T Primary Tumor Histologic Grade (G)
For urothelial histologies, a low- and high-grade designation is used
TX Primary tumor cannot be assessed to match the current WHO/ISUP recommended grading system:
T0 No evidence of primary tumor LG Low-grade
Ta Papillary noninvasive carcinoma HG High-grade
Tis Carcinoma in situ
For squamous cell carcinoma and adenocarcinoma, the following
T1 Tumor invades subepithelial connective tissue grading schema is recommended.
T2 Tumor invades the muscularis GX Grade cannot be assessed
T3 For renal pelvis only: Tumor invades beyond muscularis into G1 Well differentiated
peripelvic fat or the renal parenchyma.
G2 Moderately differentiated
For ureter only: Tumor invades beyond muscularis into
periureteric fat G3 Poorly differentiated
T4 Tumor invades adjacent organs, or through the kidney into
the perinephric fat. Table 4. AJCC Prognostic Groups
T N M
N Regional Lymph Nodes Stage 0a Ta N0 M0
NX Regional lymph nodes cannot be assessed Stage 0is Tis N0 M0
N0 No regional lymph node metastasis Stage I T1 N0 M0
N1 Metastasis ≤2 cm in greatest dimension, in a single lymph node Stage II T2 N0 M0
N2 Metastasis >2 cm in a single lymph node; or multiple lymph nodes Stage III T3 N0 M0
Stage IV T4 NX, N0 M0
M Distant Metastasis Any T N1 M0
M0 No distant metastasis Any T N2 M0
M1 Distant metastasis Any T Any N M1

Continued
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual,
Eighth Edition (2017) published by Springer International Publishing.
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Table 5. American Joint Committee on Cancer (AJCC)

TNM Staging System for Urethral Carcinoma (8th ed., 2017)
Male Penile Urethra and Female Urethra N Regional Lymph Nodes Table 6. AJCC Prognostic Groups
T Primary Tumor NX Regional lymph nodes cannot be T N M
TX Primary tumor cannot be assessed assessed Stage 0is Tis N0 M0
T0 No evidence of primary tumor N0 No regional lymph node metastasis Stage 0a Ta N0 M0
Ta Non-invasive papillary carcinoma N1 Single regional lymph node metastasis Stage I T1 N0 M0
in the inguinal region or true pelvis
Tis Carcinoma in situ [perivesical, obturator, internal Stage II T2 N0 M0
T1 Tumor invades subepithelial connective tissue (hypogastric) and external iliac], or Stage III T1 N1 M0
presacral lymph node
T2 Tumor invades any of the following: corpus T2 N1 M0
spongiosum, periurethral muscle N2 Multiple regional lymph node metastasis
in the inguinal region or true pelvis T3 N0 M0
T3 Tumor invades any of the following: corpus [perivesical, obturator, internal T3 N1 M0
cavernosum, anterior vagina (hypogastric) and external iliac], or Stage IV T4 N0 M0
T4 Tumor invades other adjacent organs (e.g., invasion of presacral lymph node
the bladder wall) T4 N1 M0
M Distant Metastasis Any T N2 M0
Prostatic Urethra
M0 No distant metastasis Any T Any N M1
T Primary Tumor
M1 Distant metastasis
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor Histologic Grade (G)
Ta Non-invasive papillary carcinoma Grade is reported by the grade value. For urothelial
histology, a low- and high-grade designation is used
Tis Carcinoma in situ involving the prostatic urethra or to match the current WHO/ISUP recommended
periurethral or prostatic ducts without stromal invasion grading system:
T1 Tumor invades urethral subepithelial connective tissue LG Low grade
immediately underlying the urothelium
HG High grade
T2 Tumor invades the prostatic stroma surrounding ducts
either by direct extension from the urothelial surface or For squamous cell carcinoma and adenocarcinoma,
by invasion from prostatic ducts the following grading schema is recommended:
T3 Tumor invades the periprostatic fat GX Grade cannot be assessed
T4 Tumor invades other adjacent organs (e.g., G1 Well differentiated
extraprostatic invasion of the bladder wall, rectal wall)
G2 Moderately differentiated
G3 Poorly differentiated
Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging Manual,
Eighth Edition (2017) published by Springer International Publishing.
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.

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Discussion This discussion corresponds to the NCCN Guidelines Radical Cystectomy ................................................................. MS-15
for Bladder Cancer. Last updated on 01/17/2020.
Partial Cystectomy ................................................................... MS-16
Table of Contents
Neoadjuvant Chemotherapy .................................................... MS-16
Overview ....................................................................................... MS-3
Adjuvant Chemotherapy ........................................................... MS-17
Literature Search Criteria and Guidelines Update
Methodology ................................................................................. MS-3 Adjuvant Radiation ................................................................... MS-18
Clinical Presentation and Workup .............................................. MS-4 Bladder Preservation ................................................................ MS-19
Pathology and Staging ................................................................ MS-5 Treatment of Stage II and IIIA Tumors ..................................... MS-21
Enhanced Cystoscopy ................................................................ MS-5
Treatment of Stage IIIB Tumors ............................................... MS-22
Histology ....................................................................................... MS-7
Treatment of Stage IVA Tumors .............................................. MS-23
Non–Muscle-Invasive Urothelial Bladder Cancer ..................... MS-8
Follow-up .................................................................................. MS-23
Intravesical Therapy ................................................................... MS-8
Recurrent or Persistent Disease .............................................. MS-24
BCG Shortage .......................................................................... MS-11
Metastatic (Stage IVB) Urothelial Bladder Cancer .................. MS-24
Pembrolizumab for Non–Muscle-Invasive Bladder Cancer ...... MS-11
Evaluation of Metastatic Disease ............................................. MS-24
Treatment of cTa, Low-Grade Tumors ..................................... MS-12
Metastasectomy for Oligometastatic Disease .......................... MS-25
Treatment of cTa, High-Grade Tumors .................................... MS-12
Molecular/Genomic Testing ..................................................... MS-25
Treatment of cT1 Tumors ......................................................... MS-12
Chemotherapy for Metastatic Disease ..................................... MS-26
Treatment of Tis ....................................................................... MS-13
Targeted Therapies .................................................................. MS-28
Surveillance .............................................................................. MS-13
Non-Urothelial Carcinomas of the Bladder ............................. MS-32
Posttreatment of Recurrent or Persistent Disease ................... MS-13
Upper Tract Urothelial Carcinoma (UTUC) .............................. MS-32
Muscle-Invasive Urothelial Bladder Cancer ............................ MS-15 Renal Pelvis Tumors ................................................................ MS-32
Additional Workup .................................................................... MS-15
Urothelial Carcinoma of the Ureter ........................................... MS-34

MS-1
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Urothelial Carcinomas of the Prostate ..................................... MS-35

Primary Carcinoma of the Urethra............................................ MS-36
Summary ..................................................................................... MS-37

MS-2
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critical concern for the third group, consisting of metastatic lesions, is

Overview how to prolong quantity and maintain quality of life. Numerous agents
An estimated 80,470 new cases of urinary bladder cancer (61,700 men with different mechanisms of action have antitumor effects on this
and 18,770 women) will be diagnosed in the United States in 2019 with disease. The goal is how to use these agents to achieve the best
approximately 17,670 deaths (12,870 men and 4,800 women) occurring possible outcome.
during this same period.1 Bladder cancer, the sixth most common
Literature Search Criteria and Guidelines Update
cancer in the United States, is rarely diagnosed in individuals younger
Methodology
than 40 years of age. Given that the median age at diagnosis is 73
Prior to the update of this version of the NCCN Guidelines for Bladder
years,2 medical comorbidities are a frequent consideration in patient
Cancer, an electronic search of the PubMed database was performed to
management.
obtain key literature using the following search terms: bladder cancer
Risk factors for developing bladder cancer include male sex, white race, OR urothelial carcinoma of the ureter urothelial carcinoma of the
smoking, personal or family history of bladder cancer, pelvic radiation, prostate OR primary carcinoma of the urethra. The PubMed database
environmental/occupational exposures, exposure to certain drugs, was chosen as it remains the most widely used resource for medical
chronic infection or irritation of the urinary tract, and certain medical literature and indexes peer-reviewed biomedical literature.8
conditions including obesity and diabetes.3-5 While diabetes mellitus
The search results were narrowed by selecting studies in humans
appears to be associated with an elevated risk of developing bladder
published in English. Results were confined to the following article
cancer,4 treatment with metformin may be associated with improved
types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial,
prognosis in patients with bladder cancer and diabetes.6 Certain genetic
Phase IV; Guideline; Meta-Analysis; Randomized Controlled Trials;
syndromes, most notably Lynch syndrome, may also predispose an
Systematic Reviews; and Validation Studies.
individual to urothelial carcinoma.7
The data from key PubMed articles as well as articles from additional
The clinical spectrum of bladder cancer can be divided into 3 categories
sources deemed as relevant to these Guidelines and discussed by the
that differ in prognosis, management, and therapeutic aims. The first
panel have been included in this version of the Discussion section (eg,
category consists of non–muscle-invasive disease, for which treatment
e-publications ahead of print, meeting abstracts). Recommendations for
is directed at reducing recurrences and preventing progression to a
which high-level evidence is lacking are based on the panel’s review of
more advanced stage. The second group encompasses
lower-level evidence and expert opinion.
muscle-invasive disease. The goal of therapy is to determine whether
the bladder should be removed or if it can be preserved without The complete details of the Development and Update of the NCCN
compromising survival, and to determine if the primary lesion can be Guidelines are available at www.NCCN.org.
managed independently or if patients are at high risk for distant spread
requiring systemic approaches to improve the likelihood of cure. The

MS-3
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Clinical Presentation and Workup resecting all visible tumor. Therefore, an adequate sample that includes
The most common presenting symptom in patients with bladder cancer bladder muscle (ie, muscularis propria) preferentially should be
is microscopic or gross hematuria, although urinary frequency due to obtained in the resection specimen, most notably in the setting of high-
irritation or a reduced bladder capacity can also develop. Less grade disease. A small fragment of tumor with few muscle fibers is
commonly, the presenting symptom is a urinary tract infection. Upper inadequate for assessing the depth of invasion and guiding treatment
tract obstruction or pain may occur in patients with a more advanced recommendations. When a large papillary lesion is noted, more than
lesion. Patients presenting with these symptoms should be evaluated one session may be needed to completely resect the tumor. With
with office cystoscopy to determine if a lesion is present. If one is carcinoma in situ (CIS), biopsy of sites adjacent to the tumor and
documented, the patient should be scheduled for a transurethral multiple random biopsies may be performed to assess for a field
resection of the bladder tumor (TURBT) to confirm the diagnosis and change. Single-dose intravesical gemcitabine or mitomycin (both
determine the extent of disease within the bladder. Urine cytology may category 1, although gemcitabine is preferred due to better tolerability
also be obtained around the time of cystoscopy. Being that smoking is a and lower cost) within 24 hours of TURBT is recommended if non–
major risk factor for bladder cancer,9 screening for smoking and muscle-invasive disease is suspected (see Intravesical Therapy).
initiation of treatment for smoking cessation, if appropriate, is Existing data support this approach largely for low-volume, low-grade
recommended during the initial evaluation (see NCCN Guidelines for disease.10-12
Smoking Cessation).
While selected mapping biopsies may be indicated in specific situations
A CT scan or MRI of the abdomen and pelvis is recommended before for lesions that are solid (sessile) or if Tis or high-grade disease is
the TURBT, as long as it is logistically feasible, in order to allow for suspected (eg, planned partial cystectomy, definitive
better anatomical characterization of the lesion and possible delineation chemoradiotherapy, evaluation of an unexplained positive urine
of the suspected depth of invasion. Additional workup for all patients cytology, certain clinical trials), random biopsies rarely yield positive
should include consideration of urine cytology, if not already tested, and results, especially for low-risk tumors.13 Therefore, mapping biopsies of
evaluation of the upper tracts with a CT or MR urography; a renal normal-appearing urothelium are not necessary for most patients.
ultrasound or CT without contrast with retrograde ureteropyelography; a
Positive urinary cytology may indicate urothelial tumor anywhere in the
ureteroscopy; or a combination of techniques. CT urography is
urinary tract. In the presence of a positive cytology and a normal
generally the preferred approach to upper tract imaging in patients who
cystoscopy, the upper tracts and the prostate (prostatic urethra) in men
can safely receive intravenous contrast agents.
must be evaluated and ureteroscopy may be considered.
TURBT with a bimanual examination under anesthesia (EUA) is
Clinical investigation of the specimen obtained by TURBT or biopsies is
performed to resect visible tumor and to sample muscle within the area
an important step in the diagnosis and subsequent management of
of the tumor to assess invasion. The goal of TURBT is to correctly
bladder cancer. The modifier “c” before the stage refers to clinical
identify the clinical stage and grade of disease while completely
staging based on bimanual EUA, endoscopic surgery (biopsy or
MS-4
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TURBT), and imaging studies. A modifier “p” would refer to pathologic the initial stage and grade, size, and multiplicity. Refining these
staging based on cystectomy and lymph node dissection. estimates for individual patients is an area of active research.

Pathology and Staging Muscle-invasive disease (T2) is defined by malignant extension into the
The most commonly used staging system is the tumor, node, detrusor muscle while perivesical tissue involvement defines T3
metastasis (TNM) staging system by the AJCC14 (see Staging in the disease. Extravesical invasion into the surrounding organs (ie, the
algorithm). The NCCN Guidelines for Bladder Cancer divide treatment prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall,
recommendations for urothelial carcinoma of the bladder according to abdominal wall) delineates T4 disease. The depth of invasion is the
non–muscle-invasive disease (Ta, T1, and Tis) and muscle-invasive most important determinant of prognosis and treatment for localized
disease (≥T2 disease). Management of bladder cancer is based on the bladder cancer.
findings of the biopsy and TURBT specimens, with attention to
The 8th edition of the AJCC Staging Manual included changes to the
histology, grade, and depth of invasion. These factors are used to
staging of urinary bladder carcinoma, including the subdivision of stages
estimate the probability of recurrence and progression to a more
III and IV disease (stage III into stage IIIA and stage IIIB; stage IV into
advanced stage. Patient bladder function, comorbidities, and life
stage IVA and stage IVB).14 Notably, the new staging system groups
expectancy are also important considerations.
T1–T4a, N1 within stage IIIA and T1–T4a, N2-3 within stage IIIB; N1–3
Approximately 75% of newly detected cases are non–muscle-invasive was previously grouped within stage IV, regardless of T stage.14,18 The
disease—exophytic papillary tumors confined largely to the mucosa NCCN Guidelines for Bladder Cancer were updated to reflect
(Ta) (70%–75%) or, less often, to the lamina propria (T1) (20%–25%) or appropriate treatment options based on this new staging system (see
flat high-grade lesions (CIS, 5%–10%).15,16 These tumors tend to be Treatment of Stage II and IIIA Tumors, Treatment of Stage IIIB Tumors,
friable and have a high propensity for bleeding. Their natural history is and Treatment of Stage IVA Tumors).
characterized by a tendency to recur in the bladder, and these
Enhanced Cystoscopy
recurrences can be either at the same stage as the initial tumor or at a
more advanced stage. White light cystoscopy (WLC) is the current standard in the evaluation
and staging of bladder cancer. While WLC has a high sensitivity for
Papillary tumors confined to the mucosa or submucosa are generally detecting papillary lesions, the technique is limited in its ability to
managed endoscopically with complete resection. Progression to a discern non-papillary and flat lesions from inflammatory lesions, thus
more advanced stage may result in local symptoms or, less commonly, reducing the accuracy of tumor staging. Additionally, small or multifocal
symptoms related to metastatic disease. An estimated 31% to 78% of lesions are more difficult to detect with WLC. Several techniques
patients with a tumor confined to the mucosa or submucosa will proposed to enhance imaging are available and include blue light
experience a recurrence or new occurrence of urothelial carcinoma cystoscopy (BLC) and narrow band imaging (NBI). Both methods report
within 5 years.17 These probabilities of recurrence vary as a function of improved staging when used in conjunction with WLC and with

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expertise; however, data are still limited for both methods and WLC P < .001) and recurrent disease (27.7%; P < .001). Another review of
remains the mainstay of bladder cancer staging. the literature included 26 studies with 5-ALA, 15 studies with HAL, and
2 studies that used both methodologies. The results from this review
Blue Light Cystoscopy
also support greater detection and reduced recurrence but no reduction
BLC is a technique that identifies malignant cells through the absorption in disease progression.27
of the photosensitizing drug into the urothelial cytoplasm where it enters
heme-biosynthesis metabolism. In normal cells, the photosensitizer is Although most studies have not found a significant reduction in disease
excreted; however, enzymatic abnormalities in malignant cells result in progression, a recent analysis reported a trend towards a lower rate
the formation of photoactive porphyrins that remain in the cell and with the use of BLC compared to WLC (12.2% vs. 17.6%, respectively;
fluorescence with a red emission in the presence of blue light. Earlier P = .085) with a longer time to progression (P = .05).28 Although BLC
studies used the photosensitizer 5-aminolevulinic acid (5-ALA), has demonstrated improved detection and reduced recurrence, the
although more recent studies use the only FDA-approved value of this technique in reducing disease progression remains less
photosensitizer hexyl-aminolevulinate (HAL). established. Therefore, BLC may have the greatest advantage in
detecting difficult-to-visualize tumors (eg, CIS tumors) that may be
Several prospective clinical studies have evaluated BLC in conjunction missed by WLC but has more limited applicability in disease monitoring.
with WLC and found higher detection rates of non–muscle-invasive Other impediments to BLC include the need for appropriate expertise
lesions with BLC.19-24 Particularly CIS, which is often missed by WLC, and equipment to employ this new technology. High false positives are
was detected at a higher rate. A meta-analysis of BLC TURBT in non– also attributed to this method and may be increased in patients who
muscle-invasive bladder cancer included 12 randomized controlled trials have had a recent TURBT or bacillus Calmette-Guérin (BCG)
with a total of 2258 patients.25 A lower recurrence rate was observed instillation, or who have inflammation.27 The limitations of BLC require
(overall response [OR], 0.5; P < .00001) with a delayed time to first judicious application of this additional diagnostic tool.
recurrence by 7.39 weeks (P < .0001). Recurrence-free survival was
improved at 1 year (HR, 0.69; P < .00001) and at 2 years (HR, 0.65; Narrow Band Imaging
P = .0004). However, no significant reduction in the rate of progression NBI uses two narrow bands of light at 415 nanometers (nm) and 540
to muscle-invasive bladder cancer was seen (OR, 0.85; P = .39). nm that are absorbed by hemoglobin. The shorter wavelength provides
analysis of the mucosa and the longer wavelength allows for evaluation
In a meta-analysis from Burger et al,26 1345 patients with Ta, T1 or CIS of the deeper submucosal blood vessels. Studies suggest that there is
disease showed improved detection of bladder tumors and a reduction an increase in bladder tumor detection compared with WLC, although
in recurrence.26 Compared to WLC, BLC detected more Ta tumors the rate of false positives is higher.29-33
(14.7%; P < .001; OR, 4.898; 95% CI, 1.937–12.390) and CIS lesions
(40.8%; P < .001; OR, 12.372; 95% CI, 6.343–0.924). Importantly, A systematic review and meta-analysis including 7 prospective studies
24.9% of patients had at least one additional Ta/T1 tumor detected and 1040 patients with non–muscle-invasive disease evaluated the
(P < .001) and improved detection was seen in both primary (20.7%; accuracy of NBI compared to WLC. In total, 1476 tumors were detected
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by biopsy in 611 patients. The additional detection rate for NBI was A benefit of NBI is that it does not require a contrast agent and can
higher on the patient level (17%; 95% CI, 10%–25%) and tumor level therefore be used as part of office cystoscopy. Higher detection rates of
(24%; 95% CI, 17%–31%). In total, 107 patients were further identified flat lesions and a reduction in tumor recurrence have been reported.35-38
as having non–muscle-invasive disease by NBI compared to the 16
patients by WLC. Similarly, 276 additional tumors were reported in 5 Histology
studies using NBI versus 13 additional tumors by WLC. Although More than 90% of urothelial tumors originate in the urinary bladder, 8%
individual studies demonstrated an increase in the rate of false originate in the renal pelvis, and the remaining 2% originate in the ureter
positives, the meta-analysis reported no statistical significance. and urethra. Urothelial carcinomas are classified as low or high grade
However, it was acknowledged that data are limited due to the relatively as defined by the extent of nuclear anaplasia and architectural
new application of this technique and interpretation is impeded by the abnormalities.
degree of heterogeneity among the studies. Finally, the meta-analysis
was unable to determine if there was a long-term advantage of NBI, as Non–muscle-invasive urothelial tumors may have flat and papillary
measured by a reduction in recurrence or progression. histologies. Flat lesions may be classified as Tis, or as dysplasia if the
criteria for CIS are not met but atypical dysplasia is present. Papillary
A randomized prospective trial followed patients for 1 year after NBI- or lesions may be benign (ie, urothelial papilloma, inverted papilloma) or of
WLC-guided transurethral resection (TUR) to evaluate recurrence. NBI malignant potential. The latter group includes papillary urothelial
had a reduced 1-year recurrence rate (32.9%; 25 of 76 patients) neoplasms of low malignant potential and noninvasive papillary
compared to WLC (32.9% vs. 51.4%, respectively; OR, 0.62).34 urothelial carcinomas (low and high grade). In some cases, a papillary
However, the small number of patients in this study is limiting. A larger or T1 lesion will be documented as having an associated Tis
international, multicenter, randomized controlled trial compared 1-year component.
recurrence rates in 965 patients who received either NBI- or WLC-
guided TUR for treatment of non–muscle-invasive bladder cancer. This Urothelial (transitional cell) carcinomas are the most common histologic
study found that while recurrence rates were similar between the two subtype in the United States and Europe and may develop anywhere
groups in the study population overall, NBI-guided TUR significantly transitional epithelium is present, from the renal pelvis to the ureter,
reduced the likelihood of disease recurrence at 1 year in low-risk bladder, and proximal two thirds of the urethra. Variant histology is
patients (5.6% for NBI vs. 27.3% for WLC; P = .002).35 These results common with higher grades. The fourth edition of the WHO
are supported by the systemic reviews and meta-analyses that have Classification of Tumors has reclassified these histologic subtypes into
also shown reduced recurrence rates following NBI-guided TUR the following: infiltrating urothelial carcinoma with divergent
compared to WLC-guided TUR.36,37 differentiation; nested, including large nested; microcystic;
micropapillary; lymphoepithelioma-like; plasmacytoid/signet ring
cell/diffuse; sarcomatoid; giant cell; poorly differentiated; lipid-rich; and
clear cell.39,40 The presence of histologic variants in urothelial carcinoma

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should be documented as data suggest that the subtype may reflect the Non–Muscle-Invasive Urothelial Bladder Cancer
risk of disease progression, reflect different genetic etiology, and Non–muscle-invasive tumors were previously referred to as superficial,
subsequently determine whether a more aggressive treatment approach which is an imprecise term that should be avoided. The NCCN
should be considered (see Bladder Cancer: Non-Urothelial and Guidelines for Bladder Cancer generally manage non–muscle-invasive
Urothelial With Variant Histology in the algorithm). In some cases with a disease with intravesical therapy or, for those at particularly high risk,
mixed histology, systemic treatment may only target cells of urothelial cystectomy.
origin and the non-urothelial component can remain.
Intravesical Therapy
Squamous cell neoplasms of the urothelial tract are a second histologic
Intravesical therapy is implemented to reduce recurrence or delay
subtype, which constitute 3% of the urinary tumors diagnosed in the
progression of bladder cancer to a higher grade or stage.
United States. In regions where Schistosoma is endemic, this subtype is
more prevalent and may account for up to 75% of bladder cancer Immediate Intravesical Therapy Post TURBT
cases. The distal third of the urethra is dominated by squamous An immediate intravesical instillation of chemotherapy may be given
epithelium. The diagnosis of squamous cell tumors requires the within 24 hours of TURBT to prevent tumor cell implantation and early
presence of keratinization in the pathologic specimen.41 Squamous cell recurrence. Immediate intravesical chemotherapy has been shown to
carcinoma of the bladder is morphologically indistinguishable from decrease recurrence in select subgroups of patients. A systematic
squamous cell carcinoma of other sites and generally presents at an review and meta-analysis of 13 randomized trials demonstrated a
advanced stage. The three variants within this subtype are pure decreased risk of recurrence by 35% (HR, 0.65; 95% CI, 0.58–0.74; P <
squamous cell carcinoma, verrucous carcinoma, and squamous cell .001) and a decreased 5-year recurrence rate from 58.8% to 44.8%
papilloma. when comparing immediate intravesical chemotherapy following TURBT
to TURBT alone, although the instillation did not prolong the time to
Other histologic subtypes derived from cells of urothelial origin include
progression or time to death from bladder cancer.12 This study also
glandular neoplasms, epithelial tumors of the upper urinary tract, and
found that the instillation did not reduce recurrences in patients who had
tumors arising in a bladder diverticulum. Glandular neoplasms include
a prior recurrence rate of >1 recurrence per year or with an EORTC
adenocarcinoma and villous adenoma. Urachal tumors are non-
recurrence score ≥5.
urothelial tumors, most commonly adenocarcinomas, which arise from
the urachal ligament and secondarily involve the midline/dome of the Phase III trials have reported a reduced risk of recurrence for patients
bladder.42 Tumors arising within the genitourinary tract but that are not with suspected non–muscle-invasive disease who are treated with
of urothelial origin (eg, tumors of Müllerian type, melanocytic tumors, immediate postoperative gemcitabine or mitomycin. A randomized,
mesenchymal tumors) are beyond the scope of these guidelines. double-blind, phase III trial of 406 patients with suspected low-grade
non–muscle-invasive bladder cancer based on cystoscopic appearance
showed that immediate post-TURBT instillation of gemcitabine reduced

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the rate of recurrence compared to saline instillation (placebo).10 In the Induction BCG has been shown to decrease the risk of bladder cancer
intention to treat analysis, 35% of patients treated with gemcitabine and recurrences following TURBT. BCG therapy is commonly given once a
47% of those who received placebo had disease recurrence within 4 week for 6 weeks, followed by a rest period of 4 to 6 weeks, with a full
years (HR, 0.66; 95% CI, 0.48–0.90; P < .001).10 Intravesical therapy for re-evaluation at week 12 (ie, 3 months) after the start of therapy.45
a previous non–muscle-invasive bladder cancer was allowed in the There are 4 meta-analyses demonstrating that BCG after TURBT is
study if received at least 6 months prior to enrollment. Another phase III, superior to TURBT alone, or TURBT and chemotherapy in preventing
prospective, multicenter, randomized study of 2844 patients with non– recurrences of high-grade Ta and T1 tumors.46-49 A meta-analysis
muscle-invasive bladder cancer showed that an immediate instillation of including 9 trials of 2820 patients with non–muscle-invasive bladder
mitomycin C after TURBT reduces recurrence regardless of the number cancer reported that mitomycin C was superior to BCG without
of adjuvant instillations. Recurrence risk was 27% for immediate maintenance in preventing recurrence, but inferior to BCG in trials using
instillation versus 36% for delayed instillation (P < .001) for all patients BCG maintenance.50 Using the SEER database, a reduction in mortality
in the study, with the benefit of immediate instillation present across risk of 23% was reported in patients receiving BCG therapy.51 Another study
groups.11 Previous intravesical chemotherapy was permitted in study reported long-term data that BCG was better at reducing recurrence in
participants as long as it was received at least 3 years prior to intermediate- and high-risk non–muscle-invasive bladder cancer when
participation. For both studies, the rate of adverse events (AEs) did not compared to mitomycin C.52
significantly differ between the treatment and control groups, indicating
that immediate intravesical instillation of gemcitabine or mitomycin was BCG has also been compared to gemcitabine and epirubicin. A
well tolerated.10,11 Gemcitabine is preferred over mitomycin based on prospective, randomized phase II trial compared the quality of life in
toxicity profiles and lower cost.43 For tumors with an intermediate or patients receiving either BCG (n = 59) or intravesical gemcitabine
high risk of progression, subsequent treatment with intravesical (n = 61) and found no significant difference.53 There were more frequent
induction (adjuvant) therapy may be given. Perioperative intravesical local and systemic side effects in the BCG arm; however, they were
treatment should not be given if there is extensive TURBT or suspected mild to moderate and the treatment was well-tolerated in both groups.
bladder perforation. The benefit of BCG with or without isoniazid compared to epirubicin
alone in a long-term study of 957 patients with intermediate- or high-risk
Induction (Adjuvant) Intravesical Chemotherapy or BCG Ta or T1 disease was measured by a reduced recurrence, greater time
Although only intravesical chemotherapy is recommended in the to distant metastases, and greater overall survival (OS) and
immediate postoperative setting, both intravesical chemotherapy and disease-specific survival (DSS); progression was similar.54 Long-term
BCG have been given as induction therapy in patients with non– data comparing BCG to epirubicin in combination with interferon54,55 in
muscle-invasive bladder cancer.44 The most commonly used patients with T1 disease showed a better reduction in recurrence with
chemotherapy agents are mitomycin C and gemcitabine, although BCG; however, no differences in progression or AEs were seen.55
gemcitabine is preferred over mitomycin due to better tolerability and Patients in both studies received 2 to 3 years of maintenance therapy.
cost.

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Maintenance Therapy followed by a maintenance regimen produced better outcomes than

Maintenance intravesical therapy may be considered following induction intravesical chemotherapy.44,46,47,56,59,60
with chemotherapy or BCG. The role of maintenance chemotherapy is
controversial. When given, maintenance chemotherapy is generally BCG Toxicity
monthly. The role of maintenance BCG in those patients with There are concerns regarding potentially severe local and systemic side
intermediate to high-risk non–muscle-invasive bladder cancer is more effects and the inconsistent availability of BCG. BCG induces a
established, though the exact regimens have varied across studies. systemic nonspecific immunostimulatory response leading to secretion
Some of the previous controversy over the effectiveness of BCG of proinflammatory cytokines. This causes patients to experience flu-like
maintenance reflects the wide array of schedules and conflicting reports symptoms that may last 48 to 72 hours.61 Installation of BCG into the
of efficacy. Quarterly and monthly installations as well as 3-week and bladder also mimics a urinary tract infection and may produce intense
6-week schedules have been evaluated. To date, the strongest data local discomfort. The side effects of treatment have translated to patient
support the 3-week BCG regimen used in the SWOG trial that refusal of BCG therapy. Dysuria has been reported in 60% of patients in
demonstrated reduced disease progression and metastasis.56 The clinical trials.61 However, the side effects are treatable in almost all
3-week timing of BCG has shown improved outcomes compared with cases62 and no increase in toxicity has been reported with cumulative
epirubicin55 or isoniazid.54 Most patients receive maintenance BCG for 1 doses. Symptom management with single-dose, short-term quinolones
to 3 years. In an evaluation of randomized controlled trials and and/or anticholinergics have been reported to reduce AEs.63,64
meta-analyses, limited evidence was found for 1 year of BCG
A reduced (one-third) dose of BCG was evaluated for the possible
maintenance.57 A study of 1355 patients with a median follow-up of 7.1
reduction of side effects. In a phase III study, 1316 patients with
years found no benefit in 3 years of maintenance BCG compared to 1
intermediate- or high-risk Ta, T1 papillary carcinoma of the bladder
year for intermediate-risk patients.58 Conversely, 3-year maintenance
were randomized to receive reduced- or full-dose BCG with either 1 or 3
BCG reduced recurrence compared to 1-year maintenance but did not
years of maintenance.65 Among all 4 groups, the percentage of patients
impact progression or survival in high-risk patients. These data suggest
with greater than or equal to 1 side effect was similar (P = .41). Though
that 1 year may be suitable for patients at intermediate risk while 3
the one-third dose of BCG was effective, side effects were not reduced.
years of maintenance is preferred for high-risk disease. It should also
Conversely, other publications suggest that the one-third dose may
be noted that duration of treatment may be limited by toxicity and
reduce side effects.66-68 Full-dose BCG is recommended by the panel
patient refusal to continue.
until more data are available to evaluate the low-dose BCG regimen.
For patients showing no residual disease at the follow-up cystoscopy, However, dose reduction may be used if there are substantial local
whether 1 or 2 courses of induction therapy were administered, symptoms during maintenance.
maintenance therapy with BCG is preferred. This recommendation is
based on findings that an induction course of intravesical therapy

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BCG Shortage similar outcomes when compared to full-dose BCG,67,80,81 a phase 3 trial
An ongoing shortage of BCG has existed in the United States, of 1355 patients with intermediate- or high-risk non–muscle-invasive
necessitating development of strategies to prioritize use of intravesical bladder cancer reported that patients receiving the full dose of BCG
BCG and identify alternative treatment approaches for some patients show a longer disease-free interval, compared with those receiving the
with non–muscle-invasive bladder cancer.69 Several organizations, one-third dose.58 In this study, the 5-year disease-free rate was 58.5%
including the American Urological Association (AUA), American for the one-third dose compared to 61.7% for the full dose; therefore,
Association of Clinical Urologists (AACU), Bladder Cancer Advocacy the null hypothesis of inferiority for duration of the disease-free interval
Network (BCAN), Society of Urologic Oncology (SUO), the Large of one-third dose BCG could not be rejected (HR, 1.15; 95% CI, 0.98–
Urology Group Practice Association (LUGPA), and the Urology Care 1.35; P = .045), although there were no differences in progression or
Foundation (UCF), issued a notice outlining strategies to maximize care survival rates.58 Based on these data, the panel recommends that one-
for patients with non–muscle-invasive bladder cancer in the context of half or one-third dose may be considered for BCG induction during
this shortage.70 NCCN Panel Members recommend several strategies times of shortage and should be used for BCG maintenance, if supply
to help alleviate problems associated with this shortage. allows. Maintenance BCG should be prioritized for patients with high-
risk non–muscle-invasive bladder cancer (cT1 high grade or CIS) in the
In the event of a BCG shortage, priority for treatment should be to early maintenance period (eg, 3- and 6-months post-induction),
provide patients with high-risk non–muscle-invasive bladder cancer although in cases of shortage, BCG induction therapy should be
(cT1 high grade or CIS) with induction BCG. For patients who do not prioritized over maintenance BCG.
receive BCG, intravesical chemotherapy may be used as an alternative.
The intravesical chemotherapies most commonly used for this purpose Pembrolizumab for Non–Muscle-Invasive Bladder Cancer
are gemcitabine43,71 and mitomycin.72 Two separate meta-analyses of Pembrolizumab is a PD-1 inhibitor that has been evaluated as treatment
randomized trials reported that there were no differences in risk of for BCG-unresponsive, non–muscle-invasive bladder cancer with CIS in
recurrence between BCG and mitomycin,44,73 although BCG may show the single-arm, phase II KEYNOTE-057 study, reported to date in
more favorable outcomes from maintenance regimens.44 Other options abstract form (pembrolizumab is also indicated for treatment of
include epirubicin,54,74 valrubicin,75 docetaxel,76 sequential metastatic urothelial carcinoma; for the metastatic setting see the
gemcitabine/docetaxel,77 or gemcitabine/mitomycin.78 Another Targeted Therapies section below). In the KEYNOTE-057 study, 103
alternative to intravesical BCG for patients with non–muscle-invasive patients with high-risk CIS, with or without papillary tumor, who received
bladder cancer at high risk of recurrence and, particularly, at high risk of previous BCG therapy and were either unable or unwilling to undergo
progression, is initial radical cystectomy.79 cystectomy were treated with pembrolizumab. The 3-month complete
response rate was 38.8% (95% CI, 29.4%–48.9%), with 72.5% of
Another option during a shortage is splitting the dose of BCG so that complete responses maintained at last follow-up (median 14.0 months).
multiple patients may be treated using a single vial. While several Therefore, of the total study population, 28% had a complete response
randomized trials have reported that one-third dose BCG showed at the time of last follow-up. The median duration of complete response
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had not yet been reached at the time of analysis. Grade ≥3 treatment- Treatment of cTa, High-Grade Tumors
related AEs were reported in 12.6% of patients, and immune-mediated Tumors staged as cTa, high-grade lesions are papillary tumors with a
AEs in 18.4%. One patient died as a result of treatment-related colitis.82 relatively high risk for recurrence and progression towards more
Clinical data included in the package insert for 96 patients on this trial invasiveness. Restaging TURBT detected residual disease in 27% of Ta
report a complete response rate of 41% (95% CI, 31%–51%) and a patients when muscle was present in the original TURBT.86 In the
median duration of response (DOR) of 16.2 months with 46% of absence of muscularis propria in the initial TURBT specimen, 49% of
complete responses maintained for at least a year.83 patients with non–muscle-invasive disease will be understaged versus
14% if muscle is present.87 Repeat resection is recommended if there is
Treatment of cTa, Low-Grade Tumors
incomplete resection, or should be strongly considered if there is no
TURBT is the standard treatment for cTa, low-grade tumors. Although a muscle in the specimen. Repeat resection may also be considered for
complete TURBT alone can eradicate these tumors, there is a relatively high-risk (large or multifocal) lesions, as recommended in the AUA/SUO
high risk for recurrence. Therefore, after TURBT, the panel Guideline.15
recommends administering a single dose of immediate intravesical
chemotherapy (gemcitabine or mitomycin [both category 1], although After TURBT, patients with cTa, high-grade tumors may be treated with
gemcitabine is preferred due to better tolerability and cost) within 24 intravesical BCG (preferred), intravesical chemotherapy, or observation.
hours of resection. The immediate intravesical chemotherapy may be In the literature, there are 4 meta-analyses confirming that BCG after
followed by observation or a 6-week induction course of intravesical TURBT is superior to TURBT alone, or TURBT and chemotherapy in
therapy. While intravesical chemotherapy is preferred in these patients preventing recurrences of high-grade Ta and T1 tumors.46-49 The NCCN
due to the low risk of disease progression, BCG may be considered Bladder Cancer Panel Members recommend BCG as the preferred
when not in a shortage. option over intravesical chemotherapy for adjuvant treatment of
high-grade lesions, followed by maintenance therapy according to risk
The need for adjuvant therapy depends on the patient prognosis. If the and availability of intravesical agents.
patient has a low risk for recurrence, a single immediate intravesical
treatment may be sufficient. Factors to consider include the size, Treatment of cT1 Tumors
number, T category, and grade of the tumor(s), as well as concomitant Based on the histologic differentiation, most cT1 lesions are high grade
CIS and prior recurrence.17 Meta-analyses have confirmed the efficacy and considered to be potentially dangerous with a higher risk for
of adjuvant intravesical chemotherapy in reducing the risk of recurrence and progression. These tumors may occur as solitary
recurrence.84,85 Close follow-up of all patients is needed, although the lesions or as multifocal tumors with or without an associated Tis
risk for progression to a more advanced stage is low (see Surveillance component.
in the discussion and algorithm).
These tumors are treated with a complete endoscopic resection, and
repeat TURBT is strongly advised.88 This is supported by a trial that

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prospectively randomized 142 patients with pT1 tumors to a second Surveillance

TURBT within 2 to 6 weeks of the initial TURBT or no repeat TURBT.89 For cTa high grade, cT1, and Tis, follow-up is recommended with a
All patients received adjuvant intravesical therapy. Although OS was urinary cytology and cystoscopy at 3- to 6-month intervals for the first 2
similar, the 3-year recurrence-free survival was significantly higher in years, and at longer intervals as appropriate thereafter. Imaging of the
the repeat TURBT arm versus the control arm (69% vs. 37%, upper tract should be considered every 1 to 2 years for high-risk tumors
respectively), especially among patients with high-grade tumors. (see Follow-up in the algorithm). Urine molecular tests for urothelial
tumor markers are now available.94 Many of these tests have a better
If residual cT1 disease is found at repeat TURBT, treatment should
sensitivity for detecting bladder cancer than urinary cytology, but
consist of BCG (category 1) or cystectomy. Within T1 disease, a
specificity is lower. Considering this, evaluation of urinary urothelial
particularly high-risk stratum can be identified: multifocal lesions, tumors
tumor markers may be considered during surveillance of high-risk non–
associated with CIS or lymphovascular invasion, variant histology (eg,
muscle-invasive bladder cancer. However, it remains unclear whether
micropapillary, plasmacytoid, nested variants), or lesions that recur after
these tests offer additional information that is useful for detection and
BCG treatment. There are data suggesting that early cystectomy may
management of non–muscle-invasive bladder tumors. Therefore, the
be preferred in these patients because of the high risk for progression to
panel considers this to be a category 2B recommendation.
a more advanced stage.90,91
For patients with low-risk non–muscle-invasive bladder cancer, if the
If no residual disease is found after the second resection, intravesical
initial follow-up surveillance cystoscopy is negative within 4 months of
therapy with BCG (preferred; category 1) or intravesical chemotherapy
TURBT, the next cystoscopy is recommended 6 to 9 months later and
is recommended. Observation may be reasonable in highly select cases
then yearly for up to 5 years. Follow-up cystoscopy after 5 years should
where low-grade, small-volume tumors had limited lamina propria
only be performed based on clinical indication. Beyond baseline
invasion and no CIS.92,93
imaging, upper tract imaging is not indicated without symptoms for
Treatment of Tis patients with low-risk non–muscle-invasive bladder cancer.
Primary Tis is a high-grade lesion of the urothelium. Standard therapy Posttreatment of Recurrent or Persistent Disease
for this lesion is resection followed by intravesical therapy with BCG.
Treatment of Patients With Positive Cystoscopy
BCG is preferred over intravesical chemotherapy based on a meta-
Patients under observation after initial TURBT, who show a
analysis of randomized trials showing that patients with CIS treated
documented recurrence by positive cystoscopy, should undergo another
with BCG had higher complete response rates (68.1% vs. 51.5%) and
TURBT and then adjuvant intravesical therapy or cystectomy based on
a longer DOR compared to intravesical chemotherapy.44 If the patient
the stage and grade of the recurrent lesion. Patients should be followed
is unable to tolerate BCG, intravesical chemotherapy may be
as indicated based on the risk of their disease (see Follow-up in the
considered, but data supporting this approach are limited.
algorithm).

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Bladder Cancer

Recurrence Following Intravesical Treatment candidates can consider concurrent chemoradiation, change of the
In a phase II multicenter study of non–muscle-invasive bladder cancer intravesical agent, or a clinical trial. Patients with persistent Tis or cTa
that recurred following 2 courses of BCG, intravesical gemcitabine disease after TURBT may be treated with a different intravesical agent,
demonstrated activity that was relegated to high-risk non– cystectomy, or pembrolizumab if Tis is present and the patient is not a
muscle-invasive bladder cancer.95 In the 47 patients with evaluable candidate for cystectomy. Concurrent chemoradiotherapy can be
response, 47% had disease-free survival (DFS) at 3 months. The 1-year considered for non-cystectomy candidates with persistent Ta or Tis
relapse-free survival (RFS) was 28% with all cases except for two disease after TURBT, although it is a category 2B recommendation for
attributed to the high-risk group. The 2-year RFS was 21%. Intravesical this setting. Valrubicin is approved for CIS that is refractory to BCG,
gemcitabine had some activity in the high-risk group, and may be an although panelists disagree on its value.75 For patients with disease that
option if a candidate is not eligible for a cystectomy; however, the study does not respond or shows an incomplete response to treatment,
results indicate that cystectomy is preferred when possible. Similarly, for subsequent management is cystectomy. Recurrences that are found to
patients with recurrence of high-grade cT1 disease after TURBT and be muscle-invasive or metastatic disease should be treated as
induction BCG, cystectomy is the recommended option with the best described in the appropriate section below.
data for cure,96 although pembrolizumab may be appropriate for
patients with BCG-unresponsive, high-risk, non–muscle-invasive Treatment of Patients With Positive Cytology
bladder cancer with CIS, with or without papillary tumors, who are In patients without a documented recurrence but with positive cytology
ineligible for or have elected not to undergo cystectomy (see and negative cystoscopy and imaging, selected mapping biopsies
Pembrolizumab for Non–Muscle-Invasive Bladder Cancer, above). The including transurethral resection of the prostate (TURP) is indicated. In
data are currently not mature enough to determine if pembrolizumab addition, the upper tract must be evaluated and ureteroscopy may be
can be considered curative in this setting. considered for detecting tumors of the upper tract. If available,
enhanced cystoscopy should be considered (see Enhanced
After the initial intravesical treatment and 12-week evaluation, patients Cystoscopy, above).
with persistent cTa, cT1, or Tis disease tumors can be given a second
induction course of induction therapy (see Recurrent or Persistent If the selected mapping biopsy of the bladder is positive (eg, Tis), then
Disease in the algorithm). No more than two consecutive induction the recommendation is to administer intravesical BCG followed by
courses should be given. If a second course is given, TURBT is maintenance BCG (preferred) if a complete response is seen. For
performed to determine the presence of residual disease at the second tumors that are unresponsive to BCG, the subsequent management
12-week follow-up. If no residual disease is found, maintenance BCG is options include cystectomy, changing the intravesical agent, or
recommended for patients who received prior BCG. participation in a clinical trial. Pembrolizumab is also an option for
patients with BCG-unresponsive, high-risk, non–muscle-invasive
If residual disease is seen following TURBT, patients with persistent bladder cancer with Tis, with or without papillary tumors, who are
cT1 tumors are recommended to proceed to cystectomy. Non-surgical ineligible for or have elected not to undergo cystectomy (see

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NCCN Guidelines Version 3.2020

Bladder Cancer

Pembrolizumab for Non–Muscle-Invasive Bladder Cancer, above). ultrasound, and MRI cannot accurately predict the true depth of
Further investigation and validation of results is warranted for invasion.
establishing the efficacy of alternative agents in second-line treatments.
The overwhelming majority of muscle-invasive tumors are high-grade
If transurethral biopsy of the prostate is positive, treatment of the urothelial carcinomas. Further treatment following initial TURBT is often
prostate should be initiated as described below (see Urothelial required for muscle-invasive tumors, although select patients may be
Carcinomas of the Prostate). If upper tract urothelial carcinoma is treated with TURBT alone.103,104 Different treatment modalities are
identified, then the treatment described below should be followed [see discussed below. These include radical cystectomy, partial cystectomy,
Upper Tract Urothelial Carcinoma (UTUC)]. neoadjuvant or adjuvant therapy, bladder-preserving approaches, and
systemic therapy for advanced disease.
If the transurethral biopsies of the bladder, prostate, and upper tract are
negative, follow-up at 3 months and then at longer intervals is Radical Cystectomy
recommended. If prior BCG was given, maintenance therapy with BCG Radical surgical treatment of bladder cancer involves a
should be considered. cystoprostatectomy in men and a cystectomy and commonly a
hysterectomy in women, followed by the formation of a urinary
Muscle-Invasive Urothelial Bladder Cancer
diversion. This surgery can be performed in an open or robotic
Additional Workup manner.105-107 Prostatectomy includes removal of the prostate, seminal
Several workup procedures are recommended to accurately determine vesicles, proximal vas deferens, and proximal urethra. Hysterectomy
clinical staging of muscle-invasive disease. Laboratory studies, such as should include removal of the uterus, ovaries, fallopian tubes, urethra,
a complete blood cell count and chemistry profile, including alkaline and part of the vagina. Forms of urinary diversion include an ileal
phosphatase, must be performed, and the patient should be assessed conduit or directing urine to an internal urinary reservoir (such as a
for the presence of regional or distant metastases. This evaluation continent pouch), with drainage to the abdominal wall or the urethra
should include chest imaging (CT [preferred], x-ray, or FDG-PET/CT (orthotopic neobladder). Relative contraindications to urethral drainage
[category 2B]) and evaluation for suspected bone metastasis in patients include Tis in the prostatic ducts or positive urethral margin. Orthotopic
with symptoms or clinical suspicion of bone metastasis (eg, elevated diversion or a neobladder provides the closest bladder function to that
alkaline phosphatase, focal bone pain). Chest imaging with CT is of a native bladder albeit with an increased risk for nighttime
preferred over chest x-ray based on studies showing better sensitivity of incontinence as well as urinary retention requiring intermittent
CT for detection of metastatic disease.97,98 Bone imaging may include a self-catheterization.
bone scan, MRI, or FDG-PET/CT (category 2B). Imaging studies help
assess the extent of tumor spread to lymph nodes or distant Unfortunately, the accuracy of the staging cystoscopy, EUA, and
organs.99,100 An abdominal/pelvic CT or MRI is used to assess the local TURBT is modest, even when combined with cross-sectional imaging
and regional extent of disease.101,102 Unfortunately, CT scans, and when understaging is frequently encountered. A retrospective study

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NCCN Guidelines Version 3.2020

Bladder Cancer

of 778 patients with bladder cancer found that 42% of patients were candidates are patients with cancer in a diverticulum or with significant
upstaged following cystectomy.108 A pelvic lymph node dissection medical comorbidities.
(PLND) is considered an integral part of the surgical management of
bladder cancer. A more extensive PLND, which may include the Similar to radical cystectomy, partial cystectomy begins with a
common iliac or even lower para-aortic or para-caval nodes, yields laparotomy (intraperitoneal) and resection of the pelvic lymph nodes.
more nodes to be examined, increases yield of positive nodes, and may Alternatively, partial cystectomy may be safely done laparoscopically. If
be associated with better survival and a lower pelvic recurrence rate.109- the intraoperative findings preclude a partial cystectomy, a radical
113
Conversely, a 2019 prospective, randomized trial concluded that an cystectomy is performed. The decision to recommend adjuvant radiation
extended LND did not show a significant advantage over limited LND for or chemotherapy is based on the pathologic stage (ie, positive nodes or
RFS, cancer-specific survival, or OS.114 However, differing definitions of perivesical tissue involvement) or presence of a positive margin, similar
“extended” versus “limited” LND between studies and specifics on how to that for patients who undergo a radical cystectomy.
the study was powered complicate these results. Therefore, additional
Neoadjuvant Chemotherapy
information will be needed to determine whether extended LND leads to
improved outcomes. Results from the SWOG-1011 trial, which is fully One of the most noteworthy issues in the treatment of bladder cancer is
accrued but not yet reported, may help to further inform this question.115 the optimal use of perioperative chemotherapy for muscle-invasive
Patient factors that may preclude a PLND include severe scarring disease. Data support the role of neoadjuvant chemotherapy before
secondary to previous treatments or surgery, advanced age, or severe cystectomy for stage II and IIIA lesions.116-121 In a SWOG randomized
comorbidities. trial of 307 patients with muscle-invasive disease, radical cystectomy
alone versus 3 (28-day) cycles of neoadjuvant methotrexate,
Partial Cystectomy vinblastine, doxorubicin, and cisplatin (MVAC) followed by radical
In fewer than 5% of cases, an initial invasive tumor develops in an area cystectomy were compared. Neoadjuvant chemotherapy increased
of the bladder where an adequate margin of soft tissue and an median survival (77 months vs. 46 months, P = .06) and lowered the
adequate amount of noninvolved urothelium can be removed along with rate of residual disease (15% vs. 38%, P < .001) with no apparent
the tumor without compromising continence or significantly reducing increase in treatment-related morbidity or mortality.116 In a
bladder capacity. Partial cystectomy is most frequently recommended meta-analysis of 11 trials involving 3005 patients, cisplatin-based
for lesions that develop on the dome of the bladder and have no multiagent neoadjuvant chemotherapy was associated with improved
associated Tis in other areas of the urothelium. Relative 5-year OS and DFS (5% and 9% absolute improvement,
contraindications to this procedure are lesions that occur in the trigone respectively).122 A review of the National Cancer Database supports
or bladder neck. The requirement for a ureteral reimplantation, however, initiation of neoadjuvant chemotherapy as soon as possible, but not
is not an absolute contraindication. Outcome data on partial cystectomy more than 8 weeks, after diagnosis to prevent upstaging after radical
are varied and, in general, partial cystectomy is not considered the gold- cystectomy.123
standard surgical treatment of muscle-invasive bladder cancer. Ideal
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NCCN Guidelines Version 3.2020

Bladder Cancer

Since the neoadjuvant trial with MVAC, the use of dose-dense MVAC Neoadjuvant chemotherapy followed by radical cystectomy is a
(ddMVAC) with growth factor support in the metastatic setting has been category 1 recommendation based on high-level data supporting its
shown to have good comparable tolerance with an increased CR rate use. For highly select patients with stage II disease who receive a
compared to standard (28-day) dosing of MVAC (11% vs. 25%; 2-sided partial cystectomy, neoadjuvant chemotherapy is a category 2A
P = .006).124 Based on these findings, ddMVAC has also been recommendation. Patients with hearing loss or neuropathy, poor
investigated in the neoadjuvant setting. In a multicenter prospective performance status, or renal insufficiency may not be eligible for
phase II trial, patients with cT2 to cT4a tumor staging and N0 or N1 cisplatin-based chemotherapy. If neoadjuvant cisplatin-based
muscle-invasive bladder cancer (n = 44) were given 3 cycles of chemotherapy cannot be given, neoadjuvant chemotherapy is not
ddMVAC with pegfilgrastim followed by radical cystectomy and lymph recommended. Cystectomy alone is an appropriate option for these
node dissection.125 ddMVAC was anticipated to have a safer profile, a patients. For patients with borderline renal function or minimal
shorter time to surgery, and a similar pathologic complete response rate dysfunction, a split-dose administration of cisplatin may be considered
compared to historical control data for neoadjuvant MVAC (category 2B). Although split-dose is a safer alternative, the relative
chemotherapy given in previous studies. Patients receiving ddMVAC efficacy remains undefined.
had no grade 3 or 4 renal toxicities and no toxicity-related deaths.
Grade 1 or 2 treatment-related toxicities were seen in 82% of patients. Adjuvant Chemotherapy
The median time to cystectomy was 9.7 weeks from the start of Data are less clear regarding the role of adjuvant systemic
chemotherapy.125 A separate single-arm phase II study also reported chemotherapy in invasive bladder cancer. Studies have shown that
pathologic downstaging in 49% of patients receiving neoadjuvant adjuvant chemotherapy may delay recurrences and improve OS;128-130
ddMVAC with a similar safety profile.126 An additional neoadjuvant however, no randomized comparisons of adequate sample size have
clinical trial of ddMVAC with bevacizumab reported 5-year survival definitively shown a survival benefit, in large part due to poor accrual.131
outcomes of 63% and 64% (OS and DSS, respectively; median Clinical trials of adjuvant chemotherapy with cyclophosphamide,
follow-up, 49 months), with pT0N0 and less than or equal to pT1N0 doxorubicin, and cisplatin (CAP); MVAC; and methotrexate, vinblastine,
downstaging rates of 38% and 53%, respectively.127 Bevacizumab had epirubicin, and cisplatin (MVEC) regimens have each suggested a
no definitive impact on overall outcomes. In an international, survival advantage.132-134 However, methodologic issues call into
multicenter, randomized trial (BA06 30894) that investigated the question the applicability of these studies to all patients with urothelial
effectiveness of neoadjuvant cisplatin, methotrexate, and vinblastine tumors. In the MVEC trial, patients who experienced relapse in the
(CMV) in 976 patients, neoadjuvant CMV resulted in a 16% reduction in control arm did not receive chemotherapy, which is not typical of more
mortality risk (HR, 0.84; 95% CI, 0.72–0.99; P = .037) at a median contemporary treatment approaches. Many of these trials were not
follow-up of 8 years.121 randomized, raising the question of selection bias in the analysis of
outcomes.
The NCCN Panel recommends neoadjuvant chemotherapy followed by
radical cystectomy for patients with stage II or IIIA bladder cancer.

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NCCN Guidelines Version 3.2020

Bladder Cancer

A meta-analysis of 6 trials found a 25% mortality reduction with adjuvant Adjuvant Radiation
chemotherapy, but the authors pointed out several limitations of the Patients with locally advanced disease (pT3–4) have high rates of pelvic
data and concluded that evidence is insufficient for treatment recurrence and poor OS after radical cystectomy, PLND, and
decisions.135 Interestingly, the follow-up analysis included 3 more perioperative chemotherapy (pelvic failure 20%–45% and survival 10%–
studies for a total of 9 trials (N = 945 patients).130 A 23% risk reduction 50% at 5 years, depending on risk factors).139-142 There is an interest in
for death was observed in the updated analysis (HR, 0.77; 95% CI, using adjuvant radiation to improve these outcomes, but data are limited
0.59–0.99; P = .049) and improved DFS was achieved (HR, 0.66; 95% and further prospective studies are needed to confirm its benefits. One
CI, 0.45–0.91; P = .014). Patients with node-positive disease had an older randomized study of 236 patients with pT3a to pT4a bladder
even greater DFS benefit.130 An observational study evaluated 5653 cancer demonstrated improvement in 5-year DFS and local control
patients of which 23% received adjuvant chemotherapy compared to surgery alone.143 A more recent randomized phase II trial
post-cystectomy.129 Patients who received adjuvant chemotherapy had compared adjuvant sequential chemotherapy and radiation versus
an improved OS (HR, 0.70; 95% CI, 0.06–0.76).129 Although evidence adjuvant chemotherapy alone in 120 patients with locally advanced
for adjuvant therapy is not as strong as for neoadjuvant therapy, the disease with 1 or more risk factors (≥pT3b, grade 3, or node-positive), in
growing body of data support the administration of adjuvant a study population with a high proportion of squamous cell carcinoma.
chemotherapy for patients with a high risk for relapse who did not This study demonstrated a significant improvement in local control for
receive neoadjuvant therapy. chemoradiation (3-year local control of 96% vs. 69%; P < .01) and
marginal improvements in DFS and OS. Late-grade ≥3 gastrointestinal
The NCCN Guidelines suggest that adjuvant chemotherapy may be
toxicity on the chemoradiation arm was low (7% of patients).144 A 2019
given to patients with high-risk pathology who did not receive
systematic review evaluating the oncologic efficacy of adjuvant radiation
neoadjuvant chemotherapy and is considered a category 2A
for bladder cancer or upper tract urothelial carcinoma concluded that
recommendation. A minimum of 3 cycles of a cisplatin-based
there was no clear benefit of adjuvant radiation following radical surgery
combination, such as ddMVAC; gemcitabine plus cisplatin (GC); or
(eg, cystectomy), although the combination of adjuvant radiation with
CMV, may be used in patients undergoing perioperative chemotherapy.
chemotherapy may be beneficial in locally advanced disease.145
Regimen and dosing recommendations are mainly based on studies in
advanced disease.116,121,136-138 Carboplatin has not demonstrated a While there are no conclusive data demonstrating improvements in OS,
survival benefit and should not be substituted for cisplatin in the it is reasonable to consider adjuvant radiation in patients with pT3/pT4
perioperative setting. It should be noted that patients with tumors that pN0–2 urothelial bladder cancer following radical cystectomy, although
are pT2 or less and have no nodal involvement or lymphovascular this approach has been evaluated in only a limited number of studies,
invasion after cystectomy are considered to have lower risk and are not reflected by the category 2B designation. Patients meeting these
recommended to receive adjuvant chemotherapy. characteristics with positive surgical margins and/or lymph nodes
identified in the pelvic dissection have especially high pelvic recurrence
rates (40%–45% by 5 years), and adjuvant radiation is reasonably well
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NCCN Guidelines Version 3.2020

Bladder Cancer

tolerated and improves local control. Radiation with a dose range of 45 With any of the alternatives to cystectomy, there is a concern that
to 50.4 Gy without concurrent chemotherapy may be used. In patients bladders that appear to be endoscopically free of tumor based on a
who have not had prior neoadjuvant chemotherapy, it may be clinical assessment (cT0) that includes a repeat TURBT may not be
reasonable to sandwich adjuvant radiation between cycles of adjuvant pathologically free of tumor (pT0). Reports have suggested that up to
chemotherapy.144 The safety and efficacy of concurrent sensitizing 45% of bladders may be clinically understaged after TURBT.152,154,155
chemotherapy and radiation in the adjuvant setting needs to be further Conversely, one series reported that all patients who achieved a
studied. complete response after radiotherapy with concurrent cisplatin and
5-FU were pT0 on immediate cystectomy.156 Although studies report
Bladder Preservation differing frequencies of residual disease after cytotoxic agents (either
All bladder-sparing approaches are based on the principle that not all radiation or chemotherapy), there is consensus that the rate is lower for
cases require an immediate cystectomy, and the decision to remove the patients who present with T2 disease than with T3 disease, which
bladder can be deferred until the response to organ-sparing therapy is should be considered when proposing a bladder-sparing approach.
assessed. Bladder-preserving approaches are reasonable alternatives
to cystectomy for patients who are medically unfit for surgery and those The decision to use a bladder-preserving approach is partially based on
seeking an alternative to radical cystectomy.146,147 Combined modality the location of the lesion, depth of invasion, size of the tumor, status of
chemoradiation therapy as an alternative to immediate cystectomy for the “uninvolved” urothelium, and status of the patient (eg, bladder
muscle-invasive bladder cancer is endorsed by multiple international capacity, bladder function, comorbidities). Bladder preservation as an
organizations that have developed evidence-based consensus alternative to cystectomy is generally reserved for patients with smaller
guidelines and recommendations, including the International solitary tumors, negative nodes, no extensive or multifocal CIS, no
Consultation on Urologic Diseases-European Association of Urology tumor-related hydronephrosis, and good pre-treatment bladder function.
(ICUD-EAU), UK National Institute for Health and Care Excellence Patients who are medically fit for radical cystectomy but who have
(NICE), and the AUA/ASCO/ASTRO/SUO.148-150 There is an apparent hydronephrosis are poor candidates for bladder-sparing
underutilization of aggressive bladder-preserving therapies for procedures.157,158 Maximal TURBT with concurrent chemoradiotherapy
non-cystectomy candidates, especially the elderly and racial should be given as primary treatment for these patients, with
minorities.151,152 Between 23% and 50% of patients with muscle-invasive radiotherapy alone or TURBT alone reserved for select patients (see
bladder cancer who are 65 years of age and older receive no treatment TURBT Alone as Primary Treatment for Muscle-Invasive Bladder
or non-aggressive therapy, despite prospective, phase II data showing Cancer below for more information). When possible, bladder-sparing
that bladder preservation with trimodality therapy has positive outcomes options should be chosen in the context of clinical trials.
and an acceptable toxicity profile for patients ≥65 years of age, with a 2-
Radiotherapy with Concurrent Chemotherapy Following TURBT as
year OS of 94.4% and 2-year DFS of 72.6%.153 For tools to aid in the Primary Treatment for Muscle-Invasive Bladder Cancer
optimal assessment and management of older adults with cancer, see Several groups have investigated the combination of concurrent or
the NCCN Guidelines for Older Adult Oncology. sequential chemotherapy and radiotherapy after TURBT. First, an
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NCCN Guidelines Version 3.2020

Bladder Cancer

endoscopic resection that is as complete as possible is performed. respectively.167 Taken together, the complete response rates ranged
Incomplete resection is an unfavorable prognostic factor for the ability to from 59% to 88%.
preserve the bladder.159-161
Up to about 80% of long-term survivors maintain an intact bladder, while
Radiation Therapy Oncology Group (RTOG) protocol 89-03 compared other patients ultimately require radical cystectomy.157-165 A combined
concurrent cisplatin and radiotherapy with or without 2 cycles of analysis of survivors from 4 of these trials, with a median follow-up of
induction MCV (methotrexate, cisplatin, and vinblastine) 5.4 years, showed that combined-modality therapy was associated with
chemotherapy.158 No difference in complete clinical response or 5-year low rates of late grade 3 toxicity (5.7% genitourinary and 1.9%
OS was observed between the treatment arms. Other studies also gastrointestinal).168 No late grade 4 toxicities or treatment-related
reported no significant survival benefit for neoadjuvant chemotherapy deaths were recorded.
before bladder-preserving chemotherapy with radiation therapy
(RT).160,162 Based on the trials described above, as well as the phase 3 BC2001
trial that demonstrated a locoregional DFS benefit for those treated with
Conversely, results from several prospective trials have demonstrated fluorouracil and mitomycin concurrently with radiotherapy compared to
the effectiveness of this approach. In the phase 3 RTOG 89-03 trial in radiotherapy alone, with no significant increase in AEs,169 bladder
which 123 patients with clinical stage T2–T4a were treated with preservation with concurrent chemoradiotherapy was given a category 1
radiotherapy plus concurrent cisplatin, with or without induction MCV designation for primary treatment of stage II or IIIA bladder cancer.
chemotherapy, 5-year OS was approximately 49% in both arms.158 The
Chemotherapy Following TURBT as Primary Treatment for Muscle-
subsequent RTOG 95-06 trial treated 34 patients with twice-daily
Invasive Bladder Cancer
irradiation and concurrent cisplatin and 5-FU and reported a 3-year OS
Chemotherapy alone is considered to be inadequate without additional
of 83%.163 The RTOG 97-06 trial treated 47 patients with twice-daily
treatment to the bladder and remains investigational. Studies showed
irradiation and concurrent cisplatin; patients also received adjuvant
that the proportions of complete pathologic response in the bladder
chemotherapy with CMV.164 Three-year OS was 61%. In the RTOG
using neoadjuvant chemotherapy alone were only up to 38%.116 A
99-06 study, 80 patients received twice-daily irradiation plus cisplatin
higher proportion of bladders can be rendered tumor-free and therefore
and paclitaxel, followed by adjuvant cisplatin and gemcitabine.
preserved when chemotherapy is combined with concurrent
Five-year OS was 56%.165 In RTOG 0233, 97 patients received
radiotherapy.
twice-daily radiation with concurrent paclitaxel plus cisplatin or 5-FU
plus cisplatin. Five-year OS was 73%.166 RTOG 0712 investigated 5-FU Radiotherapy Following TURBT as Primary Treatment for Muscle-
plus cisplatin with twice-daily radiation or gemcitabine with once daily Invasive Bladder Cancer
radiation, with 33 patients eligible for analysis on each arm. Three-year Radiotherapy alone is inferior to radiotherapy combined with
distant metastasis-free survival rates were 78% and 84%, chemotherapy for patients with an invasive bladder tumor, and is not
considered standard for patients who can tolerate combined

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NCCN Guidelines Version 3.2020

Bladder Cancer

therapy.169,170 In a randomized trial of 360 patients, radiotherapy with Primary surgical treatment for stage II and IIIA disease is a radical
concurrent mitomycin C and 5-FU improved 2-year locoregional DFS cystectomy and pelvic lymphadenectomy. Neoadjuvant chemotherapy
from 54% (radiotherapy alone) to 67% (P = .01), and 5-year OS from is recommended (category 1). Partial cystectomy along with
35% to 48% (P = .16), without increasing grade 3–4 acute or late neoadjuvant cisplatin-based chemotherapy can be considered for stage
toxicity.169 Hence, radiotherapy alone is only indicated for those who II (cT2, N0) disease with a single tumor in a suitable location and no
cannot tolerate a cystectomy or chemotherapy because of medical presence of Tis. Partial cystectomy is not an option for stage III patients.
comorbidities. If no neoadjuvant cisplatin-based chemotherapy is given, postoperative
adjuvant chemotherapy may be considered based on pathologic risk,
TURBT Alone as Primary Treatment for Muscle-Invasive Bladder Cancer
such as positive nodes, positive margins, or pT3–T4 lesions.142
TURBT alone may be an option for patients with stage II disease who Adjuvant RT is another option for these patients (category 2B).
are not candidates for cystectomy. TURBT alone may be curative in
selected cases that include solitary lesions less than 2 cm in size that Bladder preservation with maximal TURBT followed by concurrent
have minimally invaded the muscle. These cases should also have no chemoradiotherapy is another category 1 primary treatment option for
associated in situ component, palpable mass, or associated these patients. Candidates for this bladder-sparing approach include
hydronephrosis.171 patients with tumors that present without hydronephrosis or with tumors
that allow a visibly complete or a maximally debulking TURBT.
If primary treatment consists of TURBT alone, patients should undergo Radiotherapy with concurrent cisplatin-based chemotherapy or 5-FU
an aggressive re-resection of the site within 4 weeks of the primary plus mitomycin as a radiosensitizer is the most common and
procedure to ensure that no residual disease is present. If the repeat well-studied chemoradiation method used to treat muscle-invasive
TURBT is negative for residual tumor, the patient can be managed bladder cancer.156-160,169,170,172 The following radiosensitizing regimens
conservatively with repeat endoscopic evaluations and cytologies every are recommended: cisplatin plus 5-FU; cisplatin plus paclitaxel; 5-FU
3 months until a relapse is documented. The stage of the lesion plus mitomycin C; and cisplatin alone. Doublet chemotherapy is
documented at relapse would determine further management decisions. generally preferred. Low-dose gemcitabine (category 2B) may be
considered as an alternative regimen.
Treatment of Stage II and IIIA Tumors
The critical issues in the management and prognosis of these patients After a complete TURBT, 60 to 66 Gy of external beam RT (EBRT) is
are whether a palpable mass is appreciated at EUA and if the tumor has administered. Two doses of concurrent radiosensitizing chemotherapy
extended through the bladder wall. Tumors that are organ-confined (T2, may be given on weeks 1 and 4 (though weekly schedules are possible
stage II) have a better prognosis than those that have extended through as well). Alternatively, an induction dose of 40 to 45 Gy radiotherapy
the bladder wall into the perivesical fat (T3) and beyond. T4a tumors may be given following complete TURBT. The overall tumor status
involve the prostatic stroma, uterus, or vagina and are typically should be reassessed 2 to 3 months after treatment. If no residual
surgically managed similar to T3 tumors. tumor is detected, observation is appropriate. If residual disease is

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NCCN Guidelines Version 3.2020

Bladder Cancer

present, surgical consolidation of bladder-only residual disease or who were treated with chemotherapy alone (n = 1388) or
treatment as metastatic disease are appropriate. If residual disease is chemoradiotherapy (n = 395).173 This study found that patients treated
Tis, Ta, or T1, intravesical BCG may be considered. with chemoradiotherapy had a higher median OS than those treated
with chemotherapy (19.0 months vs. 13.8 months, P < .001). The
In patients with extensive comorbid disease or poor performance status improvement in outcome with chemoradiotherapy persisted upon
who are non-cystectomy candidates, treatment options include evaluation of propensity-matched populations (P < .001).173
concurrent chemoradiation (preferred, category 1) or radiotherapy Cystectomy as primary treatment or for surgical palliation may be
alone. TURBT is another option for patients with stage II disease who appropriate in very select situations, such as in patients with limiting
are non-cystectomy candidates. Based on high-level evidence showing local symptoms and/or those with comorbidities that prevent
superiority to radiotherapy alone, the NCCN Panel recommends administration of chemotherapy.
chemoradiotherapy as the preferred option for these patients.169,170 The
overall tumor status should be reassessed 2 to 3 months after Tumor status should be reassessed 2 to 3 months after treatment by
treatment. If no tumor is evident, the patient should be observed. If imaging the chest, abdomen, and pelvis using CT with contrast. If
tumor is observed, systemic therapy, concurrent chemoradiotherapy or there is no evidence of distant disease on imaging reassessment,
radiotherapy alone (if no prior radiotherapy), TURBT, or best supportive further cystoscopic assessment of tumor response in the bladder is
care may be given. recommended.

Treatment of Stage IIIB Tumors Subsequent disease management depends on the response to
Primary treatment for stage IIIB (cT1–T4a, N2–3) disease can include primary treatment. Patients who received downstaging systemic
either downstaging systemic therapy or concurrent therapy and had a complete disease response may then be
chemoradiotherapy.173,174 A population-based study of 659 patients subsequently treated with cystectomy or chemoradiotherapy or may
with cT1–T4a, node-positive urothelial bladder cancer tested the be observed until disease relapse, depending on patient-specific
effectiveness of induction chemotherapy for pathologic features. Patients who received downstaging systemic therapy and
downstaging.174 For cN1 disease, complete pathologic downstaging showed a partial response may be treated with cystectomy or
was achieved in 39% of patients who received induction chemoradiotherapy (for persistent disease confined to the bladder) or
chemotherapy compared to 5% of patients who did not receive treated as metastatic disease with additional lines of systemic therapy
induction chemotherapy. For cN2–3, the rate of pathologic (for distant disease). Patients who had disease progression following
downstaging was 27% versus 3% for these two groups. OS was also primary downstaging systemic therapy may be treated as with
improved in patients who received induction chemotherapy (P < .001), metastatic disease, with additional lines of systemic therapy.
although the nature of the study limits interpretation of the OS results.174
Patients with complete disease response following concurrent
Another study used the National Cancer Database to analyze
chemoradiotherapy should be observed until disease relapse. Partial
outcomes of 1783 patients with clinically node-positive bladder cancer
responses to concurrent chemoradiotherapy may be subsequently
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NCCN Guidelines Version 3.2020

Bladder Cancer

treated with surgical consolidation (for residual disease confined to the receive concurrent chemoradiotherapy or a cystectomy. If the disease
bladder), consideration of intravesical BCG (for Tis, Ta, or T1 residual remains stable or progresses following primary therapy, these patients
disease), or treated as metastatic disease with systemic therapy (for should follow treatment for metastatic disease.
remaining disease outside of the bladder). Progression following
concurrent chemoradiotherapy may be treated as metastatic disease Follow-up
with systemic therapy. Results from a meta-analysis of 13,185 patients who have undergone
cystectomy reported a 0.75% to 6.4% prevalence of upper tract
Treatment of Stage IVA Tumors recurrence.175 Surveillance by urine cytology or upper tract imaging
Stage IVA includes patients with cT4b, any N, M0 or any T, any N, detected recurrences in 7% and 30% of cases, respectively.
M1a disease.14 For patients with stage IVA disease, treatment options
differ depending on the presence of distant metastasis (M0 vs. M1a). Follow-up after a cystectomy should include urine cytology, liver
function tests, creatinine, and electrolytes. Imaging of the chest, upper
Primary treatment recommendations for patients with M0 disease tract abdomen, and pelvis should be conducted at intervals based on
include systemic therapy or concurrent chemoradiotherapy followed by the risk of recurrence. Patients should be monitored annually for vitamin
evaluation with cystoscopy, EUA, TURBT, and imaging of the B12 deficiency if a continent urinary diversion was created. Consider
abdomen and pelvis. If no evidence of tumor is present after primary urethral wash cytology for patients with an ileal conduit or continent
treatment, the patient may be treated with consolidation systemic catheterizable diversion, particularly if Tis was found within the bladder
therapy or adjuvant treatment with chemoradiotherapy may be initiated or prostatic urethra. For details of follow-up recommendations, see
if the patient did not receive prior radiotherapy. In general, stage IVA Follow-up in the algorithm.
disease is considered unresectable. However, in patients with disease
that responds to treatment, cystectomy may be an option if the tumor Follow-up after a partial cystectomy is similar to that for a radical
becomes technically resectable. If residual disease is noted upon cystectomy, with the addition of monitoring for relapse in the bladder by
evaluation after primary therapy, systemic therapy or cystectomy is serial cytologic examinations and cystoscopies (may include selected
recommended. Systemic therapy may include a checkpoint inhibitor, mapping biopsy).
chemoradiotherapy (if no prior radiotherapy), or chemotherapy.
For patients who have a preserved bladder, there is a risk for
Cystectomy, if feasible, is an option.
recurrence in the bladder or elsewhere in the urothelial tract and
Patients with M1a disease should receive systemic therapy as primary distantly. Imaging studies and laboratory testing should be performed as
treatment. Those select patients with metastatic disease treated with outlined under post-cystectomy follow-up. Additionally, continued
curative intent should be evaluated with cystoscopy, EUA, TURBT, monitoring of the urothelium with cystoscopy and urinary cytologies with
and abdominal/pelvic imaging. If a complete response is noted or without mapping biopsy is a routine part of the management of all
following primary treatment of metastatic disease, these patients may cases in which the bladder is preserved.

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NCCN Guidelines Version 3.2020

Bladder Cancer

Recurrent or Persistent Disease (category 2B); capecitabine (category 3); and low-dose gemcitabine
Metastatic or local recurrence of muscle-invasive disease may be (category 2B). Radiotherapy alone can also be considered as a
managed with cystectomy, systemic therapy, or palliative TURBT and subsequent-line therapy for patients with metastatic disease or local
best supportive care. recurrence following cystectomy, especially in selected cases with
regional-only recurrence or with clinical symptoms.
A positive cytology with no evidence of disease in the bladder should
prompt retrograde selective washings of the upper tract and a biopsy of Metastatic (Stage IVB) Urothelial Bladder Cancer
the prostatic urethra. If the results are positive, patients are managed as Approximately 5% of patients have metastatic disease at the time of
described in the sections below for treatment of UTUC or urothelial diagnosis.2 Additionally, about half of all patients relapse after
carcinoma of the prostate. cystectomy depending on the pathologic stage of the tumor and nodal
status. Local recurrences account for about 10% to 30% of relapses,
For patients with a preserved bladder, local recurrence or persistent whereas distant metastases are more common.
disease should be evaluated as a new cancer. Recurrences are treated
based on the extent of disease at relapse, with consideration of prior Evaluation of Metastatic Disease
treatment. As previously discussed, Tis, Ta, or T1 tumors are generally If metastasis is suspected, additional workup to evaluate the extent of
managed with intravesical therapy or cystectomy. If no response is the disease is necessary. This includes a chest CT and a bone scan if
noted following intravesical treatment, a cystectomy is advised. Invasive enzyme levels are abnormal or the patient shows signs or symptoms of
disease is generally managed with radical cystectomy, and a second skeletal involvement. Central nervous system (CNS) imaging should be
attempt at bladder preservation is not advisable. Cystectomy may not considered. An estimated glomerular filtration rate (GFR) should be
be possible in a patient who has undergone a full course of EBRT and obtained to assess patient eligibility for cisplatin. For patients with
has bulky residual disease. For these patients, systemic therapy or borderline GFR results, a timed or measured urine collection may be
palliative TURBT and best supportive care is advised. considered to more accurately determine cisplatin eligibility.176 If the
evidence of spread is limited to nodes and biopsy is technically feasible,
Subsequent-line therapy for metastatic disease or local recurrence
nodal biopsy should be considered and patients should be managed as
includes systemic therapy, chemoradiotherapy (if no previous RT), or
previously outlined for positive nodal disease (stage IIIA, stage IIIB, or
RT (see Follow-up, Recurrent or Persistent Disease in the algorithm).
stage IVA). Molecular testing should also be performed for patients with
Chemotherapy is sometimes combined with palliative radiation to treat metastatic disease (see Molecular/Genomic Testing, below).
metastases or pelvic recurrence after cystectomy. However, concurrent
Patients who present with disseminated metastatic disease are
chemotherapy is inappropriate if high-dose radiation (>3 Gy fractions) is
generally treated with systemic therapy. Metastasectomy and/or
used. The radiosensitizing chemotherapy regimens remain controversial
palliative radiotherapy of metastases may also be useful for select
in this setting. Possible options include cisplatin (category 2A);
patients.
docetaxel or paclitaxel (category 2B); 5-FU with or without mitomycin C
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Bladder Cancer

Metastasectomy for Oligometastatic Disease chemotherapy and pN0 versus pN+, but similar for cN1–3 versus
Highly select patients with oligometastatic disease who are without cM1.183 A systematic review and meta-analysis of available studies,
evidence of rapid progression may benefit from metastasectomy including a total of 412 patients with metastatic urothelial carcinoma,
following response to systemic therapy. While there are limited reported an improved OS for patients who underwent metastasectomy
prospective data supporting the role of metastasectomy for treatment of compared to non-surgical treatment of metastatic lesions. Five-year
urothelial bladder cancer, several retrospective studies have survival in these studies ranged from 28% to 72%.184 Another
demonstrated that metastasectomy can be a valid treatment option for population-based analysis of 497 patients aged ≥65 years who had at
certain patients with metastatic bladder cancer, particularly those with least one metastasectomy for treatment of urothelial carcinoma found
favorable response to systemic therapy, solitary metastatic lesions, and that with careful patient selection, metastasectomy is safe and can be
lung or lymph node sites of disease. associated with long-term survival in this patient population.185

A phase II trial of 11 patients with bladder primary urothelial carcinoma Due to the limited evidence supporting metastasectomy for bladder
metastatic to the retroperitoneal lymph nodes who underwent complete cancer, and the often extensive and difficult nature of the surgery, it is
bilateral retroperitoneal lymph node dissection reported 4-year DSS and important to carefully select appropriate patients for metastasectomy,
RFS rates of 36% and 27%. Patients with viable tumor in no more than including consideration of patient performance status, comorbidities,
2 lymph nodes and/or excellent response to presurgical systemic and overall clinical picture.
chemotherapy showed the best survival rates indicating that a low
Molecular/Genomic Testing
burden of disease or good response to presurgical chemotherapy may
be important in achieving benefit from metastastectomy.177 Another The panel recommends that molecular/genomic testing be performed
phase II trial of 70 patients who underwent complete surgical resection for stages IVA and IVB bladder cancer and may be considered for stage
of bladder cancer metastases investigated survival, performance status, IIIB. This testing should be performed only in laboratories that are
and quality of life following surgery. This study reported no survival certified under the Clinical Laboratory Improvement Amendments of
advantage from surgery, although the quality of life and performance 1988 (CLIA-88) as qualified to perform highly complex molecular
status were improved for symptomatic patients.178 pathology testing.186 The NCCN Bladder Cancer Panel recommends
that molecular/genomic testing be carried out early, ideally at diagnosis
Beyond these prospective data, several retrospective studies have of advanced bladder cancer, in order to facilitate treatment decision-
demonstrated a survival advantage following metastasectomy.179-182 A making and to prevent delays in administering later lines of therapy. In
retrospective series of 55 patients with bladder primary urothelial addition to determining eligibility for FDA-approved therapies,
carcinoma metastatic to the pelvic or retroperitoneal lymph nodes, who molecular/genomic testing may be used to screen for clinical trial
underwent post-chemotherapy lymph node dissection, reported 5-year eligibility.
DSS and RFS rates of 40% and 39%. The best outcomes were
associated with radiologic nodal complete response to preoperative

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NCCN Guidelines Version 3.2020

Bladder Cancer

Based on the FDA approval of erdafitinib (see Targeted Therapies, poor tolerance to multiagent combination programs and few complete
below), molecular testing should include analysis for FGFR3 or FGFR2 remissions, which are prerequisites for cure.
genetic alterations. The therascreen FGFR RGQ RT-PCR Kit has been
approved as a companion diagnostic for erdafitinib.187,188 For certain GC193,194 and ddMVAC124,136 are commonly used in combinations that
patients who are ineligible to receive cisplatin, the checkpoint inhibitors have shown clinical benefit. A large, international, phase III study
atezolizumab or pembrolizumab may be considered for first-line therapy randomized 405 patients with locally advanced or metastatic disease to
based on PD-L1 testing results (see Targeted Therapies, below). GC or standard (28-day) MVAC.138 At a median follow-up of 19 months,
Companion diagnostics have been approved for each of these OS and time to progression were similar in the two arms. Fewer toxic
therapies when used in this setting.188,189 deaths were recorded among patients receiving GC compared to MVAC
(1% vs. 3%), although this did not reach statistical significance. A 5-year
Genetic alterations are known to be common in bladder cancer, with update analysis confirmed that GC was not superior to MVAC in terms
data from the Cancer Genome Atlas ranking bladder cancer as the third of survival (OS, 13.0% vs. 15.3%; progression-free survival [PFS], 9.8%
highest mutated cancer.190,191 Supporting this, a study that looked at vs. 11.3%, respectively).194 Another large, randomized, phase III trial
comprehensive genomic profiling of 295 cases of advanced urothelial compared ddMVAC to standard (28-day) MVAC.124,136 At a median
carcinoma found that 93% of cases had at least 1 clinically relevant follow-up of 7.3 years, 24.6% of patients were alive in the ddMVAC
genetic alteration, with a mean of 2.6 clinically relevant genetic cohort compared with 13.2% in the standard MVAC cohort. There was
alterations per case. The most commonly identified clinically relevant one toxic death in each arm, but less overall toxicity was seen in the
genetic alterations were cyclin-dependent kinase inhibitor 2A (CDKN2A, dose-dense group. From these data, ddMVAC had improved toxicity
34%), FGFR3 (21%), phosphatidylinositol 3-kinasecatalytic subunit and efficacy as compared to standard MVAC; therefore, standard (28-
alpha (PIK3CA, 20%), and ERBB2 (17%).192 day) MVAC is no longer used. Both GC and ddMVAC with growth factor
support are category 1 recommendations for metastatic disease.
Chemotherapy for Metastatic Disease Alternative first-line regimens also include carboplatin or taxane-based
The specific chemotherapy regimen recommended partially depends on regimens (category 2B) or single-agent chemotherapy (category 2B).
the presence or absence of medical comorbidities, such as cardiac
disease and renal dysfunction, along with the risk classification of the The performance status of the patient is a major determinant in the
patient based on disease extent. In general, long-term survival with selection of a regimen. Regimens with lower toxicity profiles are
combination chemotherapy alone has been reported only in good-risk recommended in patients with compromised liver or renal status or
patients, defined as those with good performance status, no visceral (ie, serious comorbid conditions. In patients who are not cisplatin-eligible
liver, lung) or bone disease, and normal alkaline phosphatase or lactic and whose tumors express PD-L1 or in patients who are not eligible for
dehydrogenase levels. Poor-risk patients, defined as those with poor any platinum-containing chemotherapy, atezolizumab or pembrolizumab
performance status or visceral disease, have consistently shown very are appropriate first-line options (see Targeted Therapies in the
discussion). Alternatively, carboplatin may be substituted for cisplatin in

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NCCN Guidelines Version 3.2020

Bladder Cancer

the metastatic setting for cisplatin-ineligible patients such as those with Although current data are insufficient to recommend the above
a GFR less than 60 mL/min. A phase II/III study assessed 2 alternative regimens as routine first-line options, non–
carboplatin-containing regimens in medically unfit patients (performance cisplatin-containing regimens may be considered in patients who cannot
status 2).195 The overall response rate (ORR) was 42% for gemcitabine tolerate cisplatin because of renal impairment or other comorbidities
plus carboplatin and 30% for methotrexate, carboplatin, and vinblastine. (see Principles of Systemic Therapy in the algorithm). Additionally, two
However, the response rates dropped to 26% and 20%, respectively, checkpoint inhibitors, atezolizumab and pembrolizumab, have been
with increased toxicity among patients who were both unfit and had FDA approved for use as a first-line therapy in certain patients.
renal impairment (GFR <60 mL/min). Consideration of checkpoint inhibitors must be integrated into the
therapeutic planning for all patients with locally advanced and
Taxanes have been shown to be active as treatment options for metastatic disease (see Targeted Therapies in the discussion). The
urothelial bladder cancer.196-199 Based on these results, several groups NCCN Panel recommends enrollment in clinical trials of potentially less
are exploring 2- and 3-drug combinations using these agents, with and toxic therapies.
without cisplatin. A randomized phase III trial was conducted to
compare GC and GC plus paclitaxel in 626 patients with locally Independent of the specific regimen used, patients with metastatic
advanced or metastatic urothelial cancer.200 The addition of paclitaxel to disease are re-evaluated after 2 to 3 cycles of chemotherapy, and
GC resulted in higher response rates and a borderline OS advantage, treatment is continued for 2 more cycles in patients whose disease
which was not statistically significant in the intent-to-treat analysis. responds or remains stable. Chemotherapy may be continued for a
Analysis of eligible patients only (92%) resulted in a small (3.2 months) maximum of 6 cycles, depending on response. If no response is noted
but statistically significant survival advantage in favor of the 3-drug after 2 cycles or if significant morbidities are encountered, a change in
regimen (P = .03). There was no difference in PFS. The incidence of therapy is advised, taking into account the patient’s current performance
neutropenic fever was substantially higher with the 3-drug combination status, extent of disease, and specific prior therapy. A change in
(13.2% vs. 4.3%; P < .001). Panelists feel that the risk of adding therapy is also advised for patients who experience systemic relapse
paclitaxel outweighs the limited benefit reported from the trial. The after adjuvant chemotherapy.
alternative regimens, including cisplatin/paclitaxel,201
gemcitabine/paclitaxel,202 cisplatin/gemcitabine/paclitaxel,203 Surgery or radiotherapy may be feasible in highly select cases for
carboplatin/gemcitabine/paclitaxel,204 and patients who show a major partial response in a previously unresectable
cisplatin/gemcitabine/docetaxel,205 have shown modest activity in primary tumor or who have a solitary site of residual disease that is
patients with bladder cancer in phase I–II trials. Category 1 level resectable after chemotherapy. In selected series, this approach has
evidence now supports the use of checkpoint inhibitors in patients with been shown to afford a survival benefit. If disease is completely
advanced disease previously treated with a platinum-containing resected, 2 additional cycles of chemotherapy can be considered,
regimen (see Targeted Therapies in the discussion). depending on patient tolerance.

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NCCN Guidelines Version 3.2020

Bladder Cancer

Clinical trial enrollment is recommended by the NCCN Panel for all that has progressed within 12 months of neoadjuvant or adjuvant
patients when appropriate, but is strongly recommended for second-line platinum-containing chemotherapy, regardless of PD-L1 expression
and subsequent therapies since data for locally advanced or metastatic levels. Additionally, atezolizumab and pembrolizumab are approved as
disease treated with subsequent-line therapy are highly variable. The a first-line treatment option for patients with locally advanced or
available options depend on what was given as first line. Regimens metastatic urothelial cell carcinoma who are not eligible for cisplatin-
used in this setting include checkpoint inhibitors, erdafitinib, enfortumab containing chemotherapy and whose tumors express PD-L1 or in
vedotin, and the following chemotherapies: docetaxel; paclitaxel; patients who are not eligible for any platinum-containing chemotherapy
gemcitabine; ifosfamide, doxorubicin, and gemcitabine; gemcitabine regardless of PD-L1 expression. Companion diagnostic tests have been
and paclitaxel; GC; and ddMVAC. approved by the FDA for measurement of PD-L1 expression.188,189 All of
these approvals have been based on category 2 level evidence with the
Targeted Therapies exception of pembrolizumab as a subsequent treatment option, which
Platinum-based chemotherapy has been the standard of care in has category 1 level evidence supporting the approval.214
patients with metastatic disease with an OS of 9 to 15 months.194,206
Pembrolizumab
However, in patients with disease that relapses after this type of
chemotherapy, the median survival is reduced to 5 to 7 months.207 Pembrolizumab is a PD-1 inhibitor that has been evaluated as
Several new agents, notably checkpoint inhibitors, have data supporting second-line therapy for patients with bladder cancer who previously
improved outcomes compared to standard therapies for metastatic received platinum-based therapy and subsequently progressed or
urothelial carcinoma. Additionally, the FGFR inhibitor, erdafitinib, and metastasized.215 An open-label, randomized, phase III trial compared
the antibody-drug conjugate, enfortumab vedotin, have demonstrated pembrolizumab to chemotherapy (paclitaxel, docetaxel, or vinflunine) in
effectiveness for the treatment of previously treated urothelial 542 patients with advanced urothelial carcinoma that recurred or
carcinoma. Cancers with higher rates of somatic mutations have been progressed after platinum-based chemotherapy. Data from this trial
shown to respond better to checkpoint inhibitors.208-213 Data from the showed a longer median OS for patients treated with pembrolizumab
Cancer Genome Atlas rank bladder cancer as the third highest mutated compared to chemotherapy (10.3 months vs. 7.4 months; P = .002). In
cancer,190,191 suggesting that checkpoint inhibitors may have a addition, fewer grade 3, 4, or 5 treatment-related AEs occurred in the
substantial impact as a treatment option for this cancer. pembrolizumab-treated patients compared to those treated with
chemotherapy (15.0% vs. 49.4%).216 Long-term results (>2 years’
The FDA has approved the PD-L1 inhibitors atezolizumab, durvalumab, follow-up) from this same phase III trial were consistent with earlier
and avelumab as well as the PD-1 inhibitors nivolumab and reports, with longer 1- and 2- year OS and PFS results for
pembrolizumab for patients with urothelial carcinoma. Pembrolizumab, pembrolizumab compared to chemotherapy.217 The median DOR was
atezolizumab, nivolumab, durvalumab, and avelumab are approved for not reached for pembrolizumab compared to 4.4 months for
the treatment of locally advanced or metastatic urothelial cell carcinoma chemotherapy. Pembrolizumab also showed lower rates of any grade
that has progressed during or after platinum-based chemotherapy or (62% vs. 90.6%) and grade ≥3 AEs (16.5% vs. 50.2%) compared to

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NCCN Guidelines Version 3.2020

Bladder Cancer

chemotherapy. Results from this phase 3 trial have led the NCCN Panel PD-L1 expression status on infiltrating immune cells in the tumor
to assign pembrolizumab a category 1 recommendation as a second- microenvironment. Grade 3 or 4 treatment-related or immune-mediated
line therapy. AEs occurred in 16% and 5% of patients, respectively. Furthermore,
there were no treatment-related deaths in this trial, which suggests
A single-arm, phase II trial evaluated pembrolizumab as a first-line good tolerability. At the investigator’s discretion, patients on this trial
therapy in 370 patients with advanced urothelial carcinoma who were could continue atezolizumab beyond RECIST progression.220 An
ineligible for cisplatin-based therapy. Data from this study showed an analysis of post-progression outcomes showed that those who
ORR of 24%, with 5% of patients achieving a complete response. continued atezolizumab had longer post-progression OS (8.6 months)
Grade 3 or higher treatment-related AEs occurred in 16% of patients compared to those who received a different treatment (6.8 months) and
treated with pembrolizumab at the time of data cutoff.218 In May 2018, those who received no further treatment (1.2 months).
the FDA issued a safety alert for the use of first-line pembrolizumab and
atezolizumab, which warned that early reviews of data from 2 ongoing The multicenter, randomized, controlled, phase III IMvigor-211 study
clinical trials (KEYNOTE-361 and IMvigor-130) showed decreased compared atezolizumab to chemotherapy (vinflunine, paclitaxel, or
survival for patients receiving pembrolizumab or atezolizumab as first- docetaxel) in 931 patients with locally advanced or metastatic urothelial
line monotherapy compared to those receiving cisplatin- or carboplatin- carcinoma following progression with platinum-based chemotherapy.221
based therapy.189 Based on these data, the pembrolizumab prescribing The primary endpoint of this study, median OS in patients with IC2/3
information was subsequently amended to restrict first-line use to PD-L1 expression levels (n = 234), showed no significant difference
patients who either 1) are not eligible for cisplatin-containing between atezolizumab and chemotherapy (11.1 months vs. 10.6
chemotherapy and whose tumors express PD-L1 as measured by a months; P = .41). Likewise, confirmed ORR was similar between
combined positive score (CPS) of at least 10; or 2) are not eligible for atezolizumab and chemotherapy treatments in this group of patients
any platinum-containing chemotherapy regardless of PD-L1 status.83 (23% vs. 22%). While atezolizumab was not associated with
significantly longer OS compared to chemotherapy, the safety profile of
Atezolizumab
atezolizumab was favorable, with 20% of patients experiencing grade 3
Data from the two-cohort, multicenter, phase II IMvigor-210 trial or 4 adverse effects compared to 43% with chemotherapy.
evaluated atezolizumab in patients with metastatic disease. Cohort 2 of Atezolizumab was also associated with a longer DOR than
the trial enrolled 310 patients with metastatic urothelial carcinoma post- chemotherapy, including durable responses, consistent with the
platinum treatment and showed a significantly improved ORR compared observations in the previous phase II study.
to historical controls (15% vs. 10%; P = .0058).219 Follow-up to date
suggests these responses may be durable with ongoing responses The phase IIIb SAUL study evaluated atezolizumab in 1004 patients
recorded in 38 (84%) of 45 responders with a median follow-up of 11.7 with pretreated, locally advanced or metastatic urothelial or
months. Although a similar response rate was seen regardless of PD-L1 nonurothelial carcinoma of the urinary tract.222 This study sought to
status of tumor cells, a greater response was associated with increased evaluate the safety and efficacy of atezolizumab in patients more similar

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Bladder Cancer

to the real-world population, including those ineligible for IMvigor-211. platinum-containing regimen reported an ORR in 52 of 265 patients
Median OS was 8.7 months (95% CI, 7.8–9.9), median PFS was 2.2 (19.6%; 95% CI, 15.0–24.9) following treatment with nivolumab that was
months (95% CI, 2.1–2.4), and the ORR was 13% (95% CI, 11%–16%). unaffected by PD-1 tumor status.226 Out of the 270 patients enrolled in
Grade ≥3 AEs occurred in 45% of patients, leading 8% to discontinue the study, grade 3 or 4 treatment-related AEs were reported in 18% of
treatment based on toxicity. These results confirmed the tolerability of patients. Three patient deaths were the result of treatment.226 The
atezolizumab in a real-world, pretreated population, with similar efficacy median OS was 8.74 months (95% CI, 6.05–not yet reached). Based on
results to the pivotal clinical trial.222 Another, smaller, expanded access PD-L1 expression of less than 1% and 1% or greater, OS was 5.95
study of atezolizumab in patients with pretreated metastatic urothelial months to 11.3 months, respectively. These data are comparable to the
carcinoma reached a similar conclusion.223 phase I/II data that reported an ORR of 24.4% (95% CI, 15.3%–35.4%)
that was unaffected by PD-1 tumor status. Out of the 78 patients
In cohort 1 of the above-mentioned IMvigor-210 trial, atezolizumab was enrolled in this study, 2 experienced grade 5 treatment-related AEs, and
evaluated as a first-line therapy in 119 patients with locally advanced or grade 3 or 4 treatment-related AEs were reported in 22% of patients.227
metastatic urothelial carcinoma who were ineligible for cisplatin. Data An extended follow-up of this same phase I/II study (minimum follow-up
from this study showed an ORR of 23% with 9% of patients showing a of 37.7 months) reported a similar ORR of 25.6% (95% CI, 16.4%–
complete response. Median OS was 15.9 months. Grade 3 or 4 36.8%) for nivolumab monotherapy, with a median DOR of 30.5
treatment-related AEs occurred in 16% of patients.224 In May 2018, the months.228
FDA issued a safety alert for the use of first-line pembrolizumab and
atezolizumab, which warned that early reviews of data from 2 ongoing Durvalumab
clinical trials (KEYNOTE-361 and IMvigor-130) showed decreased Early results from a phase I/II multicenter study of durvalumab for 61
survival for patients receiving pembrolizumab or atezolizumab as first- patients with PD-L1–positive inoperable or metastatic urothelial bladder
line monotherapy compared to those receiving cisplatin- or carboplatin- cancer who have tumor that has progressed during or after one
based therapy.189 Based on these data, the atezolizumab prescribing standard platinum-based regimen showed that 46.4% of patients who
information was subsequently amended to restrict first-line use to were PD-L1 positive had disease that responded to treatment; no
patients who either 1) are not eligible for cisplatin-containing response was seen in patients who were PD-L1 negative.229 A 2017
chemotherapy and whose tumors express PD-L1 as measured by PD- update on this study (N = 191) showed an ORR of 17.8% (27.6% ORR
L1–stained tumor-infiltrating immune cells covering at least 5% of the for PD-L1–high disease and a 5.1% ORR for PD-L1–low or –negative
tumor area; or 2) are not eligible for any platinum-containing disease). Median OS was 18.2 months, with 55% of patients surviving
chemotherapy regardless of the level of tumor PD-L1 expression.225 at 1 year. Median DOR was not yet reached at time of data cutoff.
Grade 3 or 4 treatment-related AEs occurred in 6.8% of treated patients
Nivolumab and 4 patients had a grade 3 or 4 immune-mediated AE.230
Data from a phase II trial in patients with locally advanced or metastatic
urothelial carcinoma who progressed after at least one

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Avelumab has progressed during or after platinum-based chemotherapy and

Avelumab is another PD-L1 inhibitor currently in clinical trials to whose tumors have susceptible FGFR3 or FGFR2 genetic
evaluate its activity in the treatment of bladder cancer. Results from the alterations.234
phase 1b trial for 44 patients with platinum-refractory disease
demonstrated an ORR of 18.2% that consisted of 5 complete responses Enfortumab Vedotin
and 3 partial responses following treatment with avelumab. The median Enfortumab vedotin is a Nectin-4-directed antibody–drug conjugate that
PFS was 11.6 weeks and the median OS was 13.7 months with a has been evaluated in a global, phase II, single-arm study of 125
54.3% OS rate at 12 months. Grade 3 or 4 treatment-related AEs patients with metastatic urothelial carcinoma who had previously
occurred in 6.8% of patients treated with avelumab.231 A pooled received both a platinum-containing chemotherapy regimen and a PD-
analysis of two expansion cohorts of the same trial reported results for 1/PD-L1 checkpoint inhibitor. The confirmed ORR was 44% (95% CI,
249 patients with platinum-refractory metastatic urothelial carcinoma or 35.1%–53.2%), including 12% complete responses. Similar response
who were ineligible for cisplatin-based chemotherapy. Of the 161 post- rates were seen in subgroups of patients with liver metastases and in
platinum patients with at least 6 months of follow-up, the ORR as those with no response to prior checkpoint inhibitor therapy. The
determined by independent review was 17%, with 6% reporting median DOR was 7.6 months. Grade ≥3 treatment-related AEs were
complete responses and 11% reporting partial responses. Grade 3 or 4 reported in 54% of patients and treatment-related AEs lead to dose
treatment-related AEs occurred in 8% of patients and, likewise, 8% of reductions or discontinuation of therapy in 32% and 12% of patients,
patients had a serious AE related to treatment with avelumab.232 respectively.235

Erdafitinib NCCN Recommendations for Targeted Therapies

Erdafitinib is a pan-FGFR inhibitor that has been evaluated in a global, Based on these data, the NCCN Panel recommends pembrolizumab,
open-label phase II trial of 99 patients with a prespecified FGFR atezolizumab, nivolumab, durvalumab, avelumab, or erdafitinib as
alteration who had either previously received chemotherapy or who preferred second-line systemic therapy options after platinum-based
were cisplatin ineligible, chemotherapy naïve. Of these patients, 12% therapy. Atezolizumab and pembrolizumab are also recommended as
were chemotherapy naïve and 43% had received 2 or more prior lines preferred first-line therapy options for patients who are not eligible for
of therapy. The confirmed ORR was 40% (95% CI, 31%–50%), cisplatin-containing chemotherapy and whose tumors express PD-L1 or
consisting of 3% complete responses and 37% partial responses. in patients who are not eligible for any platinum-containing
Among patients who had previously received immunotherapy, the chemotherapy regardless of PD-L1 expression for locally advanced or
confirmed ORR was 59%. Median PFS was 5.5 months and the median metastatic disease. In addition to chemotherapy options, erdafitinib is
OS was 13.8 months. Grade ≥3 treatment-related AEs were reported in also recommended for second-line systemic therapy following a first-line
46% of patients and 13% of patients discontinued treatment due to checkpoint inhibitor and as a third- or subsequent-line therapy option for
AEs.233 Based on these data, the FDA has approved erdafitinib for patients who have already received both a platinum-containing therapy
patients with locally advanced or metastatic urothelial carcinoma that and a checkpoint inhibitor, if eligible on the basis of FGFR3 or FGFR2

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NCCN Guidelines Version 3.2020

Bladder Cancer

genetic alterations. Enfortumab vedotin is also recommended as a have benefit in patients with small cell carcinoma of the bladder and is
preferred subsequent-line systemic therapy option. See the Principles of recommended by the panel for any patient with small-cell component
Systemic Therapy within the algorithm for more information on these histology with localized disease regardless of stage.236-240 In addition, a
recommendations. With the exception of pembrolizumab as a second- retrospective analysis has shown that neoadjuvant chemotherapy may
line, post-platinum treatment option (category 1), the use of targeted have a modest benefit for other variant histologies.241 In patients with
therapies are all category 2A recommendations. non-urothelial carcinomas of any stage, no data support the use of
adjuvant chemotherapy, although the risk for relapse may be high.
Non-Urothelial Carcinomas of the Bladder Some of the general principles of management applicable to urothelial
Approximately 10% of bladder tumors are non-urothelial carcinomas are appropriate with minor variations.
(non-transitional cell) carcinoma. These pathologic entities include
mixed histology, pure squamous, adenocarcinoma, small cell tumors, Patients with small cell carcinoma of the bladder are best treated with
urachal carcinoma, or primary bladder sarcoma. Depending on the initial chemotherapy (see NCCN Guidelines for Small Cell Lung Cancer)
pathologic findings, adjuvant chemotherapy may or may not be followed by either RT or cystectomy as consolidation, if there is no
recommended. The regimens effective for urothelial carcinoma metastatic disease. Concurrent chemoradiotherapy is also an option for
histologies have limited efficacy for patients with non-urothelial these patients.242 Primary bladder sarcomas are treated as per the
carcinomas. NCCN Guidelines for Soft Tissue Sarcoma.

These individuals are often treated based on the identified histology. In Upper Tract Urothelial Carcinoma (UTUC)
general, patients with non-urothelial invasive disease are treated with Upper tract tumors, including those that originate in the renal pelvis or in
cystectomy, although those with certain urachal tumors require the ureter, are relatively uncommon.243 The treatment recommendations
complete urachal resection (en bloc resection of the urachal ligament discussed in this section are based on the most common histology of
with the umbilicus) or may be appropriately treated with partial upper tract tumors, urothelial carcinoma.
cystectomy. For example, adenocarcinomas are managed surgically
with radical or partial cystectomy and with individualized adjuvant Renal Pelvis Tumors
chemotherapy and radiotherapy for maximum benefit. Pure squamous Tumors that develop in the renal pelvis may be identified during
cell tumors are treated by cystectomy, RT, or agents commonly used for evaluation of hematuria or a renal mass. In the latter case, renal pelvic
squamous cell carcinoma of other sites such as 5-FU or taxanes. tumors must be distinguished from the more typical adenocarcinomas
However, overall experience with chemotherapy in non-urothelial that originate in the renal parenchyma. These tumors may also be
carcinomas is limited. detected during an assessment to pinpoint the source of a positive
cytology in the setting of a negative cystoscopy with a retrograde
Data are limited to support perioperative chemotherapy for ureteropyelography.
non-urothelial carcinomas; however, neoadjuvant chemotherapy may

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Bladder Cancer

Workup there is no perforation. The data supporting the use of neoadjuvant

The evaluation of a patient with a suspected renal pelvic tumor should chemotherapy for UTUC are more limited and retrospective; however, a
include cystoscopy and imaging of the upper tract collecting system with meta-analysis of 4 trials shows that neoadjuvant chemotherapy may
CT or MR urography; renal ultrasound or CT without contrast with also improve outcomes compared to no perioperative treatment.248
retrograde ureteropyelography; or ureteroscopy with biopsy and/or While mitomycin is most commonly used, gemcitabine is an option for
selective washings. A chest radiograph can help evaluate for possible select patients.
metastasis and assess any comorbid diseases that may be present.
Urine cytology obtained from a urine sample or during a cystoscopy Alternatively, a nephron-sparing procedure through a transureteroscopic
may help identify carcinoma cells. Hematologic, renal, and hepatic approach or a percutaneous approach may be used, with or without
function should also be evaluated. Additional imaging studies, such as a postsurgical intrapelvic chemotherapy or BCG. High-grade tumors or
renal scan or bone scan, may be needed if indicated by the test results those that are large and/or invade the renal parenchyma are managed
or by the presence of specific symptoms. Recent evidence has through nephroureterectomy with a bladder cuff and regional
suggested a high prevalence of Lynch syndrome in patients with lymphadenectomy with or without perioperative intravesical
UTUC.7,244 Therefore, it is recommended to take a thorough family chemotherapy. Decline in renal function following surgery may preclude
history for all patients with UTUC and consider evaluation for Lynch adjuvant therapy. Hence, in selected patients, neoadjuvant
syndrome for those who are at high risk (see NCCN Guidelines for chemotherapy may be considered based on extrapolation of data from
Genetic/Familial High-Risk Assessment: Colorectal for more bladder cancer series.116-118 If metastatic disease is documented, or
information). comorbid conditions that do not allow for surgical resection are present,
treatment should include systemic therapy with regimens similar to
Primary Treatment those used for metastatic urothelial bladder tumors.
In general, the primary form of treatment for renal pelvic tumors is
surgery. In the settings of positive upper tract cytology but negative imaging and
biopsy studies, treatment remains controversial and appropriate
Well-differentiated tumors of low grade may be managed with a management is currently poorly defined. Frequent monitoring for
nephroureterectomy with a bladder cuff with or without perioperative disease is necessary for these patients.
intravesical chemotherapy. Several prospective, randomized, clinical
trials have shown a reduction of risk of bladder recurrence following Endoscopic Management of UTUC
nephroureterectomy when a single postoperative intravesical instillation Nephron-sparing endoscopic treatment is a treatment option for certain
of chemotherapy was administered.245-247 While the studies have patients with UTUC, depending on clinical and pathologic criteria and/or
generally looked at early instillation (within 24–48 hours of the presence of comorbid conditions that may contraindicate
surgery),246,247 some centers are delaying intravesical instillation of nephroureterectomy. Favorable clinical and pathologic criteria for
chemotherapy by up to a week to administer a cystogram confirming nephron preservation include a papillary, unifocal, low-grade tumor, and
size <1.5 cm, where cross-sectional imaging shows no concern for
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NCCN Guidelines Version 3.2020

Bladder Cancer

invasive disease.243,249 Although there are no randomized controlled disease. Follow-up should be the same as pT0/pT1 disease with the
trials, systematic reviews of retrospective studies have shown that addition of chest imaging and a stronger recommendation for cytology.
nephron-sparing approaches show similar outcomes compared to
nephroureterectomy for these patients.250,251 In addition, patients with Urothelial Carcinoma of the Ureter
bilateral disease, solitary functional or anatomic kidney, chronic kidney Ureteral tumors may develop de novo or in patients who have
disease, renal insufficiency, or a hereditary predisposition to undergone successful treatment for superficial tumors that originate in
genitourinary cancers are contraindicated from nephroureterectomy and the bladder. The presentation varies as a function of disease extent.
should receive nephron-sparing treatment.243,252 Long-term surveillance Ureteral tumors may be identified in patients who have a positive
(>5 years), including urine cytology and cross-sectional urography or cytology with a negative cystoscopy in whom selective catheterization of
endoscopic visualization, is required following nephron-sparing the ureters is performed. More extensive lesions may result in pain or
treatment due to a high risk of disease recurrence.243 obstruction.

Follow-up Workup
Subsequent management is dictated by the extent of disease at The evaluation is similar to that outlined for tumors that originate in the
surgery. Tumors that are pT0 or pT1 should be followed up with serial renal pelvis.
cystoscopies at 3-month intervals for the first year and, if negative, at
Primary Treatment
longer intervals. Cytology may also be considered at similar intervals for
high-grade tumors. Tumors that are pT0 or pT1 and were treated with For resectable ureteral tumors, the primary management is surgery (see
nephron-sparing surgery should also be followed up with ureteroscopy Endoscopic Management of UTUC within the Renal Pelvis Tumors
and upper tract imaging at 3- to 12-month intervals. section of this Discussion for more discussion of nephron-sparing
approaches). The specific procedure required varies depending on the
Data on role of adjuvant chemotherapy for patients with pT2, pT3, pT4, location of the tumor (upper, mid, or distal location) and disease extent.
or nodal disease has been mixed. A retrospective study of 1544 Neoadjuvant chemotherapy may be considered in selected patients,
patients meeting these criteria across 15 centers showed no difference such as when the degree of invasiveness is established before
in OS between adjuvant chemotherapy and observation following definitive surgery.248,255
radical nephroureterectomy (HR, 1.14; 95% CI, 0.91–1.43).253 On the
other hand, initial findings from a phase 3 trial that randomized patients Tumors that originate in the upper ureter occasionally can be managed
to 4 cycles of gemcitabine plus cisplatin/carboplatin or surveillance post endoscopically but more commonly are treated with
nephroureterectomy reported that adjuvant chemotherapy improved nephroureterectomy with a bladder cuff plus regional lymphadenectomy
PFS in this population (HR, 0.49; 95% CI, 0.30–.079; P = .003).254 OS for high-grade tumors. Neoadjuvant chemotherapy should be
analysis is ongoing for this trial. Based on these data, adjuvant considered in select patients, including patients with retroperitoneal
chemotherapy may be considered for patients with pT2–4 or nodal lymphadenopathy; bulky (>3 cm) high-grade tumor; sessile histology; or

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NCCN Guidelines Version 3.2020

Bladder Cancer

suspected parenchymal invasion. A portion of the bladder is removed to Tumors, above, for more discussion of the data on adjuvant therapy for
ensure complete removal of the entire intramural ureter. UTUC.

Tumors that originate in the mid portion can be divided by grade and Urothelial Carcinomas of the Prostate
size. Small, low-grade tumors can be managed with excision followed Urothelial (transitional cell) carcinomas of the prostate represent a
by ureteroureterostomy, segmental or complete ureterectomy, or ileal distinct entity with a unique staging system. In this respect, they must
ureter interposition in highly selected patients. Alternatively, endoscopic be distinguished from urothelial carcinomas of bladder origin that invade
resection or nephroureterectomy with a bladder cuff can be performed. into the prostate through the bladder wall. Urothelial carcinomas of the
Larger, high-grade lesions are managed with nephroureterectomy with prostate may occur de novo or, more typically, concurrently or after
a bladder cuff and regional lymphadenectomy. Neoadjuvant treatment of bladder cancer. Similar to tumors originating in other sites
chemotherapy can be considered in select patients. of the urothelium, management of prostate urothelial carcinomas is
based on the extent of disease with particular reference to the urethra,
Distal ureteral tumors may be managed with a distal ureterectomy and
duct, acini, and stroma.
regional lymphadenectomy if high grade followed by reimplantation of
the ureter (preferred if clinically feasible). Other primary treatment Workup
options include endoscopic resection, or, in some cases, a The evaluation of a suspected urothelial carcinoma of the prostate
nephroureterectomy with a bladder cuff, and regional lymphadenectomy includes a digital rectal examination (DRE), cystoscopy with bladder
if high grade. Neoadjuvant chemotherapy can be considered for select biopsy, and TURP that includes the prostatic stroma. Prostate-specific
patients with distal ureteral tumors following distal ureterectomy or the antigen testing should be performed. Multiple stromal biopsies are
nephroureterectomy with bladder cuff. advised and, if the DRE is abnormal, additional needle biopsies may be
Follow-up
required in selected patients to exclude primary adenocarcinoma of the
prostate. Upper tract collecting system imaging is also recommended.
The final pathologic stage is used to guide subsequent management, as
is the case for tumors that originate in other sites. No adjuvant therapy Primary Treatment
is advised for lesions that are pT1 or less, but serial follow-up of the Pending histologic confirmation, tumors that are limited to the mucosal
urothelial tracts or remaining unit (as previously described under Renal prostatic urethra with no acinar or stromal invasion can be managed
Pelvis Tumors) is recommended. with TURP and intravesical BCG, with follow-up similar to that for
superficial disease of the bladder. If local recurrence is seen,
Patients with more extensive disease are advised to consider systemic
cystoprostatectomy with or without urethrectomy is recommended.
adjuvant treatment with chemotherapy, depending on the patient’s
Patients with tumors that invade the ducts, acini, or stroma should
anticipated tolerance to the regimen based on comorbidities. The
undergo an additional workup with chest radiograph, and
reasons for considering adjuvant therapy are similar to those for tumors
abdominal/pelvic CT if necessary, to exclude metastatic disease, and
that originate in the bladder. Please see Follow-up for Renal Pelvis
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Bladder Cancer

then a cystoprostatectomy with or without urethrectomy should be Treatment

performed. Based on data extrapolated from bladder cancer therapy, Patients with Tis, Ta, or T1 disease should have a repeat transurethral
neoadjuvant chemotherapy may be considered in patients with stromal or transvaginal resection. In select cases, TURBT is followed by
invasion.116-118 Adjuvant chemotherapy may be advised for stromal intraurethral therapy with BCG, mitomycin, or gemcitabine. A total
invasion after primary treatment if neoadjuvant therapy was not given. urethrectomy may be considered if the patient has undergone a radical
Alternatively, TURP and intravesical BCG may be offered to patients cystectomy and cutaneous diversion.
with only ductal and acini invasion. Local recurrences in patients
undergoing TURP and BCG therapy are treated with Treatment for T2 disease is based on patient gender and tumor
cystoprostatectomy with or without urethrectomy. location. For male patients with pendulous urethra, a distal
urethrectomy or partial penectomy are viable options. Patients may
Primary Carcinoma of the Urethra consider neoadjuvant chemotherapy (category 2B) or chemoradiation
Primary carcinoma that arises in the urethra is rare. Unlike for bladder (category 2A) before a urethrectomy. Patients who have positive
cancer, squamous cell carcinoma is the most common histologic margins may undergo additional surgery or radiation, preferably with
subtype for urethral cancer.256 The 5-year OS is 42%.257,258 Stage and chemotherapy. At recurrence, options include systemic therapy, total
disease location are the most important prognostic factors for male penectomy, radiation, or a combination.
patients, while tumor size and histology are prognostically significant for
Male patients with T2 tumors in the bulbar urethra should undergo
female patients.256,258 Unfortunately, there is a lack of robust,
urethrectomy with or without cystoprostatectomy. Adjuvant
prospective data to support treatment decisions due to disease rarity.
chemotherapy or chemoradiation may be considered if pT3, pT4, or
Treatment recommendations typically encompass all of the respective
nodal disease is found. Recurrent cases may be treated with systemic
histologies (ie, squamous, transitional, adenocarcinomas) with the therapy and/or radiation.
treatment approach based on location (ie, proximal vs. distal urethral
tumors). Initial treatment options for female patients with T2 tumors include
chemoradiation or urethrectomy with cystectomy. Partial urethrectomy
Workup
is possible in a minority of cases, depending on tumor location, and has
A cystourethroscopy should be performed if carcinoma of the urethra is
been associated with a high local recurrence rate.259 At recurrence, the
suspected. This includes EUA and transurethral or transvaginal biopsy.
patient may receive systemic therapy or chemoradiotherapy (both
Chest x-ray and MRI of the pelvis are recommended to evaluate the
category 2A) or pelvic exenteration (category 2B). Pelvic exenteration
extent of the disease.
for T2 urethral cancer consists of en bloc removal of the urethra,
If palpable inguinal lymph nodes are present, a chest/abdominal/pelvic bladder, and anterior vagina.
CT and lymph node biopsy should be performed.
A multimodal treatment approach (ie, surgery, systemic therapy,
radiation) is common for advanced disease. A cohort study reported a
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NCCN Guidelines Version 3.2020

Bladder Cancer

72% response rate with the following treatment scheme before surgery: Summary
cisplatin, gemcitabine, and ifosfamide for squamous cell carcinoma; Urothelial tumors represent a spectrum of diseases with a range of
5-FU, gemcitabine, and cisplatin-based regimens for adenocarcinoma; prognoses. After a tumor is diagnosed anywhere within the urothelial
and MVAC for urothelial tumors.260 Combined chemoradiation with 5-FU tract, the patient remains at risk for developing a new lesion at the same
and mitomycin C has shown efficacy in a series of male patients with or a different location and with a similar or more advanced stage. For
squamous cell carcinoma of the urethra.261 Patients receiving surgery patients with non–muscle-invasive disease, continued monitoring for
after chemoradiation had a higher 5-year DFS rate (72%) than those recurrence is an essential part of management, because most
receiving chemoradiation alone (54%). If systemic therapy is used, the recurrences are non–muscle-invasive and can be treated
choice of regimen should be based on histology. endoscopically. Within each category of disease, more refined methods
to determine prognosis and guide management, based on molecular
Both male and female patients with T3 or T4 disease but no clinical
staging, are under development with the goal of optimizing each
nodes should receive neoadjuvant chemotherapy (if urothelial
patient’s likelihood of cure and chance for organ preservation.
carcinoma) followed by consolidative surgery or, if ineligible for standard
systemic chemotherapy, radiation or chemoradiation with or without For patients with more extensive disease, newer treatments typically
consolidative surgery. Consolidative surgery alone is an option for non- involve combined modality approaches using recently developed
urothelial histologies. If node-positive, chemoradiation is the preferred surgical procedures or 3-dimensional treatment planning for more
treatment for squamous cell carcinoma. Systemic therapy or precise delivery of RT. Although these are not appropriate in all cases,
chemoradiotherapy with or without consolidative surgery are also they offer the promise of an improved quality of life and prolonged
treatment options. At recurrence, the patient may undergo pelvic survival.
exenteration (category 2B) with or without ilioinguinal lymphadenectomy
and/or chemoradiotherapy. Pelvic exenteration for T3 urethral cancer Finally, within the category of metastatic disease, several new agents
consists of urethrectomy, cystectomy, prostatectomy in males, and have been identified that seem superior to those currently considered
anterior vaginectomy with hysterectomy in females. In women with standard therapies. Checkpoint inhibitors, in particular, have emerged
highly local advanced T4 tumors, the posterior vagina and rectum may as a new therapy for the treatment of persistent disease. Experts
also need to be removed en bloc with the specimen. Systemic therapy surmise that the treatment of urothelial tumors will evolve rapidly over
is a category 2B option. the next few years, with improved outcomes across all disease stages.

Patients with distant metastases should receive similar treatment as

metastatic bladder cancer. Systemic therapies include chemotherapy
and checkpoint inhibitors as subsequent-line options. However, it
should be noted that checkpoint inhibitors have only been evaluated in
patients with urothelial histology.

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Bladder Cancer

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