NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

Bladder Cancer
Version 5.2024 — October 28, 2024

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Bladder Cancer Discussion

*Thomas W. Flaig, MD †/Chair Jean Hoffman-Censits, MD † Charles Peyton, MD ϖ

University of Colorado Cancer Center The Sidney Kimmel Comprehensive O'Neal Comprehensive Cancer Center at UAB
Cancer Center at Johns Hopkins Elizabeth R. Plimack, MD, MS † Þ
*Philippe E. Spiess, MD, MS ¶ ϖ/Vice Chair Fox Chase Cancer Center
Moffitt Cancer Center Hristos Kaimakliotis, MD ϖ
Indiana University Melvin and Bren Simon *Mark A. Preston, MD, MPH ϖ
Michael Abern, MD ¶ ϖ Comprehensive Cancer Center Dana-Farber/Brigham and
Duke Cancer Institute Women’s Cancer Center
Amar U. Kishan, MD §
Neeraj Agarwal, MD ‡ † UCLA Jonsson Comprehensive Cancer Center Kyle Richards, MD ϖ
Huntsman Cancer Institute University of Wisconsin Carbone Cancer Center
at the University of Utah Shilajit Kundu, MD ϖ
Robert H. Lurie Comprehensive Cancer Wade J. Sexton, MD ¶, ϖ
*Rick Bangs, MBA ¥ Center of Northwestern University Moffitt Cancer Center
Patient Advocate *Arlene O. Siefker-Radtke, MD †
*Subodh M. Lele, MD ≠
Mark K. Buyyounouski, MD, MS § Fred & Pamela Buffett Cancer Center The University of Texas
Stanford Cancer Institute MD Anderson Cancer Center
Ronac Mamtani, MD, MSCE †
Kevin Chan, MD ϖ Abramson Cancer Center *Tyler Stewart, MD †
City of Hope National Medical Center at the University of Pennsylvania UC San Diego Moores Cancer Center
*Sam S. Chang, MD, MBA ¶, ϖ Omar Y. Mian, MD, PhD § *Debasish Sundi, MD ϖ
Vanderbilt-Ingram Cancer Center Case Comprehensive Cancer Center/ The Ohio State University Comprehensive
Paul Chang, MD § University Hospitals Seidman Cancer Center and Cancer Center - James Cancer Hospital
Cleveland Clinic Taussig Cancer Institute and Solove Research Institute
The UChicago Medicine Comprehensive Cancer
Center Jeff Michalski, MD, MBA § Matthew Tollefson, MD ϖ
Siteman Cancer Center at Barnes- Mayo Clinic Comprehensive Cancer Center
*Terence Friedlander, MD †
UCSF Helen Diller Family Jewish Hospital and Washington Jonathan Tward, MD, PhD §
Comprehensive Cancer Center University School of Medicine Huntsman Cancer Institute
Jeffrey S. Montgomery, MD, MHSA ϖ at the University of Utah
Richard E. Greenberg, MD ϖ
Fox Chase Cancer Center University of Michigan Rogel Cancer Center Jonathan L. Wright, MD, MS ϖ
*Mamta Parikh, MD, MS † Fred Hutchinson Cancer Center
Khurshid A. Guru, MD ¶, ϖ
Roswell Park Comprehensive Cancer Center UC Davis Comprehensive Cancer Center NCCN
Harry W. Herr, MD ϖ Anthony Patterson, MD ϖ Lisa Gurski, PhD
Memorial Sloan Kettering Cancer Center St. Jude Children’s Research Hospital/ Bailee Sliker, PhD
The University of Tennessee Carly J. Cassara, MSc
Health Science Center

‡ Hematology/Hematology § Radiotherapy/Radiation
oncology oncology
Þ Internal medicine ¶ Surgery/Surgical oncology
† Medical oncology ϖ Urology
NCCN Guidelines Panel Disclosures Continue ≠ Pathology * Discussion writing
¥ Patient advocacy committee member
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NCCN Guidelines Version 5.2024 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) Find an NCCN Member Institution:
Risk Stratification of NMIBC (BL-2) https://www.nccn.org/home/member-
Management per NMIBC Risk Group (BL-3) institutions.
Management of Positive Urine Cytology (BL-4) NCCN Categories of Evidence and
• Muscle Invasive or Metastatic, Primary Evaluation/Surgical Treatment, Additional Workup (BL-1) Consensus: All recommendations
Stage II (cT2, N0) Primary and Subsequent Treatment (BL-5) are category 2A unless otherwise
Stage IIIA (cT3, N0; cT4a, N0; cT1–cT4a, N1) Primary and Subsequent Treatment (BL-7) indicated.
Stage IIIB (cT1–cT4a, N2,3) Primary and Subsequent Treatment (BL-8) See NCCN Categories of Evidence
Stage IVA (cT4b, Any N, M0; Any T, Any N, M1a) Primary and Subsequent Treatment (BL-9) and Consensus.
Metastatic Disease, Additional Workup, Primary Treatment (BL-10) NCCN Categories of Preference:
Follow-up, Recurrent, or Persistent Disease (BL-11) All recommendations are considered
• Principles of Imaging for Bladder/Urothelial Cancer (BL-A) appropriate.
• Principles of Surgical Management (BL-B) See NCCN Categories of Preference.
• Principles of Pathology Management (BL-C)
• Bladder Cancer: Non-Urothelial and Urothelial with Subtype Histology (BL-D)
• Follow-up (BL-E)
• Principles of Instillation Therapy (BL-F) Upper Genitourinary (GU) Tract Tumors
• Principles of Systemic Therapy (BL-G) • Renal Pelvis (UTT-1)
• Principles of Radiation Management of Invasive Disease (BL-H) • Urothelial Carcinoma of the Ureter (UTT-2)
• Urothelial Carcinoma of the Prostate (UCP-1)
• Primary Carcinoma of the Urethra (PCU-1)
• Staging (ST-1)
• Abbreviations (ABBR-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. ©2024.
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Table of Contents
Bladder Cancer Discussion

Terminologies in all NCCN Guidelines are being actively modified to advance the goals of equity, inclusion, and representation.
Updates in Version 5.2024 of the NCCN Guidelines for Bladder Cancer from Version 4.2024 include:
BL-G 2 of 7
• Footnote * added: Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and
hyaluronidase-tqjs has different dosing and administration instructions compared to atezolizumab for intravenous infusion.
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 4.2024 of the NCCN Guidelines for Bladder Cancer from Version 3.2024 include:
BL-3
• High risk, BCG unresponsive, regimen added: Nogapendekin alfa inbakiceptpmln + BCG (select patients)
• Footnote v added: Nogapendekin alfa inbakicept-pmln in combination with BCG may be considered for the treatment of patients with BCG-
unresponsive, high-risk NMIBC with CIS (with or without papillary) tumors.
BL-8
• Footnote gg modified: Molecular/genomic testing in a Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory, including FGFR RGQ
RT-PCR for FGFR3 genetic alterations and IHC for HER2 overexpression. See Discussion. (Also for BL-9 and BL-10)
BL-G 4 of 7
• Useful in certain circumstances regimen added: fam-trastuzumab deruxtecan-nxki (HER2-positive, IHC 3+)
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 3.2024 of the NCCN Guidelines for Bladder Cancer from Version 2.2024 include:
MS-1
• The discussion section has been updated to reflect the changes in the algorithm.

Updates in Version 2.2024 of the NCCN Guidelines for Bladder Cancer from Version 1.2024 include:
• BL-G 2 of 7
• Cisplatin eligible, preferred regimens: Pembrolizumab and enfortumab vedotin-ejfv changed from a category 2A to a category 1 recommendation
• Cisplatin eligible, moved from preferred regimens to other recommended regimens
Gemcitabine and cisplatin (category 1) followed by avelumab maintenance therapy (category 1)
Nivolumab, gemcitabine, and cisplatin followed by nivolumab maintenance therapy changed from a category 2A to a category 1 recommendation
• Cisplatin eligible, moved from preferred regimens to useful under certain circumstances regimens
DDMVAC with growth factor support (category 1) followed by avelumab maintenance therapy (category 1)
• Cisplatin ineligible, preferred regimens: Pembrolizumab and enfortumab vedotin-ejfv changed from a category 2A to a category 1 recommendation
• Cisplatin ineligible, moved from preferred regimens to other recommended regimens
Gemcitabine and carboplatin followed by avelumab maintenance therapy (category 1)
• Cisplatin ineligible, moved from other recommended regimens to useful in certain circumstances regimens
Gemcitabine
Continued
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Gemcitabine and paclitaxel

Atezolizumab (only for patients whose tumors express PD-L1) (category 2B)
BL-G 6 of 7
• Reference updated: Powles T, Perez-Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab
vedotin in combination with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma [Abstract
LBA6]. Abstract presented at: European Society for Medical Oncology Congress October 22, 2023; Madrid, Spain. Powles T, Valderrama B, Gupta S, et
al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875-888

Updates in Version 1.2024 of the NCCN Guidelines for Bladder Cancer from Version 3.2023 include:
Global Updates
• The word variant has been replaced with subtype
BL-1
• Initial Evaluation
Bullet 2 modified: Consider germline testing and genetic counselor referral especially if younger age at presentation (<45 years) and/or personal or
family history of colon/endometrial Lynch syndrome-related cancer
Bullet 3 modified: Office cystoscopy, enhanced if available
• Footnote modified: See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal – Criteria for the Evaluation of Lynch Syndrome
Based on Personal or Family History of Cancer.
BL-3
• Initial management, high/BCG unresponsive or BCG intolerant: or Nadofaragene firadenovec-vncg (select patients)
• Footnotes modified
t: Pembrolizumab is indicated may be considered for the treatment of patients with BCG-unresponsive, high-risk NMIBC with Tis (with or without
papillary) tumors (category 2A) or with BCG-unresponsive, high-risk NMIBC with high-grade papillary Ta/T1 only tumors without Tis (category 2B) who
are ineligible for or have elected not to undergo cystectomy.
u: Nadofaragene firadenovec-vncg is indicated may be considered for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with
CIS (with or without papillary) (category 2A) and may also be considered for patients or with BCG-unresponsive, high-risk, NMIBC with high-grade
papillary Ta/T1 only tumors without CIS (category 2B).
r: If not a cystectomy candidate, and recurrence is high-grade cTa or cT1, consider concurrent chemoradiotherapy (category 2B for cTa, category 2A
for cT1) or a clinical trial.
BL-4
• Page extensively revised
BL-5
• Additional workup, bullet modified: Bone scan or MRI if clinical suspicion or symptoms of bone matastases. (Also for BL-7 through BL-10)
BL-8
• Footnote ff modified: Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ RT-PCR for FGFR3 or FGFR2 genetic alterations.
(Also for BL-9, BL-10)
BL-11
• Preserved bladder pathway extensively revised
• Treatment of metastatic or local recurrence postcystectomy modified: See BL-10 Systemic therapy or Chemoradiotherapy (if no previous RT) or RT
BL-A 1 of 5
• Abdominal and Pelvic Imaging, bullet 2, sub-bullet 1 modified: Upper tract (CTU, MRU, intravenous pyelogram (IVP), or retrograde ureteropyelography Continued
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Bladder Cancer Discussion

Updates in Version 1.2024 of the NCCN Guidelines for Bladder Cancer from Version 3.2023 include:
with CT or US, or ureteroscopy) and abdomen/pelvis imaging at baseline. For patients with high-risk NMIBC, upper tract imaging also should be
performed at 12 months and every 1–2 years thereafter up to 10 years.
BL-B 1 of 4
• Bullet removed: Immediate postoperative intravesical chemotherapy within 24 hours is recommended if NMIBC and if no concern for bladder perforation
and visibly complete resection.
• Sub-bullet removed: Gemcitabine (preferred) (category 1) and mitomycin (category 1) are the most commonly used options for intravesical
chemotherapy.
BL-B 2 of 4
• Bullets removed to prevent repetition with other principles sections
• Partial cystectomy
Bullet modified: Bilateral pelvic lymphadenectomy should be performed and include common, internal iliac, external iliac, and obturator nodes. (Also
for Radical Cystectomy/Cystoprostatectomy).
BL-B 3 of 4
• Bullets removed to prevent repetition with other principles sections
• Regional Lymphadenectomy
Bullet added: Endoscopic lymph node dissections should be equivalent to open dissection.
Bullet added: For bladder, recommend pelvic lymph node dissection; for upper tract recommend regional lymph node dissection for high-grade
tumors.
Bullet removed: Recommended for patients with high-grade upper GU tract tumors.
Bullet removed: Left-sided renal pelvic, upper ureteral, and midureteral tumors
Bullet removed: Regional lymphadenectomy should include the paraaortic lymph nodes from the renal hilum to the aortic bifurcation.
Bullet removed: Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
Bullet removed: Right-sided renal pelvic, upper ureteral, and midureteral tumors
Bullet removed: Regional lymphadenectomy should include the paracaval lymph nodes from the renal hilum to the inferior vena cava (IVC) bifurcation.
Bullet removed: Most midureteral tumors will also include the common iliac, external iliac, obturator, and hypogastric lymph nodes.
Bullet removed: Distal ureteral tumors
Bullet removed: Regional lymphadenectomy should be performed and include the common iliac, external iliac, obturator, and hypogastric lymph
nodes.
BL-C 1 of 2
• Page extensively revised
BL-C 2 of 2
• Page extensively revised
BL-E 2 of 6
• Footnote c modified: Abdominal/pelvic imaging includes CT or MRI, or FDG-PET/CT (category 2B) (PET/CT not recommended for NMIBC).
BL-E 5 of 6
• Footnote modified: For patients who are not eligible for aggressive therapy, less frequent surveillance may be warranted (eg, cystoscopy every 6
months, extended to annually over time).
BL-F 1 of 4
• Immediate Postoperative Intravesical Chemotherapy
Continued
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Updates in Version 1.2024 of the NCCN Guidelines for Bladder Cancer from Version 3.2023 include:
Bullet added: Most efficacious in patients with low-grade, low-volume Ta urothelial cancer.
• Induction (Adjuvant) Intravesical Chemotherapy or BCG
Information related to BCG shortage was moved to BL-F 2 of 4 and revised.
• Maintenance Intravesical BCG
Information related to BCG shortage was moved to BL-F 2 of 4 and revised.
BL-F 2 of 4
• New section added:Intravesical BCG Principles during time of BCG shortage
BL-F 3 of 4
• Intrapelvic and Intravesical Therapy for Upper Tract Tumors
Postsurgical therapy, bullet 2, sub-bullet 2 modified: Perioperative intravesical chemotherapy with mitomycin or gemcitabine should be strongly
considered following nephroureterectomy with cuff of bladder resection as randomized trials have shown a decrease in intravesical recurrence.
BL-F 4 of 4
• References added:
O'Brien T, Ray E, Singh R, et al. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a
prospective, multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial) Eur Urol 2011;60:703-
710.
Ito A, Shintaku I, Satoh M, et al. Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory
analysis from the THPMG trial. Jpn J Clin Oncol 2013;43:1139-1144.
Yoo SH, Jeong CW, Kwak C, et al. Intravesical Chemotherapy after Radical Nephroureterectomy for Primary Upper Tract Urothelial Carcinoma: A
Systematic Review and Network Meta-Analysis. J Clin Med 2019;8:1059.
Freifeld Y, Ghandour R, Singla N, et al. Intraoperative prophylactic intravesical chemotherapy to reduce bladder recurrence following radical
nephroureterectomy. Urol Oncol 2020;38:737.e11-737.e16.
BL-G 1 of 7
• Bullet 8 modified: Neoadjuvant chemotherapy may be considered for select patients is preferred for patients with UTUC, particularly for higher stage
and/or grade tumors or concerning radiographic findings, as renal function will decline after nephroureterectomy and may preclude adjuvant therapy.
• Sub-bullet 1 added: Multicenter data supports the use of neoadjuvant, split-dose cisplatin-based chemotherapy (gemcitabine and cisplatin) for patients
with high-grade UTUC. Staging for UTUC is less precise than for bladder cancers and under-staging is common, necessitating discussion on the risk of
under- versus over-treatment.
• Reference added: Coleman J, Yip W, Wong N, et al. Multicenter Phase II Clinical trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for
Patients with High-Grade Upper Tract Urothelial Carcinoma. J Clin Oncol 2023;41:1618-1625.
BL-G 2 of 7
• Cisplatin eligible
Bullet added: Nivolumab, gemcitabine, and cisplatin followed by nivolumab maintenance therapy
Bullet added: Pembrolizumab and enfortumab vedotin-ejfv
• Cisplatin ineligible
Useful under certain circumstances, bullet modified: Atezolizumab (only for patients who are not eligible for any platinum-containing chemotherapy
regardless of PD-L1 expression) (category 32B)
Category of Preference changed from "preferred" to "useful under certain circumstances" for pembrolizumab (for the treatment of patients with locally
Continued
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Updates in Version 1.2024 of the NCCN Guidelines for Bladder Cancer from Version 3.2023 include:
advanced or metastatic urothelial carcinoma who are not eligible for any platinum-containing chemotherapy)
• References added
van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabinecisplatin in advanced urothelial carcinoma. N Engl J Med
2023;389:1778-1789.
Powles T, Perez-Valderrama B, Gupta S, et al. EV-302/KEYNOTE-A39: Open-label, randomized phase III study of enfortumab vedotin in combination
with pembrolizumab vs chemotherapy in previously untreated locally advanced or metastatic urothelial carcinoma [Abstract LBA6]. Abstract presented
at: European Society for Medical Oncology Congress October 22, 2023; Madrid, Spain.
BL-G 3 of 7
• Second-Line Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV) (post-checkpoint inhibitor)
Preferred regimens for cisplatin ineligible, chemotherapy naïve, bullet added: erdafitinib
Preferred regimens for cisplatin eligible, chemotherapy naïve, bullet added: erdafitinib
Other recommended regimens bullet removed: erdafitinib
• Added: For patients who received a first-line platinum-containing chemotherapy followed by immune checkpoint inhibitor maintenance therapy or first-
line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor, see subsequent-line options on BL-G 4 of 7
• Footnote d modified: Only for patients with susceptible FGFR3 or FGFR2 genetic alterations. (Also for BL-G 4 of 7)
BL-G 4 of 7
• Preferred regimens, bullet 2: Erdafitinib (category 1)
• Footnote modified: These therapies are appropriate for patients who received a first-line platinum-containing chemotherapy followed by avelumab
checkpoint inhibitor maintenance therapy or first-line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor.
BL-H 1 of 3
• Bullet 5 modified: Concurrent chemoradiotherapy or RT alone is most successful for patients without moderate/severe hydronephrosis and without
extensive CIS associated with their muscle-invading tumor.
UTT-1
• Workup, bullet removed: Family history; for those at high risk, consider evaluation for Lynch syndrome (<60 y at presentation, personal history of colon/
endometrial cancer).
• Workup, bullet added: Consider germline testing and genetic counselor referral if younger age at presentation and/or personal or family history of Lynch
syndrome-related cancer.
• Primary treatment for high grade modified: Nephroureterectomy with cuff of bladder + regional lymphadenectomy ± perioperative intravesical
chemotherapy and consider cisplatin based neoadjuvant chemotherapy in selected patients
• Footnote modified: See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal. See NCCN Guidelines for Genetic/Familial High-Risk
Assessment: Colorectal – Criteria for the Evaluation of Lynch Syndrome Based on Personal or Family History of Cancer
UTT-2
• Workup, bullet 10 modified: Family history; for those at high risk, consider evaluation for Lynch syndrome Consider germline testing and genetic
counselor referral if younger age at presentation and/or personal or family history of Lynch syndrome-related cancer

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INTRODUCTION

NCCN and the NCCN Bladder Cancer Panel believe

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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CLINICAL INITIAL PRIMARY EVALUATION/ PRESUMPTIVE ADDITIONAL STAGING WORKUP

PRESENTATION EVALUATIONa SURGICAL TREATMENT CLINICAL
STAGEf,g
• H&P
• Consider germline cTah
testing and genetic
counselor referral Non-muscle invasive
if younger age at bladder cancer cT1h BL-2
• Examination under (NMIBC)
presentation and/
anesthesia (EUA)
or personal or family Tis
(bimanual)
history of Lynch
• TURBTd
syndrome-related Stage II
• Single-dose
cancerb (cT2, N0)h
BL-5
intravesical
• Office cystoscopy
chemotherapy
• Consider cytology
within 24 hours of Stage IIIA
Suspicion • Abdomen/pelvis • Complete blood
TURBTe (cT3, N0;
of bladder imagingc that includes count (CBC) BL-7
cancer imaging of upper urinary
Gemcitabine
• Chemistry profile, cT4a, N0;
tract collecting system
(preferred) Muscle
including alkaline cT1–T4a, N1)h
(category 1) or invasive
before transurethral phosphatase Stage IIIB
Mitomycin bladder BL-8
resection of bladder • Chest imagingc (cT1–T4a, N2,3)h
(category 1) cancer
tumor (TURBT) • Bone imagingc if
• Imagingc of upper (MIBC) Stage IVA
• Screen and actively clinical suspicion or (cT4b, Any N, M0; BL-9
tract collecting
promote smoking symptoms of bone Any T, Any N, M1a)h
system, if not
cessation (See NCCN metastases
previously done
Guidelines for Smoking Metastatic
Cessation) (Stage IVB BL-10
Any T, Any N, M1b)
a For tools to aid optimal assessment and comprehensive care of older adults with cancer, see NCCN Guidelines for Older Adult Oncology.
b NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal – Criteria for the Evaluation of Lynch Syndrome Based on Personal or Family History of Cancer.
c Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
d Principles of Surgical Management (BL-B).
e Immediate intravesical chemotherapy reduces the recurrence rate by 35% for selected patients. Most efficacious in patients with low-grade, low-volume Ta urothelial cancer. Post-TURBT intravesical

chemotherapy should not be utilized if concern for bladder perforation. See Principles of Instillation Therapy (BL-F).
f Principles of Pathology Management (BL-C).
g Bladder Cancer: Non-Urothelial and Urothelial with Subtype Histology (BL-D).
h The modifier “c” refers to clinical staging based on bimanual EUA, endoscopic surgery (biopsy or transurethral resection [TUR]), 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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Non-Muscle Invasive Bladder Cancer Discussion

RISK STRATIFICATION OF NMIBC

Low-grade
NMIBC
Visually complete Management
resection per NMIBC risk
Carcinoma in
group
High- situ (CIS) or Taj
Residual (BL-3)
Initial TURBT grade NMIBC
NMIBC T1 or or no residual
shows NMIBC
consider for cancer
select Taj Repeat TURBTk
Visually incomplete resection
or
MIBC BL-1
High-volume tumori

AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer*

Low Risk Intermediate Risk High Risk
• Papillary urothelial neoplasm of low • Low grade urothelial carcinoma • High grade urothelial carcinoma
malignant potential T1 or CIS or
• Low grade urothelial carcinoma >3 cm or T1 or
Ta and Multifocal or >3 cm or
≤3 cm and Recurrence within 1 year Multifocal
Solitary
• High grade urothelial carcinoma • Very high risk features (any):
Ta and BCG unresponsivel
≤3 cm and Variant histologiesm
Solitary Lymphovascular invasion
Prostatic urethral invasion
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;196:1021-1029.
*Within each of these risk strata an individual patient may have more or fewer concerning features that can influence care.

i High-volume tumors (large or highly multifocal) are at high risk of residual tumor. k Muscle should be present in repeat TURBT pathology specimen if possible.
j Consider repeat TURBT for high-grade Ta particularly if large, and/or no muscle in l Kamat AM, et al. J Clin Oncol 2016;34:1935-1944.
specimen. m Montironi R, et al. Int J Surg Pathol 2005;13:143-153.

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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Non-Muscle Invasive Bladder Cancer Discussion

MANAGEMENT PER NMIBC RISK GROUP

AUA RISK INITIAL MANAGEMENT FOLLOW-UP
GROUP
(SEE BL-2)
Low Surveillanceo

Intravesical therapyp,q • Cytology positive

(preferred) • Imaging negative BL-4
Intermediate or • Cystoscopy negative
Surveillance
Follow-up
Cystectomy (preferred) (BL-E)
Very-high-risk or If prior BCG,
featuresn BCGp maintenance
Bacillus
Calmette- BCGp Reclassify
Guérin (preferred) AUA Risk
BCGp (category 1, preferred)
(BCG) naïve No very-high- or Cystoscopy positive Group and
risk features Cystectomy manage
High accordingly
Cystectomyr (preferred)
or
BCG Intravesical chemotherapyp,s
unresponsive or
or Pembrolizumab (select patients)t
BCG intolerant or
Nadofaragene firadenovec-vncg
(select patients)u
or
Nogapendekin alfa inbakicept-
pmln + BCGv (select patients)
n Lymphovascular invasion, prostatic urethral involvement of tumor, subtype histology (eg, micropapillary, plasmacytoid, sarcomatoid).
o Should consider single perioperative instillation of intravesical chemotherapy at time of TURBT.
p See Principles of Instillation Therapy (BL-F).
q Options for intravesical therapy for intermediate-risk disease include BCG and chemotherapy; should consider BCG availability in decision-making.
r If not a cystectomy candidate, and recurrence is high-grade 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).
s Valrubicin is approved for BCG-refractory CIS.
t Pembrolizumab may be considered for the treatment of patients with BCG-unresponsive, high-risk NMIBC with Tis (with or without papillary) tumors (category 2A) or with BCG-unresponsive, high-risk NMIBC
with high-grade papillary Ta/T1 only tumors without Tis (category 2B) who are ineligible for or have elected not to undergo cystectomy.
u Nadofaragene firadenovec-vncg may be considered for the treatment of patients with BCG-unresponsive, high-risk, NMIBC with CIS (with or without papillary) (category 2A) or with BCG-unresponsive, high-
risk, NMIBC with high-grade papillary Ta/T1 only tumors without CIS (category 2B).
v Nogapendekin alfa inbakicept-pmln in combination with BCG may be considered for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS (with or without papillary) tumors.

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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Management of Positive Urine Cytology Discussion

RECURRENT OR EVALUATION TREATMENT

PERSISTENT
DISEASE
FOLLOW-UP
RESULTS Follow-up at 3 mo, then at longer
intervalsw
Bladder, prostate, and upper
or
tract negative
If prior BCG, maintenance BCGp
• If initial positive cytology, consider (optional)
repeating cytology test within 3
months
or Reclassify AUA Risk Group and
• If repeated positive cytology, Bladder positive
manage accordingly (BL-3)
Consider selected mapping
biopsies including transurethral
• Cytology positive
biopsy of prostated and
• Imaging negative
Cytology of upper tract and
• Cystoscopy
Consider ureteroscopy and
negative
Consider enhanced cystoscopyd
(if available) and
Consider non-urinary tract
source (eg, vagina, cervix, Urothelial Carcinoma of the
rectum) and referral to Prostate positive
Prostate (UCP-1)
gynecology or other specialist,
as appropriate.

Upper tract positive Upper GU Tract Tumors (UTT-1)

d Principles of Surgical Management (BL-B).

p Principles of Instillation Therapy (BL-F).
w Follow-up (BL-E).

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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Muscle Invasive Bladder Cancer Discussion

CLINICAL ADDITIONAL PRIMARY TREATMENT SUBSEQUENT TREATMENT

STAGINGh WORKUPc
Neoadjuvant cisplatin-based
combination chemotherapyz followed
by radical cystectomyd (category 1)
or Adjuvant Treatment (BL-6)
Neoadjuvant cisplatin-based
combination chemotherapyz followed
• Abdomen/pelvis If Tis, Ta, or T1, consider
by partial cystectomyd (highly
CT or MRIc,x if not TURBT +/- intravesical
selected patients with solitary lesion
previously done therapyp
in a suitable location; no Tis)
• Chest imaging or
or
(CT chest) If persistent T2,
Cystectomy alone for those not
• Bone scan or consider surgical
eligible to receive cisplatin-based
MRIc,x if clinical Reassess resection (ie, cystectomy
chemotherapy
suspicion or tumor status Tumor or partial cystectomy in
Stage II
symptoms of 2–3 months highly selected
(cT2, N0) or
bone metastases after cases)d
• Estimate treatment or
Bladder preservation with concurrent
glomerular
chemoradiotherapyaa,bb,cc (category completionbb Treat as metastatic
filtration rate disease (BL-10)
1) and maximal TURBT
(GFR) to assess Reassess Follow-
eligibility for No up
or tumor status tumor Surveillance
cisplatiny 2–3 months (BL-E)
If patient is not a candidate after Systemic therapydd or
for cystectomy or definitive treatment radiation therapy (RT)
chemoradiotherapy: completionbb alone (if no prior RT)bb
RTbb or
or TURBT ± intravesical
Tumor
TURBTd therapyp
and
Best supportive care
(See NCCN Guidelines
for Palliative Care)

Footnotes on BL-6
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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Muscle Invasive Bladder Cancer Discussion

ADJUVANT TREATMENT

• Based on pathologic risk,

If no cisplatin neoadjuvant treatment given and pT3, pT4a, or pN+
◊ Adjuvant cisplatin-based chemotherapy should be discussed (preferred)z
or
◊ Consider adjuvant nivolumabz,ee
Following
or Follow-up
cystectomy
If cisplatin neoadjuvant chemotherapy given and ypT2–ypT4a or ypN+, (BL-E)
consider nivolumabz,ee
or
Consider adjuvant RT in selected patients (pT3–4, positive nodes/margins at
the time of surgery)bb (category 2B)

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

c Principles of Imaging for Bladder/Urothelial Cancer (BL-A). bb Principles of Radiation Management of Invasive Disease (BL-H).
d Principles of Surgical Management (BL-B). cc Optimal
 candidates for bladder preservation with chemoradiotherapy include
h The modifier “c” refers to clinical staging based on bimanualEUA, endoscopic patients with tumors that present without moderate/severe hydronephrosis, are
surgery (biopsy or TUR), and imaging studies. The modifier “p” refers to without concurrent extensive or multifocal Tis, and are <6 cm. Ideally, tumors
pathologic staging based on cystectomy and lymph node dissection. should allow for a visually complete or maximally debulking TURBT. See
p Principles of Instillation Therapy (BL-F). Principles of Radiation Management of Invasive Disease (BL-H).
x Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). dd Principles of Systemic Therapy (BL-G 2 of 7).
y For patients with borderline GFR, consider timed urine collection, which may ee Most appropriate for patients who value an opportunity to delay recurrence even
more accurately determine eligibility for cisplatin. if the chance of cure was not improved, and for whom the risk of side effects was
z Principles of Systemic Therapy (BL-G 1 of 7). acceptable.

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 SUBSEQUENT TREATMENT

STAGINGh WORKUPc Neoadjuvant cisplatin-based
combination chemotherapyz followed
by radical cystectomyd,ff (category 1)
Adjuvant Treatment (BL-6)
or

• Abdomen/ Cystectomy alone for those not

pelvis CT or eligible to receive cisplatin-based
MRIc,x if not chemotherapyff If Tis, Ta, or T1, consider TURBT +/-
previously intravesical therapyp
done or Tumor or
• Chest imaging Reassess If persistent T2, consider surgical resection
Bladder preservation tumor
(CT chest) with concurrent (ie, cystectomy or partial cystectomy in
status 2–3 highly selected cases)d
Stage IIIA
• Bone scan chemoradiotherapyaa,bb,cc
or MRIc,x (category 1) and maximal months after or
(cT3, N0; TURBT treatment Treat as metastatic disease (BL-10)
if clinical Follow-
cT4a, N0;
suspicion or completionbb
cT1–cT4a, or No up
symptoms Surveillance (BL-E)
N1) tumor
of bone
If patient is not Reassess
metastases a candidate for
• Estimate GFR tumor
cystectomy or definitive status 2–3
to assess chemoradiotherapy:
eligibility for RTbb
months after Systemic therapydd
cisplatiny treatment or
or completionbb Tumor TURBT ± intravesical therapyp
and
TURBTd Best supportive care (See NCCN
c Principles of Imaging for Bladder/Urothelial Cancer (BL-A). Guidelines for Palliative Care)
d Principles of Surgical Management (BL-B).
h The modifier “c” refers to clinical staging based on bimanual EUA, endoscopic surgery (biopsy or
TUR), and imaging studies. The modifier “p” refers to pathologic staging based on cystectomy and
lymph node dissection.
p Principles of Instillation Therapy (BL-F). cc Optimal candidates for bladder preservation with chemoradiotherapy include patients with tumors that
x Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). present without moderate/severe hydronephrosis, are without concurrent extensive or multifocal Tis,
y For patients with borderline GFR, consider timed urine collection, which may more accurately and are <6 cm. Ideally, tumors should allow a visually complete or maximally debulking TURBT. See
determine eligibility for cisplatin. Principles of Radiation Management of Invasive Disease (BL-H).
z Principles of Systemic Therapy (BL-G 1 of 7). dd Principles of Systemic Therapy (BL-G 2 of 7).
aa Principles of Systemic Therapy (BL-G 5 of 7). ff Patients with cN1 disease have better outcomes if they are given neoadjuvant chemotherapy and have a
bb Principles of Radiation Management of Invasive Disease (BL-H). response.
Recurrent or
Note: All recommendations are category 2A unless otherwise indicated. 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 on
BL-11 BL-7
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Muscle Invasive Bladder Cancer Discussion

CLINICAL ADDITIONAL PRIMARY SUBSEQUENT TREATMENT

STAGINGh WORKUPc TREATMENT Consolidation cystectomyd
or
Complete
Consolidation
response
• Abdomen/ chemoradiotherapyaa,bb Follow-up
pelvis CT or or (BL-E)
MRIc,x if not Surveillance
previously Reassess
tumor Cystectomyd
done Downstaging Partial
status 2–3 or
• Chest imaging systemic therapydd response
months after Chemoradiotherapyaa,bb
(CT chest)
treatmenthh or
• Bone scan
Treat as metastatic disease (BL-10)
or MRIc,x
if clinical
Stage
suspicion or Progression Treat as metastatic disease (BL-10)
IIIB
symptoms
(cT1– or
of bone
cT4a,
metastases Complete
N2,3)
• Consider response
molecular/ Follow-up
If Tis, Ta, or T1, consider (BL-E)
genomic Reassess intravesical BCGp
testinggg tumor
Partial or
• Estimate GFR Concurrent status 2–3
response Surgical consolidationd
to assess chemoradiotherapyaa,bb months after or
eligibility for treatmenthh Treat as metastatic disease
cisplatiny
(BL-10)
Progression Treat as metastatic disease (BL-10)

c Principles of Imaging for Bladder/Urothelial Cancer (BL-A). aa Principles of Systemic Therapy (BL-G 5 of 7).
d Principles of Surgical Management (BL-B). bb Principles of Radiation Management of Invasive Disease (BL-H).
h The modifier “c” refers to clinical staging based on bimanual EUA, endoscopic surgery (biopsy or dd Principles of Systemic Therapy (BL-G 2 of 7).
TUR), and imaging studies. The modifier “p” refers to pathologic staging based on cystectomy and gg Molecular/genomic testing in a Clinical Laboratory Improvement Amendments (CLIA)-approved
lymph node dissection. laboratory, including FGFR RGQ RT-PCR for FGFR3 genetic alterations and IHC for HER2
p Principles of Instillation Therapy (BL-F). overexpression. See Discussion.
x Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). hh Imaging with CT of chest/abdomen/pelvis with contrast. If there is no evidence of distant disease on
y For patients with borderline GFR, consider timed urine collection, which may more accurately imaging reassessment, further cystoscopic assessment of tumor response in the bladder may be
determine eligibility for cisplatin. considered.
Recurrent or
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.
Persistent
Disease on
BL-1 BL-8
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Muscle Invasive Bladder Cancer Discussion

CLINICAL ADDITIONAL WORKUPc PRIMARY TREATMENT SUBSEQUENT TREATMENT

STAGINGh Consider
consolidation
systemic therapydd
or
No
Chemoradio-
tumor
After 2–3 cycles, therapyaa,bb (if no
• Abdomen/ reassess with previous RT)
pelvis CT or Systemic therapydd cystoscopy, and/or
MRIc,x if not EUA, TURBT, Cystectomyd
previously and imaging of Follow-up
done or abdomen/pelvisc (BL-E)
• Chest imaging M0 disease Systemic therapydd,jj
(CT chest) or
• Bone scan Concurrent Reassess tumor Chemoradio-
chemoradiotherapyaa,bb status 2–3 months Tumor
or MRIc,x therapyaa,bb (if no
Stage IVA if clinical after treatmentbb present
previous RT)
(cT4b, suspicion or and/or
Any N, M0; symptoms Complete Cystectomyd
Any T, of bone response Consider consolidative
Any N, M1a) metastases or local therapy in selected
• Molecular/ partial casesd,aa,bb
genomic Evaluate with response
testinggg cystoscopy,
• Estimate GFR M1a disease Systemic therapydd EUA, TURBT,
to assess and imaging of
eligibility for abdomen/pelvisc Stable Treat as
cisplatiny diseaseii or metastatic
progression disease (BL-10)
c Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
d Principles of Surgical Management (BL-B). aa Principles of Systemic Therapy (BL-G 5 of 7).
h The modifier “c” refers to clinical staging based on bimanual EUA, endoscopic surgery (biopsy or bb Principles of Radiation Management of Invasive Disease (BL-H).
TUR), and imaging studies. The modifier “p” refers to pathologic staging based on cystectomy and dd Principles of Systemic Therapy (BL-G 2 of 7).
lymph node dissection. gg Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ RT-PCR for
x Consider FDG-PET/CT scan (skull base to mid-thigh) (category 2B). FGFR3 genetic alterations and IHC for HER2 overexpression. See Discussion.
y For patients with borderline GFR, consider timed urine collection, which may more accurately ii Non-bulky disease and no significant clinical progression.
determine eligibility for cisplatin. jj See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
Recurrent or
Note: All recommendations are category 2A unless otherwise indicated. 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 on
BL-11
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Muscle Invasive Bladder Cancer Discussion

CLINICAL STAGINGh ADDITIONAL WORKUPc PRIMARY TREATMENT

• Bone scan or MRIc if clinical suspicion

or symptoms of bone metastases
• Chest CT
Metastatic
• Consider central nervous system Systemic therapydd,jj
(Stage IVB Follow-up
(CNS) imagingc and/or
Any T, Any N, (BL-E)
• Estimate GFR to assess eligibility for Palliative RTbb
M1b)
cisplatiny
• Consider biopsy if technically feasible
• Molecular/genomic testinggg

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

h The modifier “c” refers to clinical staging based on bimanualEUA, endoscopic surgery (biopsy or TUR), and imaging studies. The modifier “p” refers to pathologic
staging based on cystectomy and lymph node dissection.
y For patients with borderline GFR, consider timed urine collection, which may more accurately determine eligibility for cisplatin.
bb Principles of Radiation Management of Invasive Disease (BL-H).
dd Principles of Systemic Therapy (BL-G 2 of 7).
gg Molecular/genomic testing in a CLIA-approved laboratory, including FGFR RGQ RT-PCR for FGFR3 genetic alterations and IHC for HER2 overexpression. See
Discussion.
jj See Principles of Systemic Therapy (BL-G 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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FOLLOW-UPc RECURRENT OR TREATMENT OF RECURRENT OR

PERSISTENT DISEASE PERSISTENT DISEASE
Cystectomyd,w
or
Chemoradiotherapy (if no prior RT)aa,bb
Muscle invasive or
Systemic therapydd,jj
or
Local recurrence or Palliative TURBT and best supportive care
persistent disease; (See NCCN Guidelines for Palliative Care)
Preserved bladder
Consider intravesical
therapyp
or No
Tis, Ta, or T1 Cystectomyd,w,kk
Cystectomyd,w response
or
TURBT

Preserved Bladder
Muscle invasive or
• Cytology positive
selected metastatic Follow-up
• Imaging negative
disease treated (BL-E) See BL-4
• Cystoscopy
with curative intent
negative

Metastatic or
local recurrence See BL-10
postcystectomy

c Principles of Imaging for Bladder/Urothelial Cancer (BL-A). bb Principles of Radiation Management of Invasive Disease (BL-H).
d Principles of Surgical Management (BL-B). dd Principles of Systemic Therapy (BL-G 2 of 7).
p Principles of Instillation Therapy (BL-F). jj See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
w Follow-Up (BL-E). kk If
 not a cystectomy candidate, consider concurrent chemoradiotherapy (See
aa Principles of Systemic Therapy (BL-G 5 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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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.

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, especially 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: (BL-E)
Upper tract (CTU, MRU, intravenous pyelogram (IVP), or retrograde ureteropyelography with CT or US, or ureteroscopy) and abdomen/
pelvis imaging at baseline. For patients with high-risk NMIBC, upper tract imaging also should be performed at 12 months 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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® ® ®
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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 (MIBC)

Chest Imaging
• Staging4:
CT of the chest with or without contrast (preferred)6
Posteroanterior (PA) and lateral chest x-ray
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: (BL-E)

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.
PA and lateral chest x-ray
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 the abdomen and pelvis. FDG-PET/CT should not be used to delineate the anatomy of the upper urinary tract.

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

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.
PA and lateral chest x-ray
FDG-PET/CT (category 2B) may be performed if not previously done or in patients with high-risk MIBC 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.
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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 treatment 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 (BL-E):
Upper tract and abdomen/pelvis imaging as defined previously at 3- to 6-month intervals for 2 years, then abdomen/pelvis imaging annually
for up to 5 years and as indicated thereafter.
FDG-PET/CT (category 2B) may be performed if not previously done or in patients with high-risk MIBC 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 patients at high risk, 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.

Metastatic Disease - Patients Being Observed

• See Follow-Up (BL-E 6 of 6)

Neurologic/Brain Imaging4,5
• Staging
Brain MRI without and with IV contrast is recommended only in symptomatic or selected patients at “high risk” (eg, small cell histology) .
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.
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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:
Chest CT (preferred) or PA and lateral chest x-ray.
Consider abdomen 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 the 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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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

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 CIS:
◊ 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 multifocal lesions
– Any T1 lesion
Transurethral resection (TUR) 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.

TURBT/Maximal TURBT for Treatment

• Maximally complete and safe TURBT is an essential part of bladder preservation. See Principles of Radiation Therapy (BL-H).
• 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 Instillation Therapy [BL-F]).

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 Instillation Therapy [BL-F]).

Partial Cystectomy
• May be used for cT2 muscle invasive disease with solitary lesion in location amenable to segmental resection with adequate margins, in
appropriately selected patients. May also be appropriate in other select situations including cancer in a bladder diverticulum.
• No CIS as determined by random biopsies.
• Bilateral pelvic lymphadenectomy should be performed.

Radical Cystectomy/Cystoprostatectomy
• In non-muscle invasive disease, radical cystectomy is generally reserved for residual high-grade cT1, subtype histology, lymphovascular
invasion, concomitant CIS, and BCG-unresponsive disease.
• 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.
• Bilateral pelvic lymphadenectomy should be performed.
• In appropriately selected patients, approaches that preserve the uterus, vagina, and/or ovaries should be employed when feasible.

Radical Nephroureterectomy with Cuff of Bladder

• Primary treatment option for non-metastatic high-grade upper GU tract tumors.

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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Regional Lymphadenectomy
• Endoscopic lymph node dissections should be equivalent to open dissection.
• For bladder, recommend pelvic lymph node dissection; for upper tract recommend regional lymph node dissection for high-grade tumors.

Urethrectomy
• 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 with organ-sparing approaches when feasible
in appropriately selected cases.

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.

NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms
male and female refer to sex assigned at birth.
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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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
• 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

2022 WHO Classification of Tumors of the Urothelial Tract1,2
Urothelial Tumors Mesenchymal Tumors
• Invasive urothelial carcinoma subtypes Squamous Cell Neoplasms • Rhabdomyosarcoma
Conventional urothelial carcinoma • Pure squamous cell carcinoma • Leiomyosarcoma
Infiltrating urothelial carcinoma with • Verrucous carcinoma • Angiosarcoma
squamous differentiation • Squamous cell papilloma • Malignant inflammatory myofibroblastic
Infiltrating urothelial carcinoma with tumor
glandular differentiation Glandular Neoplasms • Malignant perivascular epithelioid cell tumor
Infiltrating urothelial carcinoma with • Adenocarcinoma, NOS • Malignant solitary fibrous tumor
trophoblastic differentiation Enteric
Nested urothelial carcinoma Mucinous Urothelial Tract Hematopoietic and Lymphoid
Tubular and microcystic urothelial Mixed Tumors
carcinoma • Villous adenoma
Micropapillary urothelial carcinoma Miscellaneous Tumors
Lymphoepithelioma-like urothelial Urachal Carcinoma • Epithelial tumors of the upper urinary tract
carcinoma • Tumors arising in a bladder diverticulum
Plasmacytoid urothelial carcinoma Tumors of Müllerian Type • Urothelial tumors of the urethra
Sarcomatoid urothelial carcinoma • Clear cell carcinoma • Malignant melanoma
Giant cell urothelial carcinoma • Endometrioid carcinoma • Carcinoma of Skene, Cowper, and Littre
Lipid-rich urothelial carcinoma glands
Clear cell (glycogen rich) urothelial Neuroendocrine Tumors • Metastatic tumors and tumors extending
carcinoma • Small cell neuroendocrine carcinoma from other organs
Poorly differentiated urothelial carcinoma • Large cell neuroendocrine carcinoma
• Noninvasive urothelial neoplasms • Well-differentiated neuroendocrine tumor
Urothelial CIS • Paraganglioma
Noninvasive papillary urothelial
carcinoma, low grade
Noninvasive papillary urothelial
carcinoma, high-grade
Papillary urothelial neoplasm of low
malignant potential
Urothelial papilloma
Inverted urothelial papilloma
References
Urothelial proliferation of uncertain 1 Moch H, Amin MB, Berney DM, et al. The 2022 World Health Organization Classification of Tumours
malignant potential
Urothelial dysplasiaa of the Urinary System and Male Genital Organs - Part A: Renal, Penile, and Testicular Tumours. Eur
Urol 2022;82;458-468.
2 Netto GJ, Amin MB, Berney DM, et al. The 2022 World Health Organization Classification of Tumors of
a The term “urothelial dysplasia” is very rarely used. Its morphologic features are poorly defined and the Urinary System and Male Genital Organs - Part B: Prostate and Urinary Tract Tumours. Eur Urol
interobserver reproducibility of this diagnosis is very low. 2022;82:469-486.
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:
Include items listed in the CAP Cancer Protocol for reporting results (tumor site, histologic subtype, histologic grade, tumor extent, and
lymphovascularinvasion if present)3
Example:
◊ Urinary bladder, tumor, transurethral resection:
– High grade urothelial carcinoma
▪ Carcinoma infiltrates lamina propria
▪ Muscularis propria present with invasion by tumor
▪ Lymphovascular space invasion present
▪ pT2
For tumors with intratumoral grade heterogeneity: tumors should be classified as high grade if the high-grade component represents >5% of
the tumor. If the high-grade component is <5%, the tumor should be classified descriptively as “low grade with <5% high-grade component”
as these may have a prognosis that is closer to low-grade tumors.4
Detail if muscularis propria (detrusor muscle) is present or absent (in addition to describing if invasion is present as per the reporting
protocol).
Describe if adjacent urothelial CIS is present
Urothelial carcinomas with an inverted growth pattern should be graded similar to the system for papillary tumors as described above.
Mixed neuroendocrine carcinoma of the bladder should specify the type(s) and percentage of the neuroendocrine component(s) present.
In addition to presence or absence of lamina propria invasion, the report should attempt to describe the extent of lamina propria invasion as
earlyinvasion/microinvasion or more extensive invasion. The exact method for characterizing early invasion versus more extensive invasion
of lamina propria has not been defined/optimized; however, any of the following methods could be used as detailed in the 8th edition of the
AJCC Cancer Staging Manual5
◊ <1 high power field or greatest invasive tumor diameter of 1 mm or less or invasive tumor above muscularis mucosae extending to a
depth of 2 mm or less
• The pathology report on cystectomy specimens should:
Include items listed in the CAP Cancer Protocol for reporting results.
• Consultation/re-review from an experienced GU pathologist should be obtained as required for confirming clinically significant rare subtype
histology, confirming metastatic carcinoma of urothelial origin and in clinically discrepant scenarios

3 CAP Cancer Protocol Templates (https://www.cap.org/protocols-and-guidelines/cancer-reporting-tools/cancer-protocol-templates) .

4 Cheng L, et al. Non-invasive papillary urothelial carcinoma, high-grade. In: WHO Classification of Tumors. 5th: Urinary and Male Genital Tumors. WHO
Classification of Tumors Editorial Board; International Agency for Research on Cancer; 2022:143-146.
5 Bochner BH, et al. Urinary Bladder. In: Amin MB, ed. AJCC Cancer Staging Manual. 8th Springer; 2017:757-765.

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 SUBTYPE HISTOLOGY

Mixed Histology: Any Small Cell Component (or neuroendocrine features):
• Urothelial carcinoma plus squamous differentiation, adenocarcinoma • Neurologic/brain imaging is recommended (BL-A 3 of 5).
differentiation, micropapillary, nested, plasmacytoid, and sarcomatoid should • Concurrent chemoradiotherapy or neoadjuvant
be identified because of the potential to have a more aggressive natural chemotherapy followed by local treatment (cystectomy
history. or RT) 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.
• Micropapillary,1,2 plasmacytoid,3 and sarcomatoid histologies are generally stage (including non-muscle invasive disease).
at higher risk for progression to muscle invasive disease and a more • Neoadjuvant chemotherapy
aggressive approach should be considered. Regimens recommended in Principles of Systemic
Therapy in NCCN Guidelines for Small Cell Lung Cancer
Pure Squamous: or
• There is no proven role for neoadjuvant/adjuvant chemotherapy for pure Alternating ifosfamide + doxorubicin with etoposide +
squamous cell carcinoma of the bladder. cisplatin7-9
• Local control with surgery or chemoradiotherapy and best supportive care • Metastatic chemotherapy
(See NCCN Guidelines for Palliative Care) are recommended. Regimens recommended in Principles of Systemic
• For advanced disease, clinical trial is preferred. For selected patients, Therapy in NCCN Guidelines for Small Cell Lung Cancer
combination chemotherapy with paclitaxel, ifosfamide, and cisplatin may be or
considered.4
• Consider postoperative RT in selected cases (positive margins).5 Alternating ifosfamide + doxorubicin with etoposide +
cisplatin7-9
Pure Adenocarcinoma Including Urachal Carcinoma:
• There is no proven role for neoadjuvant/adjuvant chemotherapy for pure Primary Bladder Sarcoma:
adenocarcinomas of the bladder including urachal carcinoma. • Treatment as per NCCN Guidelines for Soft Tissue
• Local control with surgery or RT and best supportive care (See NCCN Sarcoma.
Guidelines for Palliative Care) are recommended.
• For urachal carcinoma with localized disease, a partial or complete
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 is preferred. For selected patients,
combination chemotherapy with a 5-FU–based regimen (FOLFOX or GemFLP)
or ITP (paclitaxel, ifosfamide, and cisplatin) is an option. 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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REFERENCES
1 Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int
2013;111:E325-E330.
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 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.
8 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.
9 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.

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

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
• Papillary urothelial neoplasm of low • Low grade urothelial carcinoma • High grade urothelial carcinoma
malignant potential T1 or CIS or
• Low grade urothelial carcinoma >3 cm or T1 or
Ta and Multifocal or >3 cm or
≤3 cm and Recurrence within 1 year Multifocal
Solitary • High grade urothelial carcinoma • Very high risk features (any):
Ta and BCG unresponsive
≤3 cm and Variant histologies
Solitary Lymphovascular invasion
Prostatic urethral invasion
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;196:1021-1029.
*Within each of these risk strata an individual patient may have more or less concerning features that can influence care.
Table 2: Low-Risk,a Non-Muscle Invasive Bladder Cancer
Test Year
1 2 3 5 5–10 >10 4
Cystoscopy 3, 12 Annually As clinically indicated
Upper tractb
Baseline
and abdominal/ As clinically indicated
c d imaging
pelvic imaging
Blood tests N/A
Urine tests N/A
Intermediate Risk, Non-Muscle Invasive (BL-E 2 of 6) Post-Bladder Sparing (BL-E 5 of 6)
High-Risk, Non-Muscle Invasive (BL-E 2 of 6) Metastatic Disease: Surveillance (BL-E 6 of 6)
Post-Cystectomy Non-Muscle Invasive Bladder Cancer (BL-E 3 of 6) See Recurrent or Persistent Disease (BL-11)
Post-Cystectomy Muscle Invasive Bladder Cancer (BL-E 4 of 6)
a See AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer definitions on BL-2.
b Upper tract imaging includes CTU, MRU, intravenous pyelogram (IVP), retrograde pyelography, or ureteroscopy.
c Abdominal/pelvic imaging include CT or MRI.
d Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
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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Bladder Cancer Discussion

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,a 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 b
Baseline
and abdomen/ As clinically indicated
imaging
pelvisc imagingd
Blood tests N/A
Urine cytology Urine cytology Annually As clinically indicated
Urine tests
3, 6, 12 every 6 mo
Table 4: High-Risk,a 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 tractb As clinically
imaging, and at Every 1–2 y
imagingd indicated
12 mo
Abdomen/ Baseline
As clinically indicated
pelvisc imagingd imaging
Blood tests N/A
• Urine cytology every 3 mo
As clinically
Urine tests • Consider urinary urothelial Urine cytology every 6 mo Annually
indicated
tumor markers (category 2B)

a See AUA Risk Stratification for Non-Muscle Invasive Bladder Cancer definitions on BL-2.
b Upper tract imaging includes CTU, MRU, intravenous pyelogram (IVP), c Abdominal/pelvic imaging includes CT or MRI.
retrograde pyelography, or ureteroscopy. d Principles of Imaging for Bladder/Urothelial Cancer (BL-A).

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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Bladder Cancer Discussion

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 Renal US As clinically
Imagingd CTU or MRU (image upper tracts + axial imaging of abdomen/pelvis) annually
imaging of annuallye 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 • LFTf every • LFTf annually B12 annually
3–6 mo • B12 annually
• CBC, CMP
every 3–6 mo
if received
chemotherapy
• Urine cytology every 6–12 mo
Urine cytology as clinically indicated
Urine tests • Consider urethral wash cytology
Urethral wash cytology as clinically indicated
every 6–12 mog

Post-Cystectomy MIBC (BL-E 4 of 6) Post-Bladder Sparing (BL-E 5 of 6) Recurrent or Persistent Disease (BL-11)

d Principles of Imaging for Bladder/Urothelial Cancer (BL-A). g Urethral wash cytology is reserved for patients with high-risk disease. High-risk
e Renal US to look for hydronephrosis. disease includes: positive urethral margin, multifocal CIS, and prostatic urethral
f Liver function testing (LFT) includes AST, ALT, bilirubin, and alkaline phosphatase. 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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Table of Contents
Bladder Cancer Discussion

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)
• Abdomen/pelvis CT or MRI annually
every 3–6 mo
• CT chest (preferred) or chest x-ray annually
• CT chest (preferred) or chest x-ray Renal US As clinically
Imagingd or
every 3–6 mo annuallye 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 • LFTf annually B12 annually
f
• LFT every 3–6 mo • B12 annually
• CBC, CMP every
3–6 mo if received
chemotherapy
• Urine cytology every 6–12 mo
Urine cytology as clinically indicated
Urine tests • Consider urethral wash cytology
Urethral wash cytology as clinically indicated
every 6–12 mog

Post-Bladder Sparing (BL-E 5 of 6)

Recurrent or Persistent Disease (BL-11)

d Principlesof Imaging for Bladder/Urothelial Cancer (BL-A).e Renal US to look for g Urethral wash cytology is reserved for patients with high-risk disease. High-risk
hydronephrosis. disease includes: positive urethral margin, multifocal CIS, and prostatic urethral
f LFT includes AST, ALT, bilirubin, and alkaline phosphatase. 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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Table of Contents
Bladder Cancer Discussion

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)h
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
• Abdomen/pelvis CT or MRI annually
for MIBC
• CT chest (preferred) or chest x-ray annually
• CT chest (preferred) or chest x-ray every 3–6
Imagingd or As clinically indicated
mo for MIBC
• FDG-PET/CT (category 2B) only if metastatic
or
disease suspectedi
• 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 • LFTf every 3–6 mo
• LFTf as clinically indicated
• CBC, CMP every
3–6 mo if received
chemotherapy
Urine tests Urine cytology every 6–12 mo Urine cytology as clinically indicated

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

f LFT includes AST, ALT, bilirubin, and alkaline phosphatase.
h For patients who are not eligible for aggressive therapy, less frequent surveillance may be warranted (eg, cystoscopy every 6 months, extended to annually over time).
i 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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Bladder Cancer Discussion

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 8: Metastatic Disease: Surveillance
Test Year
1 2 3 4 5 5–10 >10
Cystoscopy • As clinically indicated
• CTU or MRU (image upper tracts + axial imaging of abdomen/pelvis) every 3–6 mo if clinically indicated and with any
clinical change or new symptoms
Imagingd • CT chest/abdomen/pelvis every 3–6 mo and with any clinical change or new symptoms
or
• FDG-PET/CT (category 2B)
• CBC, CMP every 1–3 mo
Blood tests
• B12 annually for patients who had undergone a cystectomy
Urine tests • Urine cytology as clinically indicated

d 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.
BL-E
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PRINCIPLES OF INSTILLATION THERAPY

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
• 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.
• Most efficacious in patients with low-grade, low-volume Ta urothelial cancer.
• Contraindications include: bladder perforation, known drug allergy
Induction (Adjuvant) Intravesical Chemotherapy or BCG
• Treatment option for NMIBC.
• The most commonly used agents are BCG, mitomycin, and gemcitabine.
• 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
• 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 INSTILLATION THERAPY

Intravesical BCG Principles during time of BCG shortage:
• BCG induction and maintenance should be prioritized for patients at high risk for recurrence (eg, high-grade T1 and CIS), especially in the
early maintenance period (ie, 3 and 6 months post-induction).
• BCG maintenance for patients with intermediate-risk NMIBC can be risk adapted to prioritize patients with high-risk NMIBC
• BCG maintenance for patients with high-risk NMIBC should be stopped at 1 year
• Consider induction with alternative agents if BCG is completely not available
Alternative options include: sequential gemcitabine/docetaxel, mitomycin, gemcitabine, epirubicin, valrubicin, docetaxel, or sequential
gemcitabine/mitomycin.
• Consider a clinical trial if available
• 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 (for induction or high-
priority maintenance therapy).

Continued
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 INSTILLATION THERAPY

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 disease.5-11

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.

Intrapelvic and Intravesical Therapy for Upper Tract Tumors

• Primary Therapy
Complete or near complete endoscopic resection or ablation is recommended prior to mitomycin ureteral gel application, which is most
suitably indicated for a residual, low-grade, low-volume (5–15 mm), solitary tumor in the upper urinary tract for a patient who is not a
candidate for or not seeking nephroureterectomy as a definitive treatment. Mitomycin for pyelocaliceal application may be administered via
ureteral catheter or a nephrostomy tube.
• Postsurgical Therapy
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 should be strongly considered following nephroureterectomy with cuff of bladder resection as
randomized trials have shown a decrease in intravesical recurrence.15-18

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 INSTILLATION THERAPY 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.
15 O'Brien T, Ray E, Singh R, et al. Prevention of bladder tumours after nephroureterectomy for primary upper urinary tract urothelial carcinoma: a prospective,
multicentre, randomised clinical trial of a single postoperative intravesical dose of mitomycin C (the ODMIT-C Trial). Eur Urol 2011;60:703-710.
16 Ito A, Shintaku I, Satoh M, et al. Intravesical seeding of upper urinary tract urothelial carcinoma cells during nephroureterectomy: an exploratory analysis from the
THPMG trial. Jpn J Clin Oncol 2013;43:1139-1144.
17 Yoo SH, Jeong CW, Kwak C, et al. Intravesical chemotherapy after radical nephroureterectomy for primary upper tract urothelial carcinoma: A systematic review and
network meta-analysis. J Clin Med 2019;8:1059.
18 Freifeld Y, Ghandour R, Singla N, et al. Intraoperative prophylactic intravesical chemotherapy to reduce bladder recurrence following radical nephroureterectomy. Urol
Oncol 2020;38:737.e11-737.e16.

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

Neoadjuvant Chemotherapy (preferred for bladder)
Preferred regimen
• DDMVAC (dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin) with growth factor support for 3–6 cycles1,2
Other recommended regimens
• Gemcitabine and cisplatin for 4 cycles3,4

Adjuvant Therapy
No previous platinum-based neoadjuvant Preferred regimen
therapy (pT3, pT4a, pN+) • DDMVAC with growth factor support for 3–6 cycles1,2
Other recommended regimens
• Gemcitabine and cisplatin for 4 cycles3,4
• Nivolumab5
Previous platinum-based neoadjuvant Other recommended regimen
therapy (ypT2–ypT4a or ypN+) • Nivolumab5
• 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) for MIBC.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 is preferred for patients with UTUC, particularly for higher stage and/or grade tumors or concerning radiographic findings, as
renal function will decline after nephroureterectomy and may preclude adjuvant therapy.
Multicenter data supports the use of neoadjuvant, split-dose cisplatin-based chemotherapy (gemcitabine and cisplatin) for patients with high-grade
UTUC11. Staging for UTUC is less precise than for bladder cancers and understaging is common, necessitating discussion on the risk of under- versus
over-treatment.
Adjuvant therapy should be considered if neoadjuvant therapy was not given for UTUC.12
• Carboplatin should not be substituted for cisplatin in the perioperative bladder cancer 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 eligibility 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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Bladder Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY

First-Line Systemic Therapy for Locally Advanced or Metastatic Disease (Stage IV)
Preferred regimens
Cisplatin eligible • Pembrolizumab and enfortumab vedotin-ejfv15 (category 1)

Other recommended regimens

• Gemcitabine and cisplatin4 (category 1) followed by avelumab maintenance therapy (category 1)a,13
• Nivolumab, gemcitabine, and cisplatin (category 1) followed by nivolumab maintenance therapy14 (category 1)

Useful under certain circumstances

• DDMVAC with growth factor support (category 1)2,8 followed by avelumab maintenance therapy (category 1)a,13
Preferred regimens
Cisplatin ineligible • Pembrolizumab and enfortumab vedotin-ejfv15,17 (category 1)

Other recommended regimens

• Gemcitabine and carboplatin16 followed by avelumab maintenance therapy (category 1)a,13

Useful under certain circumstances

• Gemcitabine18
• Gemcitabine and paclitaxel19
• Ifosfamide, doxorubicin, and gemcitabine21 (for patients with good kidney function and good performance
status)
• Pembrolizumab22 (for the treatment of patients with locally advanced or metastatic urothelial carcinoma who
are not eligible for any platinum-containing chemotherapy)
• Atezolizumab20,* (only for patients whose tumors express PD-L1b or who are not eligible for any platinum-
containing chemotherapy regardless of PD-L1 expression) (category 2B)
• 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.23
• 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 Maintenance therapy with avelumab only if there is no progression on first-line platinum-containing chemotherapy.
b Atezolizumab: SP142 assay, PD-L1–stained tumor-infiltrating immune cells covering ≥5% of the tumor area.
* Atezolizumab and hyaluronidase-tqjs subcutaneous injection may be substituted for IV atezolizumab. Atezolizumab and hyaluronidase-
tqjs has different dosing and administration instructions compared to atezolizumab for intravenous infusion. 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 or other chemotherapy)c
Participation in clinical trials of new agents is recommended.
Preferred regimen Other recommended regimens
• Pembrolizumab (category 1 post-platinum)24 • Paclitaxel30 or docetaxel31
• Gemcitabine18
• Pembrolizumab and enfortumab vedotin-ejfv (category 2B)17
Alternative preferred regimens Useful in certain circumstances based on prior medical therapy
• Immune checkpoint inhibitor • Ifosfamide, doxorubicin, and gemcitabine22
Nivolumab 25 • Gemcitabine and paclitaxel19
Avelumab 26,27 • Gemcitabine and cisplatin4
• Erdafitinibd,28 • DDMVAC with growth factor support2
• Enfortumab vedotin-ejfv e,29

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 regimens for cisplatin ineligible, Other recommended regimens
chemotherapy naïve • Paclitaxel or docetaxel31
• Enfortumab vedotin-ejfv29 • Gemcitabine18
• Gemcitabine and carboplatin
• Erdafitinibd,28
Preferred regimens for cisplatin eligible, Useful in certain circumstances based on prior medical therapy
chemotherapy naïve • Ifosfamide, doxorubicin, and gemcitabine22
• Gemcitabine and cisplatin4 • Gemcitabine and paclitaxel19
• DDMVAC with growth factor support 2
• Erdafitinibd,28

For patients who received a first-line platinum-containing chemotherapy followed by immune checkpoint inhibitor
maintenance therapy or first-line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor,
see subsequent-line options on BL-G 4 of 7

c Ifprogression-free survival >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 genetic alterations.
e Indicated for cisplatin ineligible patients who have received one or more prior lines of therapy.
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)f,g
Participation in clinical trials of new agents is recommended.
Preferred regimens Other recommended regimens Useful in Certain Cirumstances regimens
• Enfortumab vedotin-ejfv (category 1)32,33 • Sacituzumab govitecan-hziy34 • Fam-trastuzumab deruxtecan-nxki
• Erdafitinibd,28 (category 1) • Gemcitabine18 (HER2-positive, IHC 3+)43
30
• Paclitaxel or docetaxel 31
• Ifosfamide, doxorubicin, and gemcitabine22
• Gemcitabine and paclitaxel19
• Gemcitabine and cisplatin4
• DDMVAC with growth factor support2

dOnly for patients with susceptible FGFR3 genetic alterations.

f Patient should have already received platinum and a checkpoint inhibitor, if eligible.
g These therapies are appropriate for patients who received a first-line platinum-containing chemotherapy followed by checkpoint inhibitor maintenance therapy or first-
line therapy containing both platinum chemotherapy and an immune checkpoint inhibitor.
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-G
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Bladder Cancer Discussion

PRINCIPLES OF SYSTEMIC THERAPY

Radiosensitizing Chemotherapy Regimensi

Preferred regimens
• Cisplatinh alone35,36
• Low-dose gemcitabine37-39
• 5-FU and mitomycin40
Other recommended regimen
• Cisplatin and 5-FU37,41
• Cisplatin and paclitaxel37,42
Useful in certain circumstances (not generally used for curative-intent
chemoradiotherapy for organ preservation)
• Taxane (docetaxel or paclitaxel) (category 2B)
• 5-FU (category 2B)
• Capecitabine (category 3)

h Carboplatin is 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;20:3061-3071.)
i In select cases these regimens may be used with palliative intent.
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 SYSTEMIC THERAPY - REFERENCES

1 Grossman 11 Coleman J, Yip W, Wong N, et al. Multicenter Phase II Clinical trial of
HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus
cystectomy compared with cystectomy alone for locally advanced bladder cancer. Gemcitabine and Cisplastin as Neoadjuvant Chemotherapy for Patients with High-
N Engl J Med 2003;349:859-866. Grade Upper Tract Urothelial Carcinoma. J Clin Oncol 2023;41:1618-1625.
2 Sternberg CN, de Mulder PH, Schornagel JH, et al. Randomized phase III trial of 12 Birtle A, Johnson M, Chester J, et al. Adjuvant chemotherapy in upper tract
high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised
chemotherapy and recombinant human granulocyte colony-stimulating factor controlled trial. Lancet 2020;395:1268-1277.
13 Powles
 T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced
versus classic MVAC in advanced urothelial tract tumors: European Organization
for Research and Treatment of Cancer Protocol no. 30924. J Clin Oncol or metastatic urothelial carcinoma. N Engl J Med 2020;383:1218-1230
14 van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus gemcitabine-
2001;19:2638-2646.
3 Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in advanced urothelial carcinoma. N Engl J Med 2023;389:1778-1789.
15 Powles T, Valderrama B, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab
cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective
experience. Cancer 2008;113:2471-2477. in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875-888.
4 Von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin 16 De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing
versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients
or metastatic bladder cancer: results of a large, randomized, multinational, with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy:
multicenter, phase III study. J Clin Oncol 2000;18:3068-3077. EORTC study 30986. J Clin Oncol 2012;30:191-199.
5 Bajorin D, Witjes JA, Gschwend J, et al. Adjuvant nivolumab versus placebo in 17 Hoimes C, Flaig T, Milowsky M, et al. Enfortumab vedotin plus pembrolizumab in
muscle-invasive urothelial carcinoma. N Engl J Med 2021;384:2102-2114. previously untreated advanced urothelial cancer. J Clin Oncol 2023;41:22-31.
6 Advanced Bladder Cancer Meta-analysis Collaboration. Neoadjuvant 18 Stadler WM, Kuzel T, Roth B, et al: Phase II study of single-agent gemcitabine
chemotherapy in invasive bladder cancer: update of a systematic review and in previously untreated patients with metastatic urothelial cancer. J Clin Oncol
meta-analysis of individual patient data advanced bladder cancer (ABC) meta- 1997;15:3394-3398.
19 Albers P, Park SI, Niegisch G, et al. Randomized phase III trial of 2nd line
analysis collaboration. Eur Urol 2005;48:202-205; discussion 205-206.
7 Advanced Bladder Cancer Meta-analysis Collaboration. Adjuvant chemotherapy gemcitabine and paclitaxel chemotherapy in patients with advanced bladder
in invasive bladder cancer: a systematic review and meta-analysis of individual cancer: short-term versus prolonged treatment [German Association of
patient data Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Eur Urological Oncology (AUO) trial AB 20/99]. Ann Oncol 2011; 22:288-294.
20 Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment
Urol 2005;48:189-199; discussion 199-201.
8 Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an in cisplatin-ineligible patients with locally advanced and metastatic urothelial
EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389:67-76.
21 Siefker-Radtke AO, Dinney CP, Shen Y, et al: A phase 2 clinical trial of sequential
versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer
2006;42:50-54. neoadjuvant chemotherapy with ifosfamide, doxorubicin, and gemcitabine
9 von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of followed by cisplatin, gemcitabine, and ifosfamide in locally advanced urothelial
a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, cancer: final results. Cancer 2013;119:540-547.
22 Powles T, Csőszi T, Özgüroğlu M, et al. Pembrolizumab alone or combined with
vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin
Oncol 2005;23:4602-4608. chemotherapy versus chemotherapy as first-line therapy for advanced urothelial
10 Soto Parra H, Cavina R, Latteri F, et al. Three-week versus four-week schedule carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet
of cisplatin and gemcitabine: results of a randomized phase II study. Ann Oncol Oncol 2021;22:931-945.
2002;13:1080-1086.

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

23 Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with
locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC Intergroup Study 30987. J Clin Oncol 2012;30:1107-1113.
24 Bellmunt, de Wit R, Vaughn D, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017;376:1015-1026.
25 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 2017;18:312-322.
26 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 2017;35:2117-2124.
27 Patel M, Ellerton J, Infante J, et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion
cohorts or an open-label, phase 1 trial. Lancet Oncol 2018;19:51-64.
28 Loriot Y, Necchi A, Park SH, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N Engl J Med 2019;381:338-348.
29 Yu E, Petrylak D, O'Donnell P, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV 201): a
multicentre, single-arm, phase 2 trial. Lancet Oncol 2021;22:872-882.
30 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.
31 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.
32 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.
33 Powles T, Rosenberg JE, Sonpavde G, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021;384:1125-1135.
34 Tagawa S, Balar AV, Petrylak DP, et al. TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma
progressing after platinum based chemotherapy and checkpoint inhibitors. J Clin Oncol 2021;39:2474-2485.
35 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;14:119-126.36 Shipley WU, Kaufman DS, Zehr E, et al. Selective bladder preservation by combined
modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urology 2002;60:62-67; discussion 67-68.
37 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.
38 Kent E, Sandler H, Montie J, 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.
39 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.
40 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.
41 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.
42 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.
43 Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From
the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol 2024;42:47-58.

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 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 moderate/severe hydronephrosis and without extensive CIS 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 RT 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 dose-volume histogram (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 (preferred) or RT alone should be considered as potentially curative therapy for patients who are medically inoperable.
Concurrent chemoradiotherapy or RT alone should be considered 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.
• Conduct tumor status assessment after completion of full-dose primary chemoradiotherapy. See Table 7 on BL-E 5 of 6.
• In highly selected T4b tumor cases, may consider intraoperative RT.
• Concurrent chemoradiotherapy is generally most suitable for patients with solitary tumors, negative nodes, no extensive or multifocal CIS, no moderate/
severe tumor-related hydronephrosis, and good pre-treatment bladder function.
• For palliative RT, consider a dose of 30 Gy in 10 fractions or 21 Gy in 3 fractions.
• A meta-analysis of individual patient data from two randomized, phase III studies (BC2001 and BCON) found that a hypofractionated schedule of 55 Gy in
20 fractions over 4 weeks is noninferior to the standard fractionation schedule of 64 Gy in 32 fractions over 6.5 weeks for both invasive local control and
toxicity and that the hypofractionated schedule is superior regarding invasive local control.
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-H
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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 RT
◊ 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.

NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms
male and female refer to sex assigned at birth.
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 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.
Choudhury A, Porta N, Hall E, et al. Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and
BCON trials. Lancet Oncol 2021;22:246-255.
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, 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.

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

• Imaging of upper tract Endoscopic resectione

collecting systema ± postsurgical intrapelvic
• Cytology chemotherapy or BCGf
• Cystoscopy or
• Ureteroscopy and biopsy or Low gradec Nephroureterectomy with
percutaneous biopsy and/or cuff of bladder ±
selective washings perioperative intravesical
• Renal function tests chemotherapyf
• Chest x-ray or CT Non- Adjuvant
• CBC, chemistry profile metastatic Treatment and
• Nuclear medicine renal scan Nephroureterectomy Follow-up
(optional) (UTT-3)
• Bone scana if clinical
with cuff of bladder +
suspicion or symptoms of regional lymphadenectomy
bone metastases High grade,c large, ± perioperative intravesical
• Consider germline testing or parenchymal chemotherapyf
and genetic counselor invasion and
Renal referral if younger age cisplatin based neoadjuvant
pelvis at presentation and/or chemotherapyg in selected
personal or family history patients
of Lynch syndrome-related
cancerb

Metastatic Systemic therapyh

e Complete or near complete endoscopic resection or ablation is recommended prior to

a Principles of Imaging for Bladder/Urothelial Cancer (BL-A). mitomycin ureteral gel application, which is most suitably indicated for a residual, low-grade,
b See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal – Criteria for low-volume (5–15 mm), solitary tumor in the upper urinary tract for a patient who is not a
the Evaluation of Lynch Syndrome Based on Personal or Family History of Cancer candidate for or not seeking nephroureterectomy as a definitive treatment. Mitomycin for
c Montironi R, Lopez-Beltran A. The 2004 WHO classification of bladder tumors: A summary pyelocaliceal application may be administered via ureteral catheter or a nephrostomy tube.
and commentary. Int J Surg Pathol 2005;13:143-153. See Principles of Pathology f See Principles of Instillation Therapy (BL-F).
Management (BL-C). g Principles of Systemic Therapy (BL-G 1 of 7).
d Principles of Surgical Management (BL-B). h 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 ±
• Imaging of upper tract collecting perioperative intravesical chemotherapyf and
systema regional lymphadenectomy if high grade and consider
• Cytology Upper neoadjuvant chemotherapyg in selected patients
• Cystoscopy
or
• Ureteroscopy and biopsy or
percutaneous biopsy Endoscopic resection (low gradec)e
and/or selective washings
• Renal function tests Endoscopic resection (low gradec)e
• Nuclear medicine renal scan or
(optional) Nephroureterectomy with cuff of bladder ±
Urothelial • Chest x-ray or CT perioperative intravesical chemotherapyf (plus
carcinoma • CBC, chemistry profile
regional lymphadenectomy and consider neoadjuvant
• Bone scana if clinical suspicion or
of the ureter
symptoms of bone metastases chemotherapy in selected patients with high-gradec
Mid disease)
• Consider germline testing and
or Adjuvant
genetic counselor referral if
younger age at presentation and/or Excision and ureteroureterostomy/ileal ureter ± Treatment
personal or family history of Lynch perioperative intravesical chemotherapyf in highly and Follow-
syndrome-related cancerb selected patients up (UTT-3)

Distal ureterectomy and regional lymphadenectomy

if high gradec and reimplantation of ureter (preferred
if clinically feasible) ± perioperative intravesical
a Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
b See NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal – chemotherapyf and consider
Criteria for the Evaluation of Lynch Syndrome Based on Personal or Family History
neoadjuvant chemotherapyg in selected patients
of Cancer. or
c Montironi R, Lopez-Beltran A. The 2004 WHO classification of Endoscopic resectione (low gradec)
bladder tumors: A summary and commentary. Int J Surg Pathol Distal or
2005;13:143-153. See Principles of Pathology Management (BL-C). Nephroureterectomy with cuff of bladder ± perioperative
d Principles of Surgical Management (BL-B).
e Complete or near complete endoscopic resection or ablation is recommended prior intravesical chemotherapyf
to mitomycin ureteral gel application, which is most suitably indicated for a residual, and regional lymphadenectomy if high
low-grade, low-volume (5–15 mm), solitary tumor in the upper urinary tract for a gradec and consider neoadjuvant chemotherapyg in
patient who is not a candidate for or not seeking nephroureterectomy as a definitive selected patients
treatment. Mitomycin for pyelocaliceal application may be administered via ureteral
catheter or a nephrostomy tube.
f See Principles of Intravesical Treatment Instillation Therapy (BL-F).

Systemic therapyh
g Principles of Systemic Therapy (BL-G 1 of 7).
h See Principles of Systemic Therapy (BL-G 2 of 7, 3 of 7, and 4 of 7). Metastatic

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 ADJUVANT TREATMENT FOLLOW-UP

STAGINGi

• 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 ± abdomen/pelvis CT or MRI
with and without contrast
Adjuvant treatment for
renal pelvis
and
urothelial carcinoma
of the ureter • If no platinum neoadjuvant treatment given
• Cystoscopy and cytology every 3
and pT3, pT4, or pN+
months for 1 year, then at longer
Adjuvant platinum-based chemotherapy
intervals
should be discussedg,j or
• If nephron-sparing surgery, imaging
pT2, pT3, Consider adjuvant nivolumabg,j,k (category
of upper tract collecting systema or
pT4, pN+ 2B)
ureteroscopy at 3- to 12-month intervals
or
+ abdomen/pelvis CT or MRI with and
• If platinum neoadjuvant chemotherapy given
without contrast + chest imaging
and ypT2-ypT4 or ypN+, consider adjuvant
nivolumabg,j,k

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

g Principles of Systemic Therapy (BL-G 1 of 7).
i The modifier “p” refers to pathologic staging based on surgical resection and lymph node dissection.
j Follow recommendations for adjuvant chemotherapy after ensuring that patient is fully staged to rule out metastatic disease.
k Most appropriate for patients who value an opportunity to delay recurrence even if the chance of cure was not improved, and for whom the risk of side effects was
acceptable.

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.

UTT-3
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Urothelial Carcinoma of the Prostate Discussion

WORKUP PATHOLOGYADDITIONAL PRIMARY TREATMENTb THERAPY FOR

WORKUP RECURRENCE

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

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

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

b Principles of Surgical Management (BL-B).
c 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 UCP-1

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

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

a Referral to a specialized
center is recommended.
b Principles of Imaging for
Bladder/Urothelial Cancer (BL-A).
NCCN recommendations have been developed to be inclusive of individuals of all sexual and gender identities to the greatest extent possible. On this page, the terms
male and female refer to sex assigned at birth.

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

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 Follow-up Systemic therapyj,l,m
Bulbar Urethrectomyf ± imaging with Recurrence and/or
urethra cystoprostatectomy Consider cystoscopyk RTh,n
pT3/pT4
chemotherapyi,j
T2 or Systemic therapyj,l,m
or
pN1/pN2 or
Chemoradiotherapyg,h
Chemoradiotherapyg,h
Chemoradiotherapyg,h (if no prior RT)
or or
Urethrectomyf + cystectomy Follow-up imaging Pelvic exenteration
Female Recurrence
or with cystoscopyk (category 2B)
Distal urethrectomyf
(depending on tumor location)
j Chemotherapy regimen based on histology. (Dayyani F, et al. Urol Oncol
c Principles of Surgical Management (BL-B). 2013;31:1171-1177.) Also see Non-Urothelial Cell and Urothelial with Subtype
d In patients with a prior radical cystectomy and
a cutaneous diversion, consider a Histology (BL-D).
total urethrectomy. k Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
e Principles of Instillation Therapy (BL-F). l Principles of Systemic Therapy (BL-G 2 of 7).
f Consider neoadjuvant chemotherapy (category 2B) or chemoradiation. m See Principles of Systemic Therapy (BL-G 3 of 7 and 4 of 7).
g Principles of Systemic Therapy (BL-G 5 of 7). n Consider for local recurrence (± chemotherapy).
h Principles of Radiation Management of Invasive Disease-Carcinoma of the NCCN recommendations have been developed to be inclusive of individuals of
Urethra (BL-H 2 of 3). all sexual and gender identities to the greatest extent possible. On this page, the
i Principles of Systemic Therapy (BL-G 1 of 7). terms male and female refer to sex assigned at birth.

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

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 abdomen/ lymphadenectomy
Surgery alone for non-urothelial histology Follow-up
inguinal pelvis CT Recurrence and/or
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 therapyj,l ± consolidative surgery
cN2
or
Chemoradiotherapyg,h ± consolidative
surgery

Distant
Metastatic Disease (BL-10)
metastasis

c Principles of Surgical Management (BL-B).

g Principles of Systemic Therapy (BL-G 5 of 7).
h Principles of Radiation Management of Invasive Disease-Carcinoma of the Urethra (BL-H 2 of 3).
i Principles of Systemic Therapy (BL-G 1 of 7).
j Chemotherapy regimen based on histology. (Dayyani F, et al. Urol Oncol 2013;31:1171-1177.) Also see Non-Urothelial Cell and Urothelial with Subtype Histology (BL-
D).
k Principles of Imaging for Bladder/Urothelial Cancer (BL-A).
l 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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Bladder Cancer Discussion

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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Bladder Cancer Discussion

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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Bladder Cancer Discussion

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 T3 N0 M0
in the inguinal region or true pelvis
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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ABBREVIATIONS
BCG Bacillus Calmette-Guérin NOS not otherwise specified
CAP College of American PA posteroanterior
Pathologists PSA prostate-specific antigen
CBC complete blood count TUR transurethral resection
CIS carcinoma in situ TURBT transurethral resection of
CLIA Clinical Laboratory bladder tumor
Improvement Amendments TURP transurethral resection of the
CMP comprehensive metabolic prostate
panel UTUC upper tract urothelial cancer
CNS central nervous system
CTU computed tomography
urography
CTV clinical target volume
DRE digital rectal examination
EBRT external beam radiation
therapy
ECOG Eastern Cooperative Oncology
Group
EUA examination under anesthesia
FDG fluorodeoxyglucose
GFR glomerular filtration rate
GU genitourinary
H&P history and physical
IVP intravenous pyelogram
LFT liver function test
MIBC muscle invasive bladder
cancer
MRU magnetic resonance
urography
NMIBC non–muscle-invasive bladder
cancer

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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

for Bladder Cancer. Last updated October 28, 2024.
Adjuvant Systemic Therapy ....................................................MS-19

Adjuvant Radiation .................................................................MS-21

Table of Contents
Bladder Preservation ..............................................................MS-21
Overview .................................................................................... MS-2
NCCN Recommendations for Treatment of Muscle Invasive Bladder
Guidelines Update Methodology............................................... MS-2
Cancer ...................................................................................MS-24
Literature Search Criteria .......................................................... MS-2
Follow-up ...............................................................................MS-26
Sensitive/Inclusive Language Usage ........................................ MS-3
Recurrent or Persistent Disease .............................................MS-26
Clinical Presentation and Workup ............................................ MS-3
Pathology and Staging .............................................................. MS-4 Metastatic (Stage IVB) Urothelial Bladder Cancer .................. MS-27

Enhanced Cystoscopy .............................................................. MS-5 Evaluation of Metastatic Disease ............................................MS-27

Histology .................................................................................... MS-7 Metastasectomy for Oligometastatic Disease ..........................MS-27

Non-Muscle Invasive Urothelial Bladder Cancer ...................... MS-8 Molecular/Genomic Testing ....................................................MS-28

Intravesical Therapy ................................................................. MS-8 First-Line Systemic Therapy for Metastatic Disease ................MS-29

BCG Shortage........................................................................ MS-10 Second-Line and Subsequent Therapy for Metastatic Disease MS-33

Treatments for BCG-Unresponsive or BCG-Intolerant NMIBC. MS-11 NCCN Recommendations for Systemic Therapy of Metastatic
Disease ..................................................................................MS-37
NCCN Recommendations for Treatment of NMIBC ................. MS-12
Non-Urothelial Carcinomas of the Bladder ............................. MS-39
Surveillance ........................................................................... MS-14
Upper Tract Urothelial Carcinoma .......................................... MS-39
Posttreatment of Recurrent or Persistent Disease................... MS-15
Urothelial Carcinomas of the Prostate .................................... MS-43
Muscle Invasive Urothelial Bladder Cancer ............................ MS-16 Primary Carcinoma of the Urethra .......................................... MS-44
Additional Workup .................................................................. MS-16 Summary .................................................................................. MS-45
Cystectomy ............................................................................ MS-16 References ............................................................................... MS-47
Neoadjuvant Chemotherapy ................................................... MS-17

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Overview The critical concern for the third group, consisting of metastatic lesions,
is how to prolong survival and maintain quality of life. Numerous agents
An estimated 83,190 new cases of urinary bladder cancer (63,070
with different mechanisms of action have antitumor effects on this
males and 20,120 females) will be diagnosed in the United States in
disease. The goal is to use these agents to increase survival and quality
2024 with approximately 16,840 deaths (12,290 males and 4550
of life.
females) occurring during this same period.1 Bladder cancer, the sixth
most common cancer in the United States, is rarely diagnosed in Guidelines Update Methodology
individuals <40 years. Given that the median age at diagnosis is 73
The complete details of the Development and Update of the NCCN
years,2 and the associated risk factors, comorbid medical conditions are
Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are
a frequent consideration in comprehensive care of patients with bladder
available at www.NCCN.org.
cancer.

Risk factors for developing bladder cancer include male sex, white race,
Literature Search Criteria
smoking, personal or family history of bladder cancer, pelvic radiation, Prior to the update of this version of the NCCN Guidelines® for Bladder
environmental/occupational exposures, exposure to certain Cancer, an electronic search of the PubMed database was performed to
medications, chronic infection or irritation of the urinary tract, and obtain key literature using the following search terms: bladder cancer
certain medical conditions including obesity and diabetes.3-6 While OR urothelial carcinoma of the ureter OR urothelial carcinoma of the
diabetes mellitus appears to be associated with an elevated risk of prostate OR primary carcinoma of the urethra. The PubMed database
developing bladder cancer,4 treatment with metformin may be was chosen as it remains the most widely used resource for medical
associated with improved prognosis in patients with bladder cancer and literature and indexes peer-reviewed biomedical literature.9
diabetes.7 Certain genetic syndromes, most notably Lynch syndrome,
The search results were narrowed by selecting studies in humans
may also predispose an individual to urothelial carcinoma.8
published in English. Results were confined to the following article
The clinical spectrum of bladder cancer can be divided into three types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial,
categories that differ in prognosis, management, and therapeutic aims. Phase IV; Guideline; Meta-Analysis; Randomized Controlled Trials;
The first category consists of non–muscle-invasive bladder cancer Systematic Reviews; and Validation Studies. The data from key
(NMIBC), for which treatment is directed at reducing recurrences and PubMed articles as well as articles from additional sources deemed as
preventing progression to a more advanced stage, while minimizing relevant to these Guidelines as discussed by the panel during the
adverse events (AEs) related to treatment. The second group Guidelines update have been included in this version of the Discussion
encompasses muscle invasive, non-metastatic disease. Unlike NMIBC, section. Recommendations for which high-level evidence is lacking are
muscle invasive disease poses a much greater risk for progression and based on the panel’s review of lower-level evidence and expert opinion.
requires more aggressive therapy, often a multidisciplinary approach
including a combination of systemic therapy, surgery, and/or radiation.

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Sensitive/Inclusive Language Usage tumor (TURBT) to confirm the diagnosis and determine the extent of
NCCN Guidelines strive to use language that advances the goals of disease within the bladder. Urine cytology may also be obtained around
equity, inclusion, and representation.10 NCCN Guidelines endeavor to the time of cystoscopy. Because smoking is a major risk factor for
use language that is person-first; not stigmatizing; anti-racist, anti- bladder cancer,11 screening for smoking and initiation of treatment for
classist, anti-misogynist, anti-ageist, anti-ableist, and anti-weight- smoking cessation, if appropriate, is recommended during the initial
biased; and inclusive of individuals of all sexual orientations and gender evaluation (see NCCN Guidelines for Smoking Cessation).
identities. NCCN Guidelines incorporate non-gendered language,
Evidence has suggested that bladder cancer has a substantial
instead focusing on organ-specific recommendations. This language is
hereditary component, including a high prevalence of Lynch syndrome
both more accurate and more inclusive and can help fully address the
in patients with urothelial carcinoma.8,12 Therefore, it is recommended to
needs of individuals of all sexual orientations and gender identities.
take a thorough family history for all patients with bladder cancer and
NCCN Guidelines will continue to use the terms men, women, female,
consider germline testing and referral to a genetic counselor for those
and male when citing statistics, recommendations, or data from
who are at higher risk of Lynch syndrome based on younger age at
organizations or sources that do not use inclusive terms. Most studies
presentation and/or a personal or family history of Lynch syndrome-
do not report how sex and gender data are collected and use these
related cancers (see NCCN Guidelines for Genetic/Familial High-Risk
terms interchangeably or inconsistently. If sources do not differentiate
Assessment: Colorectal for information on the criteria and strategies for
gender from sex assigned at birth or organs present, the information is
evaluation of Lynch syndrome).
presumed to predominantly represent cisgender individuals. NCCN
encourages researchers to collect more specific data in future studies A CT scan or MRI of the abdomen and pelvis is recommended before
and organizations to use more inclusive and accurate language in their the TURBT, as long as it is logistically feasible, to allow for better
future analyses. anatomical characterization of the lesion and possible delineation of the
suspected depth of invasion. Additional workup for all patients should
Clinical Presentation and Workup include consideration of urine cytology, if not already tested, and
The most common presenting symptom in patients with bladder cancer evaluation of the upper tracts with a CT or MR urography; a renal
is microscopic or gross hematuria, although urinary frequency due to ultrasound or CT without contrast with retrograde ureteropyelography; a
irritation or reduced bladder capacity can also develop. Less commonly, ureteroscopy; or a combination of techniques. CT urography is
the presenting symptom is a urinary tract infection. Upper tract generally the preferred approach to upper tract imaging in patients who
obstruction or pain may occur in patients with a more advanced lesion. can safely receive intravenous contrast agents.
Patients presenting with these symptoms should be evaluated with
office cystoscopy to determine if a lesion is present. Enhanced TURBT with a bimanual examination under anesthesia (EUA) is
cystoscopy may be used if available. If a lesion is documented, the performed to resect visible tumor and to sample muscle within the area
patient should be scheduled for a transurethral resection of the bladder of the tumor to assess invasion. In a case where the tumor is clearly not
invasive (eg, multiple small papillary tumors), EUA would not be

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necessary. The goal of TURBT is to correctly identify the clinical stage TURBT), and imaging studies. A modifier “p” would refer to pathologic
and grade of disease while completely resecting all visible tumor. staging based on cystectomy and lymph node dissection.
Therefore, an adequate sample that includes bladder muscle (ie,
muscularis propria) preferentially should be obtained in the resection Pathology and Staging
specimen, most notably in high-grade disease. A small fragment of The most commonly used staging system is the tumor, node,
tumor with few muscle fibers is inadequate for assessing the depth of metastasis (TNM) staging system by the AJCC20 (see Staging in the
invasion and guiding treatment recommendations. When a large algorithm). The NCCN Guidelines® for Bladder Cancer divide treatment
papillary lesion is noted, more than one session may be needed to recommendations for urothelial carcinoma of the bladder according to
completely resect the tumor. With carcinoma in situ (CIS), biopsy of non-muscle invasive disease (Ta, T1, and CIS) and muscle invasive
sites adjacent to the tumor and multiple random biopsies may be disease (≥T2 disease). Management of bladder cancer is based on the
performed to assess for a field change. Single-dose intravesical findings of the biopsy and TURBT specimens, with attention to
gemcitabine or mitomycin (both category 1, although gemcitabine is histology, grade, and depth of invasion. These factors are used to
preferred due to better tolerability and lower cost) within 24 hours of estimate the probability of recurrence and progression to a more
TURBT is recommended if non-muscle invasive disease is suspected advanced stage. Patient bladder function, comorbidities, and life
(see Intravesical Therapy). Existing data support this approach largely expectancy are also important considerations.
for low-volume, low-grade disease.13-15
Approximately 75% of newly detected cases are non-muscle invasive
Mapping or random biopsies of normal-appearing urothelium rarely yield disease—exophytic papillary tumors confined largely to the mucosa
positive results and lack sensitivity for CIS, especially for low-risk (Ta) (70%–75%) or, less often, to the lamina propria (T1) (20%–25%) or
tumors.16-19 In addition, these biopsies often cause additional damage to flat high-grade lesions (CIS, 5%–10%).21 These tumors tend to be
the bladder without benefit to the patient. Therefore, mapping biopsies friable and have a high propensity for bleeding. Their natural history is
of normal-appearing urothelium are not recommended for most patients. characterized by a tendency to recur in the bladder, and these
recurrences can either be at the same stage as the initial tumor or at a
Positive urinary cytology may indicate urothelial tumor anywhere in the more advanced stage. While not fully endorsed by the AJCC staging
urinary tract. In the presence of a positive cytology and a normal system, there are data to support that pT1 sub-staging may have
cystoscopy, the upper tracts and the prostate (prostatic urethra) must prognostic value, with microscopic or focal invasion into the lamina
be evaluated and ureteroscopy may be considered. propria showing better outcomes than more extensive pT1 disease.22-24
If feasible, pT1 sub-staging may be useful for prognostication, although
Clinical investigation of the specimen obtained by TURBT or biopsy is
it is currently not widely utilized and relies on specialized pathology
an important step in the diagnosis and subsequent management of
review, which may not be available at all centers.
bladder cancer. The modifier “c” before the stage refers to clinical
staging based on bimanual EUA, endoscopic surgery (biopsy or

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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.25 These probabilities of recurrence vary as a function of improved staging when used in conjunction with WLC and expertise;
the initial stage and grade, size, and multiplicity. Refining these however, data are still limited for both methods and WLC remains the
estimates for individual patients is an area of active research. mainstay of bladder cancer staging.

Muscle invasive disease (T2) is defined by malignant extension into the Blue Light Cystoscopy
detrusor muscle while perivesical tissue involvement defines T3 BLC is a technique that identifies malignant cells through the absorption
disease. Extravesical invasion into the surrounding organs (ie, the of the photosensitizing drug into the urothelial cytoplasm where it enters
prostatic stroma, seminal vesicles, uterus, vagina, pelvic wall, the heme biosynthesis pathway. In normal cells, the photosensitizer is
abdominal wall) delineates T4 disease. The depth of invasion is the excreted; however, enzymatic abnormalities in malignant cells result in
most important determinant of prognosis and treatment for localized the formation of photoactive porphyrins that remain in the cell and
bladder cancer. fluoresce with a red emission in the presence of blue light. Earlier
studies used the photosensitizer 5-aminolevulinic acid (5-ALA),
The 8th edition of the AJCC Cancer Staging Manual includes changes to although more recent studies use only the U.S. Food and Drug
the staging of urinary bladder carcinoma, including the subdivision of Administration (FDA)-approved photosensitizer hexyl-aminolevulinate
stages III and IV disease (stage III into stage IIIA and stage IIIB; stage (HAL).
IV into stage IVA and stage IVB).20 Notably, the new staging system
groups T1–T4a, N1 within stage IIIA and T1–T4a, N2–3 within stage Several prospective clinical studies have evaluated BLC in conjunction
IIIB; N1–3 was previously grouped within stage IV, regardless of T with WLC and found higher detection rates of non-muscle invasive
stage.20,26 The NCCN Guidelines for Bladder Cancer were updated to lesions with BLC.27-32 Particularly CIS, which is often missed by WLC,
reflect appropriate treatment options based on this new staging system was detected at a higher rate. A meta-analysis of BLC TURBT in
(see Treatment of Stage II and IIIA Tumors, Treatment of Stage IIIB NMIBC included 12 randomized controlled trials with a total of 2258
Tumors, and Treatment of Stage IVA Tumors). patients.33 A lower recurrence rate was observed (overall response
[OR], 0.5; P < .00001) with a delayed time to first recurrence by 7.39
Enhanced Cystoscopy weeks (P < .0001). Recurrence-free survival (RFS) was improved at 1
White light cystoscopy (WLC) is the current standard in the evaluation year (hazard ratio [HR], 0.69; P < .00001) and at 2 years (HR, 0.65;
and staging of bladder cancer. While WLC has a high sensitivity for

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P = .0004). However, no significant reduction in the rate of progression Narrow-Band Imaging

to muscle invasive bladder cancer was seen (OR, 0.85; P = .39). NBI uses two narrow bands of light at 415 nanometers and 540
nanometers that are absorbed by hemoglobin. The shorter wavelength
In a meta-analysis from Burger et al,34 1345 patients with Ta, T1, or CIS provides analysis of the mucosa and the longer wavelength allows for
disease showed improved detection of bladder tumors and a reduction evaluation of the deeper submucosal blood vessels. Studies suggest
in recurrence.34 Compared to WLC, BLC detected more Ta tumors that there is an increase in bladder tumor detection compared with
(14.7%; P < .001; OR, 4.898; 95% CI, 1.937–12.390) and CIS lesions WLC, although the rate of false positives is higher.37-41
(40.8%; P < .001; OR, 12.372; 95% CI, 6.343–0.924). Importantly,
24.9% of patients had at least one additional Ta/T1 tumor detected A systematic review and meta-analysis including seven prospective
(P < .001), and improved detection was seen in both primary (20.7%; studies and 1040 patients with non-muscle invasive disease evaluated
P < .001) and recurrent disease (27.7%; P < .001). Another review of the accuracy of NBI compared to WLC. In total, 1476 tumors were
the literature included 26 studies with 5-ALA, 15 studies with HAL, and detected by biopsy in 611 patients. The additional detection rate for NBI
two studies that used both methodologies. The results from this review was higher on the patient level (17%; 95% CI, 10%–25%) and tumor
also support greater detection and reduced recurrence but no reduction level (24%; 95% CI, 17%–31%). In total, 107 patients were further
in disease progression.35 identified as having non-muscle invasive disease by NBI compared to
the 16 patients by WLC. Similarly, 276 additional tumors were reported
Although most studies have found no significant reduction in disease in five studies using NBI versus 13 additional tumors by WLC. Although
progression, a recent analysis reported a trend towards a lower rate individual studies demonstrated an increase in the rate of false
with the use of BLC compared to WLC (12.2% vs. 17.6%, respectively; positives, the meta-analysis reported no statistical significance.
P = .085) with a longer time to progression (P = .05).36 Although BLC However, it was acknowledged that data are limited due to the relatively
has demonstrated improved detection and reduced recurrence, the new application of this technique and interpretation is impeded by the
value of this technique in reducing disease progression remains less degree of heterogeneity among the studies. Finally, the meta-analysis
established. Therefore, BLC may have the greatest advantage in was unable to determine if there was a long-term advantage of NBI, as
detecting difficult-to-visualize tumors (eg, CIS tumors) that may be measured by a reduction in recurrence or progression.
missed by WLC but has more limited applicability in disease monitoring.
Other impediments to BLC include the need for appropriate expertise A randomized prospective trial followed patients for 1 year after NBI- or
and equipment to use this new technology. High false positives are also WLC-guided transurethral resection (TUR) to evaluate recurrence. NBI
attributed to this method and may be increased in patients who have had a reduced 1-year recurrence rate (32.9%; 25 of 76 patients)
had a recent TURBT or bacillus Calmette-Guérin (BCG) instillation, or compared to WLC (32.9% vs. 51.4%, respectively; OR, 0.62).42
who have inflammation.35 The limitations of BLC require judicious However, the small number of patients in this study is limiting. A larger
application of this additional diagnostic tool. international, multicenter, randomized controlled trial compared 1-year
recurrence rates in 965 patients who received either NBI- or WLC-

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guided TUR for treatment of NMIBC. This study found that while ureter, bladder, and proximal two thirds of the urethra. The fifth edition
recurrence rates were similar between the two groups in the study of the World Health Organization (WHO) Classification of Tumors of the
population overall, NBI-guided TUR significantly reduced the likelihood Urinary System and Male Genital Organs, published in November 2022,
of disease recurrence at 1 year in patients with low-risk disease (5.6% provided new information into the grading of invasive urothelial
for NBI vs. 27.3% for WLC; P = .002).43 These results are supported by carcinomas, as well as noninvasive urothelial neoplasms, and the
the systemic reviews and meta-analyses that have also shown reduced definition of precursor lesions.47
recurrence rates following NBI-guided TUR compared to WLC-guided
TUR.44,45 Subtype (variant) histology is common with higher grades. The fifth
edition of the WHO Classification included the adoption of a modified
A benefit of NBI is that it does not require a contrast agent and can terminology where the designation of “subtype” was adopted to replace
therefore be used as part of office cystoscopy. Higher detection rates of “variant” histology when referring to distinct morphologic categories
flat lesions and a reduction in tumor recurrence have been reported.43-46 within a given tumor type.48,49 The reasoning behind this change is that
the term “variant” has increasingly been used to describe genomic,
Histology rather than morphologic alterations, and therefore the WHO
More than 90% of urothelial tumors originate in the urinary bladder, 8% Classification system reserves “variant” for this purpose to avoid
originate in the renal pelvis, and the remaining 2% originate in the ureter confusion. The presence of histologic subtypes of urothelial carcinoma
and urethra. Urothelial carcinomas are classified as low or high grade should be documented as data suggest that the subtype may help
as defined by the extent of cytologic and architectural atypia. define the natural history and inherent risk of progression, reflect
different genetic etiology, and subsequently determine whether a more
Non-muscle invasive urothelial tumors may have flat and/or papillary aggressive treatment approach should be considered (see Bladder
histology. Flat urothelial lesions may be classified as urothelial CIS, a Cancer: Non-Urothelial and Urothelial with Subtype Histology in the
type of high-grade noninvasive urothelial carcinoma. The term urothelial algorithm).50-52 In some cases with a mixed histology, systemic
dysplasia may be used in rare circumstances where the morphologic treatment may only target cells of urothelial origin and the non-urothelial
features fall short for a diagnosis of CIS. Papillary lesions may be component can remain.
benign (ie, urothelial papilloma, inverted papilloma) or malignant. The
latter group includes papillary urothelial neoplasms of low malignant Squamous cell neoplasms of the urothelial tract constitute 3% of the
potential (PUNLMP) and papillary urothelial carcinoma (low and high urinary tumors diagnosed in the United States. In regions where
grade). In some cases, a Ta or T1 NMIBC will have an associated Schistosoma is endemic, this subtype is more prevalent and may
urothelial CIS component. account for up to 75% of bladder cancer cases. The distal third of the
urethra is dominated by squamous epithelium. The diagnosis of
Urothelial (transitional cell) carcinoma is the most common histologic squamous cell tumors requires the presence of keratinization in the
subtype of bladder cancer in the United States and Europe and may pathologic specimen.53 Squamous cell carcinoma of the bladder is
develop anywhere urothelium is present, from the renal pelvis to the
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NCCN Guidelines Version 5.2024

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morphologically indistinguishable from squamous cell carcinoma of .001) and a decreased 5-year recurrence rate from 58.8% to 44.8%
other sites and generally presents at an advanced stage. The three when comparing immediate intravesical chemotherapy following TURBT
variants within this subtype are pure squamous cell carcinoma, to TURBT alone, although the instillation did not prolong the time to
verrucous carcinoma, and squamous cell papilloma. progression or time to death from bladder cancer.15 This study also
found that the instillation did not reduce recurrences in patients who had
Other histologic subtypes derived from cells of urothelial origin include a prior recurrence rate of greater than one recurrence per year or with a
glandular neoplasms, epithelial tumors of the upper urinary tract, and European Organization for Research and Treatment of Cancer
tumors arising in a bladder diverticulum. Glandular neoplasms include (EORTC) recurrence score greater than or equal to 5.
adenocarcinoma and villous adenoma. Urachal tumors are non-
urothelial tumors, most commonly adenocarcinomas, which arise from Phase III trials have reported a reduced risk of recurrence for patients
the urachal ligament and secondarily involve the midline/dome of the with suspected non-muscle invasive disease who are treated with
bladder.54 Tumors arising within the genitourinary tract but that are not immediate postoperative gemcitabine or mitomycin. A randomized,
of urothelial origin (eg, tumors of Müllerian type, melanocytic tumors, double-blind, phase III trial of 406 patients with suspected low-grade
mesenchymal tumors) are beyond the scope of these guidelines. NMIBC based on cystoscopic appearance showed that immediate post-
TURBT instillation of gemcitabine reduced the rate of recurrence
Non-Muscle Invasive Urothelial Bladder Cancer compared to saline instillation (placebo).13 In the intention to treat (ITT)
Non-muscle invasive tumors were previously referred to as superficial, analysis, 35% of patients treated with gemcitabine and 47% of those
which is an imprecise term that should be avoided. Treatment for who received placebo had disease recurrence within 4 years (HR, 0.66;
non-muscle invasive disease often includes intravesical therapy or, for 95% CI, 0.48–0.90; P < .001).13 Intravesical therapy for a previous
those with particularly high-risk disease, cystectomy. NMIBC was allowed in the study if received at least 6 months prior to
enrollment. Another phase III, prospective, multicenter, randomized
Intravesical Therapy study of 2844 patients with NMIBC showed that an immediate
Intravesical therapy is implemented to reduce recurrence or delay instillation of mitomycin C after TURBT reduces recurrence regardless
progression of bladder cancer to a higher grade or stage. of the number of adjuvant instillations. Recurrence risk was 27% for
immediate instillation versus 36% for delayed instillation (P < .001) for
Immediate Intravesical Therapy Post TURBT all patients in the study, with the benefit of immediate instillation present
An immediate intravesical instillation of chemotherapy may be given across risk groups.14 Previous intravesical chemotherapy was permitted
within 24 hours of TURBT to prevent tumor cell implantation and early in study participants as long as it was received at least 3 years prior to
recurrence. Immediate intravesical chemotherapy has been shown to participation. For both studies, the rate of AEs did not significantly differ
decrease recurrence in select subgroups of patients. A systematic between the treatment and control groups, indicating that immediate
review and meta-analysis of 13 randomized trials demonstrated a intravesical instillation of gemcitabine or mitomycin was well
decreased risk of recurrence by 35% (HR, 0.65; 95% CI, 0.58–0.74; P < tolerated.13,14 Gemcitabine is preferred over mitomycin based on toxicity

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NCCN Guidelines Version 5.2024

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profiles and lower cost.55 For tumors with an intermediate or high risk of patients receiving either BCG (n = 59) or intravesical gemcitabine
progression, subsequent treatment with intravesical induction (adjuvant) (n = 61) and found no significant difference.68 There were more frequent
therapy may be given. Perioperative intravesical treatment should not local and systemic side effects in the BCG arm; however, they were
be given if there is extensive TURBT or concern for bladder perforation. mild to moderate and the treatment was well tolerated in both groups.
The benefit of BCG with or without isoniazid compared to epirubicin
Induction (Adjuvant) Intravesical Chemotherapy or BCG
alone in a long-term study of 957 patients with intermediate- or high-risk
Although only intravesical chemotherapy is recommended in the Ta or T1 disease was measured by a reduced recurrence, greater time
immediate postoperative setting, both intravesical chemotherapy and to distant metastases, and greater overall survival (OS) and
BCG have been given as induction therapy in patients with NMIBC.56 disease-specific survival (DSS); progression was similar.69 Long-term
The most commonly used chemotherapy agents are mitomycin C and data comparing BCG to epirubicin in combination with interferon69,70 in
gemcitabine, although gemcitabine is preferred over mitomycin due to patients with T1 disease showed a better reduction in recurrence with
better tolerability and cost. In addition, in systematic reviews and meta- BCG; however, no differences in progression or AEs were seen.70
analyses, gemcitabine has shown superior efficacy compared to Patients in both studies received 2 to 3 years of maintenance therapy.
mitomycin, in that it demonstrated reduced rates of recurrence and
progression.57,58 Maintenance Therapy
Maintenance intravesical therapy may be considered following induction
Induction BCG has been shown to decrease the risk of bladder cancer with chemotherapy or BCG. The role of maintenance chemotherapy is
recurrence following TURBT. BCG therapy is commonly given once a controversial. When given, maintenance chemotherapy is generally
week for 6 weeks, followed by a rest period of 4 to 6 weeks, with a full monthly. The role of maintenance BCG in those patients with
re-evaluation at week 12 (ie, 3 months) after the start of therapy.59 intermediate- to high-risk NMIBC is more established, although the
There are several meta-analyses demonstrating that BCG after TURBT exact regimens have varied across studies. Some of the previous
is superior to TURBT alone, or TURBT and chemotherapy in preventing controversy over the effectiveness of BCG maintenance reflects the
recurrences of high-grade Ta and T1 tumors.60-63 A meta-analysis wide array of schedules and conflicting reports of efficacy. Quarterly
including nine trials of 2820 patients with NMIBC reported that and monthly installations as well as 3- and 6-week schedules have
mitomycin C was superior to BCG without maintenance in preventing been evaluated. To date, the strongest data support the 3-week BCG
recurrence, but inferior to BCG in trials using BCG maintenance.64 regimen used in the SWOG trial that demonstrated reduced disease
Using the SEER database, a reduction in mortality of 23% was reported progression and metastasis.71 The 3-week timing of BCG has shown
in patients receiving BCG therapy.65 Other studies have also reported improved outcomes compared with epirubicin70 or isoniazid.69 Most
that BCG was better at reducing recurrence in intermediate- and patients receive maintenance BCG for 1 to 3 years. In an evaluation of
high-risk NMIBC when compared to mitomycin C.66,67 randomized controlled trials and meta-analyses, limited evidence was
found for 1 year of BCG maintenance.72 A study of 1355 patients with a
BCG has also been compared to gemcitabine and epirubicin. A
median follow-up of 7.1 years found no benefit in 3 years of
prospective, randomized phase II trial compared the quality of life in

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maintenance BCG compared to 1 year for patients with intermediate- or high-risk Ta, T1 papillary carcinoma of the bladder
intermediate-risk disease.73 Conversely, 3-year maintenance BCG were randomized to receive reduced- or full-dose BCG with either 1 or 3
reduced recurrence compared to 1-year maintenance but did not impact years of maintenance.80 Among all four groups, the percentage of
progression or survival in patients with high-risk disease. These data patients with greater than or equal to one side effect was similar
suggest that 1 year may be suitable for patients at intermediate risk (P = .41). Although the one-third dose of BCG was effective, side
while 3 years of maintenance is preferred for high-risk disease. It should effects were not reduced. Conversely, other publications suggest that
also be noted that duration of treatment may be limited by toxicity and the one-third dose may reduce side effects.81-83 Full-dose BCG is
patient refusal to continue. recommended by the panel until more data are available to evaluate the
low-dose BCG regimen. However, dose reduction may be used if there
For patients showing no residual disease at the follow-up cystoscopy, are substantial local symptoms during maintenance.
whether 1 or 2 courses of induction therapy were administered,
maintenance therapy with BCG is preferred. This recommendation is A reduction in the frequency of BCG instillations with the goal of
based on findings that an induction course of intravesical therapy reducing treatment-related AEs was tested in the phase III NIMBUS
followed by a maintenance regimen produced better outcomes than trial.84 In this trial, 345 patients with NMIBC were randomized to receive
intravesical chemotherapy.56,60,61,71,74,75 standard-dose BCG for 6 weeks of induction, followed by 3 weeks of
maintenance at 3, 6, and 12 months (15 total instillations) or standard-
BCG Toxicity
dose BCG for 3 weeks of induction, followed by 2 weeks of
There are concerns regarding potentially severe local and systemic side maintenance at 3, 6, and 12 months (9 total instillations). After 12
effects and the inconsistent availability of BCG. BCG induces a months of follow-up the ITT population showed a higher number of
systemic, nonspecific, immunostimulatory response leading to secretion recurrences in the reduced frequency treatment group (46/170)
of proinflammatory cytokines. This causes patients to experience flu-like compared to the standard treatment group (21/175) and a safety
symptoms that may last 48 to 72 hours.76 Installation of BCG into the analysis HR of 0.40, with the upper part of the one-sided 95% CI of
bladder can mimic a urinary tract infection and may produce intense 0.68, meeting the predefined criteria for immediately stopping the trial
local discomfort. The side effects of treatment have translated to due to inferiority of the reduced frequency arm.
discontinuation of BCG therapy. Dysuria has been reported in 60% of
patients in clinical trials.76 However, the side effects are treatable in BCG Shortage
almost all cases77 and no increase in toxicity has been reported with An ongoing shortage of BCG has existed in the United States,
cumulative doses. Symptom management with single-dose, short-term necessitating development of strategies to prioritize use of intravesical
quinolones and/or anticholinergics have been reported to reduce BCG and identify alternative treatment approaches for some patients
AEs.78,79 with NMIBC.85 Several organizations, including the American Urological
Association (AUA), American Association of Clinical Urologists (AACU),
A reduced (one-third) dose of BCG was evaluated for the possible
Bladder Cancer Advocacy Network (BCAN), Society of Urologic
reduction of side effects. In a phase III study, 1316 patients with

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Oncology (SUO), the Large Urology Group Practice Association there were no differences in progression or survival rates.73 Based on
(LUGPA), and the Urology Care Foundation (UCF), issued a notice these data, the panel recommends that one-half or one-third dose may
outlining strategies to maximize care for patients with NMIBC in the be considered for BCG induction during a shortage and should be used
context of this shortage.86 NCCN Panel Members recommend several for BCG maintenance, if supply allows. Maintenance BCG should be
strategies to help alleviate problems associated with this shortage. prioritized for patients with high-risk NMIBC (cT1 high grade and/or CIS)
in the early maintenance period (eg, 3 and 6 months post-induction),
In the event of a BCG shortage, priority for treatment should be to although in cases of shortage, BCG induction therapy should be
provide patients with high-risk NMIBC (cT1 high grade or CIS) with prioritized over maintenance BCG.
induction BCG. For patients who do not receive BCG, intravesical
chemotherapy may be used as an alternative. The intravesical Treatments for BCG-Unresponsive or BCG-Intolerant NMIBC
chemotherapies most commonly used for this purpose are Nadofaragene Firadenovec-vncg
gemcitabine55,87 and mitomycin.88 Two separate meta-analyses of Nadofaragene firadenovec is a non-replicating adenoviral vector-based
randomized trials reported that there were no differences in risk of gene therapy that is indicated for the treatment of patients with high-
recurrence between BCG and mitomycin,56,89 although BCG may show risk, BCG-unresponsive NMIBC with CIS, with or without papillary
more favorable outcomes from maintenance regimens.56 Other options tumors. A phase III, open-label, multicenter study evaluated
include epirubicin,69,90 valrubicin,91 docetaxel,92 sequential nadofaragene firadenovec in 157 patients with BCG-unresponsive
gemcitabine/docetaxel,93 or gemcitabine/mitomycin.94 Another NMIBC.98 Of the 103 patients on the study with CIS, with or without a
alternative to intravesical BCG for patients with NMIBC at high risk of high-grade Ta or T1 tumor, 25 remained free of high-grade recurrence
recurrence and, particularly, at high risk of progression, is initial radical at 12 months (24.3% 12-month complete response rate; 95% CI, 16.4-
cystectomy.95 33.7). Urinary urgency was the most common grade ≥3 treatment-
related AE (1% of patients). A longer-term follow-up from this same
Another option during a shortage is splitting the dose of BCG so that
cohort of patients was reported on in a 2021 AUA Conference abstract
multiple patients may be treated using a single vial. While several
with a mean follow-up of 23.5 months.99 Twenty-four months after the
randomized trials have reported that one-third-dose BCG showed
first dose, 19.4% of patients remained free of high-grade recurrence,
similar outcomes when compared to full-dose BCG,82,96,97 a phase 3 trial
with a median duration of high-grade RFS of 12.2 months. Of the 55
of 1355 patients with intermediate- or high-risk NMIBC reported that
patients who achieved a complete response, 20 (36.4%) remained free
patients receiving the full dose of BCG show a longer disease-free
of high-grade recurrence at 24 months. By 24 months, cystectomy-free
interval, compared with those receiving the one-third dose.73 In this
survival was 64.6% and OS was 94.4%. The most common drug-related
study, the 5-year disease-free rate was 58.5% for the one-third dose
AEs were instillation site discharge (24.3%), fatigue (23.4%), bladder
compared to 61.7% for the full dose; therefore, the null hypothesis of
spasm (17.8%), and urinary urgency (16.8%), with most AEs being
inferiority for duration of the disease-free interval of one-third-dose BCG
grades 1–2. Two patients discontinued treatment due to drug-related
could not be rejected (HR, 1.15; 95% CI, 0.98–1.35; P = .045), although
AEs.

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NCCN Guidelines Version 5.2024

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A second cohort of the same phase III trial detailed above included 48 Pembrolizumab for NMIBC
patients with BCG-unresponsive NMIBC, high-grade Ta/T1 tumors only. Pembrolizumab is a programmed cell death protein 1 (PD-1) inhibitor
A 2021 AUA Conference abstract reported on 2-year follow-up results that has been evaluated as systemic therapy for BCG-unresponsive
from this cohort.100 Of the 48 patients in this cohort, 72.9%, 43.8%, and NMIBC with CIS in the single-arm, phase II KEYNOTE-057 study
33.3% were high-grade recurrence-free at 3, 12, and 24 months, (pembrolizumab is also indicated for treatment of metastatic urothelial
respectively. Of those who were free of high-grade recurrence at 3 carcinoma; see section on Metastatic (Stage IVB) Urothelial Bladder
months, 45.7% were high-grade recurrence-free at 24 months, with a Cancer, below). In the KEYNOTE-057 study, 101 patients with high-risk
median duration of high-grade RFS of 19.8 months. As estimated at 24 CIS, with or without papillary tumor, who received previous BCG
months, cystectomy-free survival was 69.8% and OS was 93.2%. therapy and were either unable or unwilling to undergo cystectomy were
treated with pembrolizumab.103 Ninety-six patients were eligible for
Nogapendekin alfa inbakicept-pmln (N-803) inclusion in the efficacy analysis. The 12-month complete response rate
N-803 is an immune cell-activating interleukin-15 superagonist that was was 19% (18 of 96 total patients on the study), and the median duration
studied in combination with BCG for patients with BCG-unresponsive, of response (DOR) from time of onset was 16.2 months (95% CI, 6.7–
high-risk NMIBC in the phase II/III QUILT-3.032 study.101 QUILT-3.032 36.2). Grade ≥3 treatment-related AEs were reported in 13% of
included three cohorts of patients: those with bladder CIS, with or patients, with arthralgia and hyponatremia being the most common.
without Ta/T1 papillary disease, who were treated with N-803 plus BCG Serious treatment-related AEs occurred in 8% of patients.
(cohort A); those with high-grade papillary Ta/T1 only disease who were
treated with N-803 plus BCG (cohort B); and those with bladder CIS, Cohort B of the KEYNOTE-057 study included 132 patients with high-
with or without Ta/T1 papillary disease, who were treated with N-803 risk, BCG-unresponsive NMIBC with high-grade Ta or any-grade T1
alone (cohort C). In cohort A, complete response was reported in 71% papillary tumors (without CIS). A 2023 ASCO Genitourinary Cancers
of 82 patients, with a median duration of complete response of 26.6 Symposium abstract reported efficacy data after a median follow-up of
months. For the 72 patients in cohort B, DFS was 55.4% at 12 months, 45.4 months.104 Median high-risk disease-free survival (DFS) was 7.7
with a median DFS of 19.3 months. For cohort C, only 2 of 10 patients months and progression-free survival (PFS) to worsening of grade,
showed complete response after 3 months and cohort C was ultimately stage, or death was 44.5 months. Thirty-one patients (23.5%)
discontinued approximately 6 months into the study due to futility. Most underwent radical cystectomy after discontinuation of pembrolizumab.
treatment-related AEs for N-803 plus BCG were grade 1-2 (86%), 2% of Twelve-month OS was 96.2%.
patients treated with the combination reported at least one grade 3
immune-related treatment-emergent AE. A study on patient-reported NCCN Recommendations for Treatment of NMIBC
outcomes in the QUILT-3.032 study concluded that the combination of The NCCN Panel recommends management of NMIBC based on
N-803 and BCG had a favorable risk to benefit ratio and quality of life AUA/SUO risk stratification,105 with the caveat that an individual patient
following treatment.102 within each of the risk strata may have more or less concerning features
that can influence care decisions (see AUA Risk Stratification for Non-

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NCCN Guidelines Version 5.2024

Bladder Cancer

Muscle Invasive Bladder Cancer in the algorithm). Retrospective Treatment of Low-Risk NMIBC
reviews have shown that the AUA/SUO risk classification accurately By the AUA/SUO risk stratification, low-risk NMIBC includes PUNLMP
stratifies patients with NMIBC by the likelihood of recurrence and and low-grade urothelial carcinoma that is a solitary Ta and less than or
progression.106 equal to 3 cm.105 For these tumors, risk of recurrence or progression is
low following TURBT and no further treatment is necessary,112 although
After the initial TURBT shows NMIBC, a repeat TURBT is a single instillation of intravesical chemotherapy immediately post-
recommended for visually incomplete or high-volume tumors and for TURBT can be helpful in reducing the risk of recurrence.15 An
high-grade NMIBC, which is found to be T1 on the initial TURBT.107 This appropriate surveillance schedule is recommended for early detection of
is supported by a trial that prospectively randomized 142 patients with disease recurrence.
pT1 tumors to a second TURBT within 2 to 6 weeks of the initial TURBT
or no repeat TURBT.108 All patients received adjuvant intravesical Treatment of Intermediate-Risk NMIBC
therapy. Although OS was similar, the 3-year recurrence-free survival Intermediate-risk NMIBC includes low-grade urothelial carcinoma that
was significantly higher in the repeat TURBT arm versus the control arm has any of the following characteristics: T1, size greater than 3 cm,
(69% vs. 37%, respectively), especially among patients with high-grade multifocal, or recurrence within 1 year. In addition, high-grade urothelial
tumors. Similarly, a randomized 10-year extension trial of 210 patients carcinoma that is solitary, Ta, and less than or equal to 3 cm is also
with pT1 NMIBC found that patients who underwent repeat TURBT had considered intermediate risk.105 Although a complete TURBT alone can
a significantly higher 5-, 7-, and 10-year RFS and PFS and, in addition, eradicate intermediate-risk NMIBC, there is a relatively high risk for
the 10-year OS rate was significantly higher in patients with repeat recurrence. Therefore, after TURBT and immediate intravesical
TURBT (59.1% vs. 40.8%; P = .004).109 Repeat TURBT was found to be chemotherapy, the panel recommends a 6-week induction course of
an independent determinant of prolonged OS on multivariate analysis. intravesical therapy. Options for intravesical therapy for intermediate-
risk NMIBC include BCG or chemotherapy. The availability of BCG
Repeat TURBT may also be considered for select patients with high- should be considered in decision-making as it may be prioritized for
grade Ta on initial TURBT, particularly if the tumor is large and/or there treatment of higher risk disease. A systematic review and meta-analysis
was no muscle present in the initial TURBT specimen. Restaging has reported that intravesical treatment with BCG does not appear
TURBT detected residual disease in 27% of Ta patients when muscle superior to chemotherapy for reduction of disease recurrence in patients
was present in the original TURBT.110 In the absence of muscularis with intermediate-risk NMIBC.113 If maintenance BCG is given following
propria in the initial TURBT specimen, 49% of patients with non-muscle the induction course, data support limiting maintenance BCG to one
invasive disease will be understaged versus 14% if muscle is year for intermediate-risk disease since no additional benefit is derived
present.111 from the full 3 years.73 While an induction course of intravesical therapy
is preferred, surveillance is also an option for intermediate-risk disease.
If muscle invasive disease is found during repeat TURBT, then
additional staging for muscle invasive disease and appropriate
treatment depending on stage should be followed.

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NCCN Guidelines Version 5.2024

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The value of an induction course of intravesical therapy depends on the Treatment options for high-risk NMIBC depend on whether the tumor
patient’s prognosis and likelihood of disease recurrence. Factors to has previously been shown to be unresponsive or intolerant to BCG.
consider include the size, number, T category, and grade of the For BCG-naïve NMIBC, the options are cystectomy or BCG. When very
tumor(s), as well as concomitant CIS and prior recurrence.25 high-risk features are present, cystectomy is preferred because of the
Meta-analyses have confirmed the efficacy of adjuvant (induction) high risk for progression to a more advanced stage,117,118 while BCG is
intravesical chemotherapy in reducing the risk of recurrence.114,115 In the preferred when these are not present. BCG is also a category 1
literature, there are four meta-analyses confirming that BCG after recommendation for BCG-naïve, high-risk NMIBC without very-high-risk
TURBT is superior to TURBT alone, or TURBT and chemotherapy in features. A prospective study including 50 patients with high-risk, BCG-
preventing recurrences of Ta and T1 tumors.60-63 Close follow-up of all naïve NMIBC randomized patients to either radical cystectomy or
patients is needed, although the risk for progression to a more induction, then maintenance, BCG.119 During follow-up, two (10%) of 23
advanced stage is low (see Surveillance in the discussion and patients in the BCG arm developed metastatic bladder cancer, while all
algorithm). participants in the cystectomy arm remained disease-free.

Treatment of High-Risk NMIBC For some patients, BCG is not an option due to side effects or a tumor
High-risk NMIBC has a relatively high risk for recurrence and that is BCG-resistant. For these patients, cystectomy is preferred
progression towards more invasiveness. According to the AUA/SUO although other intravesical chemotherapy, N-803, pembrolizumab, or
risk stratification, high-risk NMIBC includes high-grade urothelial nadofaragene firadenovec are other options (see Treatments for BCG-
carcinoma that has any of the following characteristics: CIS, T1, size Unresponsive or BCG-Intolerant Disease for patient and disease
greater than 3 cm, or multifocal. In addition, a subgroup of very-high-risk characteristics for which these treatment options would be appropriate).
features includes BCG unresponsiveness, variant histologies, Non-cystectomy candidates with recurrent or persistent high-grade cTa
lymphovascular invasion, and prostatic urethral invasion.105 Based on or cT1 disease may also consider concurrent chemoradiotherapy as an
the histologic differentiation, most cT1 lesions are high grade and option (category 2A for cT1, category 2B for cTa). Valrubicin is
considered to be potentially dangerous with a higher risk for recurrence approved for CIS that is refractory to BCG, although panelists disagree
and progression. These tumors may occur as solitary lesions or as on its value.91
multifocal tumors with or without an associated CIS component. The
presence of CIS is associated with an increased risk of invasive Surveillance
disease, including increased cancer progression rates and worse For intermediate and high-risk NMIBC, follow-up is recommended with a
cancer-specific outcomes.20 If untreated, 50% of CIS progresses to urinary cytology and cystoscopy at 3- to 6-month intervals for the first 2
muscle invasive disease within 5 years and, even with treatment, 30% years, and at longer intervals as appropriate thereafter. Imaging of the
to 40% progresses within 10 years.116 upper tract should be considered every 1 to 2 years for high-risk tumors
(see Follow-up in the algorithm). Urine molecular tests for urothelial
tumor markers are now available.120 Many of these tests have a better

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sensitivity for detecting bladder cancer than urinary cytology, but cytology and no demonstrable clinical disease in the urinary tract,
specificity is lower. Considering this, evaluation of urinary urothelial evaluation of the contiguous organs (eg, vagina, cervix, uterus, or
tumor markers may be considered during surveillance of high-risk anorectum) via referral to an appropriate specialist may be warranted.
NMIBC. However, it remains unclear whether these tests offer Several case reports have described the detection of urothelial
additional useful information for detection and management of carcinoma spread to the vagina, cervix, or vulva.121-123 It has also been
non-muscle invasive bladder tumors. Therefore, the panel considers reported that as many as 14% of patients with a positive urine cytology
this to be a category 2B recommendation. and no visible disease in the bladder had tumors in contiguous organs
as the source of the positive cytology finding.124 If the bladder, prostate,
For patients with low-risk NMIBC, if the initial follow-up surveillance and upper tract continue to show negative results on further evaluation,
cystoscopy is negative within 4 months of TURBT, the next cystoscopy additional follow-up is indicated after 3 months, then at longer intervals.
is recommended 6 to 9 months later and then yearly for up to 5 years. If BCG was given previously, maintenance BCG may be considered.
Follow-up cystoscopy after 5 years should only be performed based on
clinical indication. Beyond baseline imaging, upper tract imaging is not If transurethral biopsy of the prostate is positive, treatment of the
indicated without symptoms for patients with low-risk NMIBC. prostate should be initiated as described below (see Urothelial
Carcinomas of the Prostate). If upper tract urothelial carcinoma (UTUC)
Posttreatment of Recurrent or Persistent Disease is identified, then the treatment described below should be followed
Treatment of Patients with Positive Cystoscopy (see Upper Tract Urothelial Carcinoma).
Patients under surveillance after initial TURBT, who show a
documented recurrence by positive cystoscopy, should undergo another If the selected mapping biopsy of the bladder is positive, then the AUA
TURBT to reclassify the AUA/SUO risk group. Patients should be risk group should be reclassified and the tumor managed according to
treated and followed as indicated based on the risk of their recurrent NCCN Recommendations for Treatment of NMIBC, above.
disease.
In a phase II multicenter study of NMIBC that recurred following two
Treatment of Patients with Positive Cytology courses of BCG, intravesical gemcitabine demonstrated activity that
In patients without a documented recurrence but with initial positive was relegated to high-risk NMIBC.125 In the 47 patients with evaluable
cytology and negative cystoscopy and imaging, it may be appropriate to response, 47% had DFS at 3 months. The 1-year RFS was 28% with all
repeat the cytology test within 3 months. If subsequent cytology tests cases except for two attributed to the high-risk group. The 2-year RFS
are positive, selected mapping biopsies including transurethral resection was 21%. Intravesical gemcitabine had some activity in the high-risk
of the prostate (TURP) may be considered. In addition, the upper tract group, and may be an option if a candidate is not eligible for a
must be evaluated and ureteroscopy may be considered for detecting cystectomy; however, the study results indicate that cystectomy is
tumors of the upper tract. If available, enhanced cystoscopy should be preferred when possible. Similarly, for patients with recurrence of
considered (see Enhanced Cystoscopy, above). With persistent positive high-grade cT1 disease after TURBT and induction BCG, cystectomy is
the recommended option with the best data for cure.126 Surveillance

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NCCN Guidelines Version 5.2024

Bladder Cancer

may be reasonable in highly select cases where low-grade, Unfortunately, CT scans, ultrasound, and MRI cannot accurately predict
small-volume tumors had limited lamina propria invasion and no the true depth of invasion.
CIS.127,128 Further investigation and validation of results is warranted for
establishing the efficacy of alternative agents for BCG-unresponsive or - The overwhelming majority of muscle invasive tumors are high-grade
refractory disease.129 Recurrences that are found to be muscle invasive urothelial carcinomas. Further treatment following initial TURBT is often
or metastatic disease should be treated as described in the appropriate required for muscle invasive tumors, although select patients may be
section below. treated with TURBT alone.137,138 Different treatment modalities are
discussed below. These include radical cystectomy, partial cystectomy,
Muscle Invasive Urothelial Bladder Cancer neoadjuvant or adjuvant therapy, bladder-preserving approaches, and
Additional Workup systemic therapy for advanced disease.

Several workup procedures are recommended to accurately determine Cystectomy

clinical staging of muscle invasive disease. Laboratory studies, such as Radical Cystectomy
a complete blood count (CBC) and chemistry profile, including alkaline Radical surgical treatment of bladder cancer involves a
phosphatase, must be performed. Since cisplatin-based chemotherapy cystoprostatectomy or a cystectomy and commonly a hysterectomy for
is a preferred approach both for neoadjuvant therapy prior to those with a uterus, followed by the formation of a urinary diversion,
cystectomy and as part of trimodal therapy for bladder preservation, an although in appropriately selected patients, approaches that preserve
estimated glomerular filtration rate (GFR) should be obtained to assess the uterus, vagina, fallopian tubes, and/or ovaries may be used.139,140
patient eligibility for cisplatin. For patients with borderline GFR results, a This surgery can be performed in an open or robotic manner.141-144
timed or measured urine collection may be considered to more Prostatectomy includes removal of the prostate, seminal vesicles,
accurately determine cisplatin eligibility.130 proximal vas deferens, and proximal urethra. Hysterectomy should
Patients should also be assessed for regional or distant metastases. include removal of the uterus, ovaries, fallopian tubes, urethra, and part
This evaluation should include chest imaging (CT [preferred], x-ray, or of the vagina. Forms of urinary diversion include an ileal conduit or
fluorodeoxyglucose [FDG]-PET/CT [category 2B]) and evaluation for directing urine to an internal urinary reservoir (such as a continent
suspected bone metastasis in patients with symptoms or clinical pouch), with drainage to the abdominal wall or the urethra (orthotopic
suspicion of bone metastasis (eg, elevated alkaline phosphatase, focal neobladder). Relative contraindications to urethral drainage include CIS
bone pain). Chest imaging with CT is preferred over chest x-ray based in the prostatic ducts or positive urethral margin. Orthotopic diversion or
on studies showing better sensitivity of CT for detection of metastatic a neobladder provides the closest bladder function to that of a native
disease.131,132 Bone imaging may include a bone scan, MRI, or FDG- bladder albeit with an increased risk for nighttime incontinence as well
PET/CT (category 2B). Imaging studies help assess the extent of tumor as urinary retention requiring intermittent self-catheterization.
spread to lymph nodes or distant organs.133,134 An abdominal/pelvic CT
or MRI is used to assess the local and regional extent of disease.135,136

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NCCN Guidelines Version 5.2024

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Unfortunately, the accuracy of the staging cystoscopy, EUA, and is not an absolute contraindication. Outcomes data on partial
TURBT is modest, even when combined with cross-sectional imaging cystectomy are varied and, in general, partial cystectomy is not
and when understaging is frequently encountered. A retrospective study considered the standard surgical treatment of muscle invasive bladder
of 778 patients with bladder cancer found that 42% of patients were cancer. Ideal candidates are patients with cancer in a diverticulum or
upstaged following cystectomy.145 A pelvic lymph node dissection with significant 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.146- the intraoperative findings preclude a partial cystectomy, a radical
150
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 systemic therapy is based on the pathologic stage (ie, positive nodes
RFS, cancer-specific survival, or OS.151 However, differing definitions of or perivesical tissue involvement) or presence of a positive margin,
“extended” versus “limited” LND between studies and specifics on how similar 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 answer this the optimal use of perioperative chemotherapy for muscle invasive
question.152 Patient factors that may preclude a PLND include severe disease. Data support the role of neoadjuvant chemotherapy before
scarring secondary to previous treatments or surgery, advanced age, or cystectomy for stage II and IIIA lesions.153-158 In a SWOG randomized
severe 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 vs. 46 months; P = .06) and lowered the rate of
adequate amount of noninvolved urothelium can be removed along with residual disease (15% vs. 38%; P < .001) with no apparent increase in
the tumor without compromising continence or significantly reducing treatment-related morbidity or mortality.153 In a meta-analysis of 11 trials
bladder capacity. Partial cystectomy is most frequently recommended involving 3005 patients, cisplatin-based multiagent neoadjuvant
for lesions that develop on the dome of the bladder and have no chemotherapy was associated with improved 5-year OS and DFS (5%
associated CIS in other areas of the urothelium. Relative and 9% absolute improvement, respectively).157 The randomized, phase
contraindications to this procedure are lesions that occur in the trigone III JCOG0209 study comparing neoadjuvant MVAC to no neoadjuvant
or bladder neck. The requirement for a ureteral reimplantation, however, chemotherapy also found no difference in health-related quality of life

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NCCN Guidelines Version 5.2024

Bladder Cancer

after cystectomy, further supporting the use of neoadjuvant Gemcitabine and cisplatin (GC) has also been evaluated for
chemotherapy in all patients who are eligible to receive it.159 A review of neoadjuvant therapy of muscle invasive bladder cancer, albeit mainly in
the National Cancer Database (NCDB) supports initiation of smaller phase II or retrospective studies. Overall, these studies showed
neoadjuvant chemotherapy as soon as possible, but not more than 8 that GC is effective and well-tolerated when used as neoadjuvant
weeks after diagnosis to prevent upstaging after radical cystectomy.160 therapy for muscle invasive bladder cancer,165-169 although some of the
studies report lower pathologic response compared to MVAC168 and
Since the neoadjuvant trial with MVAC, the use of dose-dense MVAC lack of a demonstrated OS benefit due to short follow-up or small study
(ddMVAC) with growth factor support in the metastatic setting has been size.166,167 More recently, the phase II COXEN trial has evaluated
shown to have good comparable tolerance with an increased complete ddMVAC and GC as neoadjuvant therapy for muscle invasive bladder
response rate compared to standard (28-day) dosing of MVAC (11% vs. cancer with the aim of validating scoring from a coexpression
25%; 2-sided P = .006).161 Based on these findings, ddMVAC has also extrapolation algorithm-generated gene expression model.170,171 In the
been investigated in the neoadjuvant setting. In a multicenter ITT population of 227 patients, pT0 rates for ddMVAC and GC were
prospective phase II trial, patients with cT2 to cT4a tumor staging and 28% and 30% (P = .75) and downstaging was 47% and 40% (P = .27),
N0 or N1 muscle invasive bladder cancer (n = 44) were given 3 cycles respectively.170 No significant difference between ddMVAC and GC was
of ddMVAC with pegfilgrastim followed by radical cystectomy and lymph reported for OS or event-free survival.171 Dose-dense GC has been
node dissection.162 ddMVAC was anticipated to have a safer profile, a evaluated as neoadjuvant therapy in a prospective, phase II trial
shorter time to surgery, and a similar pathologic complete response rate including 46 evaluable patients.172 The primary endpoint of this trial was
compared to historical control data for neoadjuvant MVAC met as 57% of patients had their disease downstaged to NMIBC (less
chemotherapy given in previous studies. Patients receiving ddMVAC than pT2, N0). Pathologic response also correlated with improved RFS
had no grade 3 or 4 renal toxicities and no toxicity-related deaths. and OS. Thirty-nine percent of patients experienced dose modifications
Grade 1 or 2 treatment-related toxicities were seen in 82% of patients. due to treatment toxicity, but no patients were unable to undergo
The median time to cystectomy was 9.7 weeks from the start of cystectomy due to treatment-related AEs. The most frequent treatment-
chemotherapy.162 A separate single-arm phase II study also reported related AE was anemia (12% grade 3).
pathologic downstaging in 49% of patients receiving neoadjuvant
ddMVAC with a similar safety profile.163 An additional neoadjuvant The randomized phase III GETUG/AFU V05 VESPER trial compared
clinical trial of ddMVAC with bevacizumab reported 5-year survival the efficacy of ddMVAC to GC in the perioperative setting for 500
outcomes of 63% and 64% (OS and DSS, respectively; median patients with muscle invasive bladder cancer.173,174 Of the 437 patients
follow-up, 49 months), with pT0N0 and less than or equal to pT1N0 who received neoadjuvant chemotherapy, organ-confined response
downstaging rates of 38% and 53%, respectively.164 Bevacizumab had (less than ypT3, N0) was observed more frequently with ddMVAC than
no definitive impact on overall outcomes. GC (77% vs. 63%; P = .001).173 PFS at 3 years was also significantly
higher among those who received neoadjuvant ddMVAC compared to
neoadjuvant GC (66% vs. 56%; HR, 0.70; 95% CI, 0.51–0.96; P =

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NCCN Guidelines Version 5.2024

Bladder Cancer

.025). An analysis comparing secondary endpoints of the VESPER trial trial, ddMVAC is the preferred regimen for perioperative treatment of
also reported a higher complete pathologic response rate for muscle invasive bladder cancer. For patients with borderline renal
neoadjuvant ddMVAC compared to GC (42% vs. 36%).174 Reported function or minimal dysfunction, a split-dose administration of cisplatin
toxicity was similar between the therapies, with 52% of patients may be considered (category 2B). Although split-dose is a safer
experiencing grade 3 or higher AEs with ddMVAC compared to 55% alternative, the relative efficacy remains undefined.
with GC. Grade 3 or higher AEs that were more frequently observed
with ddMVAC included gastrointestinal disorders (P = .003) and Adjuvant Systemic Therapy
asthenia (P = .001). A systematic review and meta-analysis similarly Data are less clear regarding the role of adjuvant systemic therapy in
showed a significantly higher rate of pathologic complete response and invasive bladder cancer. Studies have shown that adjuvant
OS for neoadjuvant therapy with ddMVAC compared to GC.175 chemotherapy may delay recurrences and improve OS176-178; however,
no randomized comparisons of adequate sample size have definitively
In an international, multicenter, randomized trial (BA06 30894) that shown a survival benefit, in large part due to poor accrual.179 Clinical
investigated the effectiveness of neoadjuvant cisplatin, methotrexate, trials of adjuvant chemotherapy with cyclophosphamide, doxorubicin,
and vinblastine (CMV) in 976 patients, neoadjuvant CMV resulted in a and cisplatin (CAP); MVAC; and methotrexate, vinblastine, epirubicin,
16% reduction in mortality risk (HR, 0.84; 95% CI, 0.72–0.99; P = .037) and cisplatin (MVEC) regimens have each suggested a survival
at a median follow-up of 8 years.158 However, based on NCCN Panel advantage.180-182 However, methodologic issues question the
consensus that this regimen is not used in their practices, CMV is no applicability of these studies to all patients with urothelial tumors. In the
longer recommended as an option for neoadjuvant or adjuvant therapy. MVEC trial, patients who experienced relapse in the control arm did not
receive chemotherapy, which is not typical of more contemporary
The NCCN Panel recommends neoadjuvant chemotherapy followed by
treatment approaches. Many of these trials were not randomized,
radical cystectomy for patients with stage II or IIIA bladder cancer.
raising the question of selection bias in the analysis of outcomes.
Neoadjuvant chemotherapy followed by radical cystectomy is a
category 1 recommendation based on high-level data supporting its A meta-analysis of 6 trials found a 25% mortality reduction with adjuvant
use. For highly select patients with stage II disease who receive a chemotherapy, but the authors pointed out several limitations of the
partial cystectomy, neoadjuvant chemotherapy is a category 2A data and concluded that evidence is insufficient for treatment
recommendation. Patients with hearing loss or neuropathy, poor decisions.183 Interestingly, the follow-up analysis included 3 more
performance status, or renal insufficiency may not be eligible for studies for a total of 9 trials (N = 945 patients).178 A 23% risk reduction
cisplatin-based chemotherapy. If cisplatin-based chemotherapy cannot for death was observed in the updated analysis (HR, 0.77; 95% CI,
be given, neoadjuvant chemotherapy is not recommended. Carboplatin 0.59–0.99; P = .049) and improved DFS was achieved (HR, 0.66; 95%
has not demonstrated a survival benefit and should not be substituted CI, 0.45–0.91; P = .014). Patients with node-positive disease had an
for cisplatin in the perioperative setting. Cystectomy alone is an even greater DFS benefit.178 An observational study evaluated 5653
appropriate option for these patients. Based on results of the VESPER patients of which 23% received adjuvant chemotherapy

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NCCN Guidelines Version 5.2024

Bladder Cancer

post-cystectomy.177 Patients who received adjuvant chemotherapy had previous cisplatin-based neoadjuvant therapy. Treatment-related AEs of
an improved OS (HR, 0.70; 95% CI, 0.06–0.76).177 Other studies have grade 3 or higher occurred in 17.9% of those treated with nivolumab
reported similar results.184 Although evidence for adjuvant therapy is not and 7.2% of those treated with placebo. Further follow-up is ongoing to
as strong as for neoadjuvant therapy, the growing body of data support assess OS outcomes. While atezolizumab has also been tested in the
the administration of adjuvant therapy for certain patients with a high adjuvant setting for patients with high-risk muscle invasive urothelial
risk for relapse. carcinoma in the phase 3 IMvigor010 study, this study did not meet its
primary endpoint of improved DFS with adjuvant atezolizumab
The VESPER trial, described in detail above, included a subgroup of 55 compared to observation.186 Median DFS was 19.4 months with
patients who were treated with either ddMVAC or GC as adjuvant atezolizumab compared to 16.6 months with observation (HR, 0.89;
therapy.173,174 While results were not conclusive due to small sample 95% CI, 0.74–1.08; P = .24).
size for the adjuvant group, 3-year PFS was improved in the ddMVAC
group compared to the GC group for all patients who received The NCCN Guidelines suggest that adjuvant systemic therapy should
perioperative therapy (64% vs. 56%; HR, 0.77; 95% CI, 0.57–1.02; P = be discussed with patients with high-risk pathology after cystectomy. If
.066) as was time to progression (3-year rate 69% vs. 58%; HR, 0.68; cisplatin-based neoadjuvant therapy was not given and the tumor is
95% CI, 0.50–0.93; P = .014). Based on these results, ddMVAC is found to be pT3, pT4, or pN+ following resection, adjuvant cisplatin-
preferred over GC for adjuvant chemotherapy. based chemotherapy is the preferred approach, although adjuvant
nivolumab may also be considered. If cisplatin-based neoadjuvant
Checkpoint inhibitors have also been investigated in the adjuvant therapy was given and the tumor is ypT2–ypT4a or ypN+, nivolumab
setting, with the phase 3 CheckMate 274 trial of adjuvant nivolumab may be considered, although consideration of this approach should
reporting positive results for its primary endpoints across the entire balance its effect at delaying progression of disease with the risk of side
study population, although the authors note the possibility of a larger effects. A minimum of 3 cycles of a cisplatin-based combination, such
effect size for bladder compared to UTUC (see Adjuvant Treatment and as ddMVAC (preferred) or GC, may be used in patients undergoing
Follow-up under UTUC, below, for more discussion on these data).185 In perioperative chemotherapy. Chemotherapy regimen and dosing
the ITT population of 709 patients with muscle invasive urothelial recommendations are mainly based on studies in advanced
carcinoma treated with radical surgery on CheckMate 274, DFS was disease.153,165,187,188 Carboplatin has not demonstrated a survival benefit
20.8 months with nivolumab compared to 10.8 months with placebo and should not be substituted for cisplatin in the perioperative setting. It
(HR, 0.70; 98.22% CI, 0.55–0.90; P < .001). For patients with a should be noted that patients with tumors that are pT2 or less and have
programmed death-ligand 1 (PD-L1) expression level of 1% or more, no nodal involvement or lymphovascular invasion after cystectomy are
DFS was 74.5% with nivolumab and 55.7% with placebo (HR, 0.55; considered to have lower risk and are not recommended to receive
98.72% CI, 0.35–0.85; P < .001). Importantly, adjuvant nivolumab was adjuvant therapy.
tested both in patients who had received neoadjuvant therapy as well
as those who did not; 43.4% of the trial participants had received

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NCCN Guidelines Version 5.2024

Bladder Cancer

Adjuvant Radiation reasonably well tolerated and improves local control. Radiation with a
Patients with locally advanced disease (pT3–4) have high rates of pelvic dose range of 45 to 50.4 Gy without concurrent chemotherapy may be
recurrence and poor OS after radical cystectomy, PLND, and used. In patients who have not had prior neoadjuvant chemotherapy, it
perioperative chemotherapy (pelvic failure 20%–45% and survival 10%– may be reasonable to sandwich adjuvant radiation between cycles of
50% at 5 years, depending on risk factors).189-192 There is an interest in adjuvant chemotherapy.194 The safety and efficacy of concurrent
using adjuvant radiation to improve these outcomes, but data are limited sensitizing chemotherapy and radiation in the adjuvant setting needs to
and further prospective studies are needed to confirm its benefits. One be further studied.
older randomized study of 236 patients with pT3a to pT4a bladder
Bladder Preservation
cancer demonstrated improvement in 5-year DFS and local control
compared to surgery alone.193 A more recent randomized phase II trial All bladder-sparing approaches are based on the principle that not all
compared adjuvant sequential chemotherapy and radiation versus cases require an immediate cystectomy, and the decision to remove the
adjuvant chemotherapy alone in 120 patients with locally advanced bladder can be deferred until the response to organ-sparing therapy is
disease with one or more risk factors (≥pT3b, grade 3, or node- assessed. In fact, a meta-analysis of 73 studies comprising 9110
positive), in a study population with a high proportion of squamous cell patients reported that only 19.2% of patients who initially receive
carcinoma. This study demonstrated a significant improvement in local bladder-preserving therapy for muscle invasive bladder cancer
control for chemoradiation (3-year local control of 96% vs. 69%; P < eventually require radical cystectomy due to recurrence or lack of
.01) and marginal improvements in DFS and OS. Late-grade ≥3 response.196 Another multicenter retrospective analysis of 287 patients
gastrointestinal toxicity on the chemoradiation arm was low (7% of with cN+ M0 bladder cancer showed no difference in OS (HR, 0.94;
patients).194 A 2019 systematic review evaluating the oncologic efficacy 95% CI, 0.63–1.41; P = .76) or PFS (HR, 0.74; 95% CI, 0.50–1.08; P =
of adjuvant radiation for bladder cancer or UTUC concluded that there .12) between radical cystectomy versus organ preservation with radical
was no clear benefit of adjuvant radiation following radical surgery (eg, dose radiotherapy.197 Receiving radical cystectomy or bladder-sparing
cystectomy), although the combination of adjuvant radiation with trimodality therapy was, however, associated with improved OS
chemotherapy may be beneficial in locally advanced disease.195 compared to palliative treatment (P < .001).

While there are no conclusive data demonstrating improvements in OS, Bladder-preserving approaches are reasonable alternatives to
it is reasonable to consider adjuvant radiation in patients with pT3/pT4 cystectomy for patients who are medically unfit for surgery and those
urothelial bladder cancer with positive nodes or margins at the time of seeking an alternative to radical cystectomy.198,199 Combined modality
surgery, although this approach has been evaluated in only a limited chemoradiation therapy as an alternative to immediate cystectomy for
number of studies, reflected by the category 2B designation. Patients muscle invasive bladder cancer is endorsed by multiple international
meeting these characteristics with positive surgical margins and/or organizations that have developed evidence-based consensus
lymph nodes identified in the pelvic dissection have especially high guidelines and recommendations, including the International
pelvic recurrence rates (40%–45% by 5 years), and adjuvant radiation is Consultation on Urologic Diseases-European Association of Urology

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NCCN Guidelines Version 5.2024

Bladder Cancer

(ICUD-EAU), UK National Institute for Health and Care Excellence solitary tumors, negative nodes, no extensive or multifocal CIS, no
(NICE), and the AUA/ASCO/ASTRO/SUO.200-202 There is an apparent tumor-related moderate or severe hydronephrosis, and good
underutilization of aggressive bladder-preserving therapies for pre-treatment bladder function. Patients who are medically fit for radical
non-cystectomy candidates, especially in patients who are older and cystectomy but who have hydronephrosis are poor candidates for
Black patients.203,204 Between 23% and 50% of patients with muscle bladder-sparing procedures.209,210 Maximal TURBT with concurrent
invasive bladder cancer who are ≥65 years receive no treatment or chemoradiotherapy should be given as primary treatment for these
non-aggressive therapy, despite prospective, phase II data showing that patients, with radiotherapy alone or TURBT alone reserved for select
bladder preservation with trimodality therapy has positive outcomes and patients (see TURBT Alone as Primary Treatment for Muscle Invasive
an acceptable toxicity profile for patients ≥65 years, with a 2-year OS of Bladder Cancer below for more information). When possible,
94.4% and 2-year DFS of 72.6%.205 For tools to aid in the optimal bladder-sparing options should be chosen in the context of clinical trials.
assessment and care of older adults with cancer, see the NCCN
Radiotherapy with Concurrent Chemotherapy Following TURBT as
Guidelines for Older Adult Oncology.
Primary Treatment for Muscle Invasive Bladder Cancer
With any of the alternatives to cystectomy, there is concern that Several groups have investigated the combination of concurrent or
bladders that appear to be endoscopically free of tumor based on a sequential chemotherapy and radiotherapy after TURBT. First, an
clinical assessment (cT0) that includes a repeat TURBT may not be endoscopic resection that is as complete as possible is performed.
pathologically free of tumor (pT0). Reports have suggested that up to Incomplete resection is an unfavorable prognostic factor for the ability to
45% of bladders may be clinically understaged after TURBT.204,206,207 preserve the bladder.211-213
Conversely, one series reported that all patients who achieved a
Radiation Therapy Oncology Group (RTOG) protocol 89-03 compared
complete response after radiotherapy with concurrent cisplatin and
concurrent cisplatin and radiotherapy with or without 2 cycles of
fluorouracil (5-FU) were pT0 on immediate cystectomy.208 Although
induction MCV (methotrexate, cisplatin, and vinblastine)
studies report differing frequencies of residual disease after cytotoxic
chemotherapy.210 No difference in complete clinical response or 5-year
agents (either radiation or chemotherapy), there is consensus that the
OS was observed between the treatment arms. Other studies also
rate is lower for patients who present with T2 disease than with T3
reported no significant survival benefit for neoadjuvant chemotherapy
disease, which should be considered when proposing a bladder-sparing
before bladder-preserving chemotherapy with radiation therapy
approach.
(RT).212,214
The decision to use a bladder-preserving approach is partially based on
In the phase 3 RTOG 89-03 trial in which 123 patients with clinical stage
the location of the lesion, depth of invasion, size of the tumor, status of
T2–T4a were treated with radiotherapy plus concurrent cisplatin, with or
the “uninvolved” urothelium, and status of the patient (eg, bladder
without induction MCV chemotherapy, 5-year OS was approximately
capacity, bladder function, comorbidities). Bladder preservation as an
49% in both arms.210 The subsequent RTOG 95-06 trial treated 34
alternative to cystectomy is generally reserved for patients with smaller
patients with twice-daily irradiation and concurrent cisplatin and 5-FU

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NCCN Guidelines Version 5.2024

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and reported a 3-year OS of 83%.215 The RTOG 97-06 trial treated 47 over 6.5 weeks and a hypofractionated schedule of 55 Gy in 20
patients with twice-daily irradiation and concurrent cisplatin; patients fractions over 4 weeks.222 This analysis found that the hypofractionated
also received adjuvant chemotherapy with CMV.216 Three-year OS was schedule is noninferior to the standard fractionation schedule for both
61%. In the RTOG 99-06 study, 80 patients received twice-daily invasive local control and toxicity and that the hypofractionated
irradiation plus cisplatin and paclitaxel, followed by adjuvant cisplatin schedule is superior regarding invasive local control.
and gemcitabine. Five-year OS was 56%.217 In RTOG 0233, 97 patients
Chemotherapy Following TURBT as Primary Treatment for Muscle
received twice-daily radiation with concurrent paclitaxel plus cisplatin or
Invasive Bladder Cancer
5-FU plus cisplatin. Five-year OS was 73%.218 RTOG 0712 investigated
Chemotherapy alone is considered to be inadequate without additional
5-FU plus cisplatin with twice-daily radiation or gemcitabine with once-
treatment to the bladder and it remains investigational. Studies showed
daily radiation, with 33 patients eligible for analysis on each arm. Three-
that the proportions of complete pathologic response in the bladder
year distant metastasis-free survival rates were 78% and 84%,
using neoadjuvant chemotherapy alone were only up to 38%.153 A
respectively.219 Taken together, the complete response rates ranged
higher proportion of bladders can be rendered tumor-free and therefore
from 59% to 88%.
preserved when chemotherapy is combined with concurrent
Up to approximately 80% of long-term survivors maintain an intact radiotherapy.
bladder, while other patients ultimately require radical cystectomy.209-217
Radiotherapy Following TURBT as Primary Treatment for Muscle
A combined analysis of survivors from four of these trials, with a median Invasive Bladder Cancer
follow-up of 5.4 years, showed that combined-modality therapy was Radiotherapy alone is inferior to radiotherapy combined with
associated with low rates of late grade 3 toxicities (5.7% genitourinary chemotherapy for patients with an invasive bladder tumor, and is not
and 1.9% gastrointestinal).220 No late grade 4 toxicities or considered standard for patients who can tolerate combined
treatment-related deaths were recorded. therapy.221,223 In a randomized trial of 360 patients, radiotherapy with
concurrent mitomycin C and 5-FU improved 2-year locoregional DFS
Based on the trials described above, as well as the phase 3 BC2001
from 54% (radiotherapy alone) to 67% (P = .01), and 5-year OS from
trial that demonstrated a locoregional DFS benefit for those treated with
35% to 48% (P = .16), without increasing grade 3–4 acute or late
5-FU and mitomycin concurrently with radiotherapy compared to
toxicities.221 Hence, radiotherapy alone is only indicated for those who
radiotherapy alone, with no significant increase in AEs,221 bladder
cannot tolerate a cystectomy or chemotherapy because of medical
preservation with concurrent chemoradiotherapy was given a category 1
comorbidities.
designation for primary treatment of stage II or IIIA bladder cancer.
TURBT Alone as Primary Treatment for Muscle Invasive Bladder Cancer
A meta-analysis of individual patient data from two randomized, phase
TURBT alone may be an option for patients with stage II disease who
III studies (BC2001 and BCON) compared two radiotherapy
are not candidates for cystectomy. TURBT alone may be curative in
fractionation schedules that are commonly used in treatment of locally
selected cases that include solitary lesions less than 2 cm in size that
advanced bladder cancer, a standard schedule of 64 Gy in 32 fractions

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NCCN Guidelines Version 5.2024

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have minimally invaded the muscle. These cases should also have no neoadjuvant therapy was given and the tumor is ypT2–ypT4a or ypN+,
associated in situ component, palpable mass, or associated nivolumab may be considered. Adjuvant RT is another option for
hydronephrosis.224 patients with tumors that are pT3–4, with positive nodes or margins, at
the time of surgery (category 2B).
If primary treatment consists of TURBT alone, patients should undergo
an aggressive re-resection of the site within 4 weeks of the primary Bladder preservation with maximal TURBT followed by concurrent
procedure to ensure that no residual disease is present. If the repeat chemoradiotherapy is another category 1 primary treatment option for
TURBT is negative for residual tumor, treatment can be managed these patients. Candidates for this bladder-sparing approach include
conservatively with repeat endoscopic evaluations and cytologies every patients with tumors that present without moderate or severe
3 months until a relapse is documented. The stage of the lesion hydronephrosis and tumors that allow a visibly complete or a maximally
documented at relapse would determine further management decisions. debulking TURBT. Radiotherapy with concurrent cisplatin-based
chemotherapy or 5-FU plus mitomycin as a radiosensitizer is the most
NCCN Recommendations for Treatment of Muscle Invasive common and well-studied chemoradiation method used to treat muscle
Bladder Cancer
invasive bladder cancer.208-212,221,223,225 Therefore, based on clinical
Treatment of Stage II and IIIA Tumors practice and strength of the data, the following radiosensitizing
The critical issues in the care and prognosis of these patients are regimens are preferred for organ-preserving chemoradiation: 5-FU plus
whether a palpable mass is appreciated at EUA and if the tumor has mitomycin C, cisplatin alone, or low-dose gemcitabine. Cisplatin plus 5-
extended through the bladder wall. Tumors that are organ-confined (T2, FU or cisplatin plus paclitaxel may be considered as alternative
stage II) have a better prognosis than those that have extended through regimens. Other radiosensitizing chemotherapy regimens that may be
the bladder wall into the perivesical fat (T3) and beyond. T4a tumors used with palliative intent, but would rarely be appropriate for curative-
involve the prostatic stroma, uterus, or vagina and are typically intent chemoradiotherapy for organ preservation, are docetaxel
surgically managed similar to T3 tumors. (category 2B), paclitaxel (category 2B), 5-FU (category 2B), or
capecitabine (category 3) monotherapies.
Primary surgical treatment for stage II and IIIA disease is a radical
cystectomy and pelvic lymphadenectomy. Neoadjuvant chemotherapy The overall tumor status should be reassessed 2 to 3 months after
is recommended (category 1). Partial cystectomy along with treatment completion. If no residual tumor is detected, surveillance is
neoadjuvant cisplatin-based chemotherapy can be considered for stage appropriate. If residual disease is present, surgical consolidation of
II (cT2, N0) disease with a single tumor in a suitable location and no bladder-only residual disease or treatment as metastatic disease may
presence of CIS. Partial cystectomy is not an option for patients with be appropriate. If residual disease is CIS, Ta, or T1, TURBT with or
stage III disease. If cisplatin-based neoadjuvant therapy was not given without intravesical therapy may be considered.
and the tumor is found to be pT3, pT4, or pN+ following resection,
adjuvant cisplatin-based chemotherapy is the preferred approach, In patients with extensive comorbid disease or poor performance status
although adjuvant nivolumab may also be considered. If cisplatin-based who are not candidates for cystectomy or definitive chemoradiotherapy,

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NCCN Guidelines Version 5.2024

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treatment options include radiotherapy alone or TURBT. The overall Tumor status should be reassessed 2 to 3 months after treatment by
tumor status should be reassessed 2 to 3 months after treatment imaging of the chest, abdomen, and pelvis using CT with contrast. If
completion. If no tumor is evident, the patient should be observed. If there is no evidence of distant disease on imaging reassessment,
tumor is observed, systemic therapy, radiotherapy (if no prior further cystoscopic assessment of tumor response in the bladder may
radiotherapy), TURBT with or without intravesical therapy, or best be considered.
supportive care may be given.
Subsequent disease management depends on the response to
Treatment of Stage IIIB Tumors primary treatment. Patients who received downstaging systemic
Primary treatment for stage IIIB (cT1–T4a, N2–3) disease can include therapy and had a complete disease response may then be
either downstaging systemic therapy or concurrent subsequently treated with cystectomy or chemoradiotherapy or may
chemoradiotherapy.226,227 A population-based study of 659 patients be observed until disease relapse, depending on patient-specific
with cT1–T4a, node-positive urothelial bladder cancer tested the features. Patients who received downstaging systemic therapy and
effectiveness of induction chemotherapy for pathologic showed a partial response may be treated with cystectomy or
downstaging.227 For cN1 disease, complete pathologic downstaging chemoradiotherapy (for persistent disease confined to the bladder) or
was achieved in 39% of patients who received induction treated as with metastatic disease with additional lines of systemic
chemotherapy compared to 5% of patients who did not receive therapy (for distant disease). Patients who had disease progression
induction chemotherapy. For cN2–3, the rate of pathologic following primary downstaging systemic therapy may be treated as
downstaging was 27% versus 3% for these two groups. OS was also with metastatic disease, with additional lines of systemic therapy.
improved in patients who received induction chemotherapy (P < .001),
although the nature of the study limits interpretation of the OS results.227 Patients with complete disease response following concurrent
Another study used the NCDB to analyze outcomes of 1783 patients chemoradiotherapy should be observed until disease relapse. Disease
with clinically node-positive bladder cancer who were treated with with partial responses to concurrent chemoradiotherapy may be
chemotherapy alone (n = 1388) or chemoradiotherapy (n = 395).226 subsequently treated with surgical consolidation (for residual disease
This study found that patients treated with chemoradiotherapy had a confined to the bladder), with consideration of intravesical BCG (for
higher median OS than those treated with chemotherapy (19.0 vs. CIS, Ta, or T1 residual disease), or as metastatic disease with
13.8 months; P < .001). The improvement in outcome with systemic therapy (for remaining disease outside the bladder).
chemoradiotherapy persisted upon evaluation of propensity-matched Progression following concurrent chemoradiotherapy may be treated
populations (P < .001).226 Cystectomy as primary treatment or for as metastatic disease with systemic therapy.
surgical palliation may be appropriate in very select situations, such as
Treatment of Stage IVA Tumors
in patients with limiting local symptoms and/or those with comorbidities
Stage IVA includes patients with cT4b, any N, M0 or any T, any N,
that prevent administration of chemotherapy.
M1a disease.20 For patients with stage IVA disease, treatment options
differ depending on the presence of distant metastasis (M0 vs. M1a).

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Primary treatment recommendations for patients with M0 disease Follow-up after a cystectomy should include urine cytology, liver
include systemic therapy or concurrent chemoradiotherapy followed by function tests, creatinine, and electrolytes. Imaging of the chest, upper
evaluation with cystoscopy, EUA, TURBT, and imaging of the tract abdomen, and pelvis should be conducted at intervals based on
abdomen and pelvis. If no evidence of tumor is present after primary the risk of recurrence. Patients should be monitored annually for vitamin
treatment, the patient may be treated with consolidation systemic B12 deficiency if a continent urinary diversion was created. Consider
therapy or adjuvant treatment with chemoradiotherapy may be initiated urethral wash cytology for patients with an ileal conduit or continent
if the patient did not receive prior radiotherapy. In general, stage IVA catheterizable diversion, particularly if CIS was found within the bladder
disease is considered unresectable. However, in patients with disease or prostatic urethra. For details of follow-up recommendations, see
that responds to treatment, cystectomy may be an option if the tumor Follow-up in the algorithm.
becomes technically resectable. If residual disease is noted on
evaluation after primary therapy, systemic therapy or cystectomy is Follow-up after a partial cystectomy is similar to that for a radical
recommended. Systemic therapy may include targeted therapy, cystectomy, with the addition of monitoring for relapse in the bladder by
chemoradiotherapy (if no prior radiotherapy), or chemotherapy. serial cytologic examinations and cystoscopies (may include selected
Cystectomy, if feasible, is an option. mapping biopsy).

Patients with M1a disease should receive systemic therapy as primary For patients who have a preserved bladder, there is a risk for
treatment. Those select patients with metastatic disease treated with recurrence in the bladder or elsewhere in the urothelial tract and
curative intent should be evaluated with cystoscopy, EUA, TURBT, distantly. Imaging studies and laboratory testing should be performed as
and abdominal/pelvic imaging. If a complete or partial response is outlined under post-cystectomy follow-up. Additionally, continued
noted following primary treatment of metastatic disease, consolidative monitoring of the urothelium with cystoscopy and urinary cytologies with
local therapy with concurrent chemoradiotherapy or cystectomy may or without mapping biopsy is a routine part of the management of all
be considered in select cases. If the disease remains stable or cases in which the bladder is preserved.
progresses following primary therapy, these patients should follow
Recurrent or Persistent Disease
treatment for metastatic disease.
A positive cytology with no evidence of disease in the bladder following
Follow-up imaging and cystoscopy should be managed as described in the
Results from a meta-analysis of 13,185 patients who have undergone Posttreatment of Recurrent or Persistent Disease under Non-Muscle
cystectomy reported a 0.75% to 6.4% prevalence of upper tract Invasive Urothelial Bladder Cancer, above.
recurrence.228 Surveillance by urine cytology or upper tract imaging
For patients with a preserved bladder, local recurrence or persistent
detected recurrences in 7% and 30% of cases, respectively.
disease should be evaluated as a new cancer. Recurrences are treated
based on the extent of disease at relapse, with consideration of prior
treatment. As previously discussed, CIS, Ta, or T1 tumors are generally

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NCCN Guidelines Version 5.2024

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managed with intravesical therapy, cystectomy, or TURBT. If no considered and patients’ disease should be managed as previously
response is noted, a cystectomy is advised. Invasive disease is outlined for positive nodal disease (stage IIIA, stage IIIB, or stage IVA).
generally managed with radical cystectomy, and a second attempt at Molecular testing should also be performed for patients with metastatic
bladder preservation is not advisable. Cystectomy may not be possible disease (see Molecular/Genomic Testing, below).
in a patient who has undergone a full course of EBRT and has bulky
residual disease. For these patients, systemic therapy or palliative Patients who present with disseminated metastatic disease are
TURBT and best supportive care is advised. generally treated with systemic therapy. Metastasectomy and/or
palliative radiotherapy may also be useful for select patients.229
Subsequent-line therapy for metastatic disease or local recurrence
following cystectomy generally would include systemic therapy. Metastasectomy for Oligometastatic Disease
Radiotherapy alone can also be considered as a subsequent-line Highly select patients with oligometastatic disease who are without
therapy for patients with metastatic disease or local recurrence following evidence of rapid progression may benefit from metastasectomy
cystectomy, especially in selected cases with regional-only recurrence following response to systemic therapy. While there are limited
or with clinical symptoms. prospective data supporting the role of metastasectomy for treatment of
urothelial bladder cancer, several retrospective studies have
Metastatic (Stage IVB) Urothelial Bladder Cancer demonstrated that metastasectomy can be a valid treatment option for
Approximately 5% of patients have metastatic disease at the time of certain patients with metastatic bladder cancer, particularly those with
diagnosis.2 Additionally, approximately half of all patients relapse after favorable response to systemic therapy, solitary metastatic lesions, and
cystectomy depending on the pathologic stage of the tumor and nodal lung or lymph node sites of disease.
status. Local recurrences account for approximately 10% to 30% of
relapses, whereas distant metastases are more common. A phase II trial of 11 patients with bladder primary urothelial carcinoma
metastatic to the retroperitoneal lymph nodes who underwent complete
Evaluation of Metastatic Disease bilateral retroperitoneal lymph node dissection reported 4-year DSS and
If metastasis is suspected, additional workup to evaluate the extent of RFS rates of 36% and 27%. Patients with viable tumor in no more than
the disease is necessary. This includes a chest CT and a bone scan if two lymph nodes and/or excellent response to presurgical systemic
enzyme levels are abnormal or the patient shows signs or symptoms of chemotherapy showed the best survival rates indicating that a low
skeletal involvement. Central nervous system (CNS) imaging should be burden of disease or good response to presurgical chemotherapy may
considered. An estimated GFR should be obtained to assess patient be important in achieving benefit from metastastectomy.230 Another
eligibility for cisplatin. For patients with borderline GFR results, a timed phase II trial of 70 patients who underwent complete surgical resection
or measured urine collection may be considered to more accurately of bladder cancer metastases investigated survival, performance status,
determine cisplatin eligibility.130 If the evidence of spread is limited to and quality of life following surgery. This study reported no survival
nodes and biopsy is technically feasible, nodal biopsy should be

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NCCN Guidelines Version 5.2024

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advantage from surgery, although the quality of life and performance nature of the surgery, it is important to carefully select appropriate
status were improved for symptomatic patients.231 patients for metastasectomy, including consideration of patient
performance status, comorbidities, and overall clinical picture.
Beyond these prospective data, several retrospective studies have
demonstrated a survival advantage following metastasectomy.232-235 A Molecular/Genomic Testing
retrospective series of 55 patients with bladder primary urothelial The panel recommends that molecular/genomic testing be performed
carcinoma metastatic to the pelvic or retroperitoneal lymph nodes, who for stages IVA and IVB bladder cancer and may be considered for stage
underwent post-chemotherapy lymph node dissection, reported 5-year IIIB. This testing should be performed only in laboratories that are
DSS and RFS rates of 40% and 39%. The best outcomes were certified under the Clinical Laboratory Improvement Amendments of
associated with radiologic nodal complete response to preoperative 1988 (CLIA-88) as qualified to perform highly complex molecular
chemotherapy and pN0 versus pN+, but were similar for cN1–3 versus pathology testing.240 The NCCN Bladder Cancer Panel recommends
cM1.236 A systematic review and meta-analysis of available studies, that molecular/genomic testing be conducted early, ideally at diagnosis
including a total of 412 patients with metastatic urothelial carcinoma, of advanced bladder cancer, to facilitate treatment decision-making and
reported an improved OS for patients who underwent metastasectomy to prevent delays in administering later lines of therapy. In addition to
compared to non-surgical treatment of metastatic lesions. Five-year determining eligibility for FDA-approved therapies, molecular/genomic
survival in these studies ranged from 28% to 72%.237 Another testing may be used to screen for clinical trial eligibility.
population-based analysis of 497 patients ≥65 years who had at least
one metastasectomy for treatment of urothelial carcinoma found that Based on the FDA approvals for erdafitinib and fam-trastuzumab
with careful patient selection, metastasectomy is safe and can be deruxtecan, molecular testing should include analysis for FGFR3
associated with long-term survival in this patient population.238 genetic alterations and HER2 overexpression by immunohistochemistry
Conversely, a study that queried the NCDB database from 2004 to 2016 (IHC). For certain patients who are ineligible to receive cisplatin, the
reported no difference in OS between propensity score-matched checkpoint inhibitor atezolizumab may be considered for first-line
patients with urothelial carcinoma who had undergone metastasectomy therapy based on PD-L1 testing results (see Checkpoint Inhibitor
compared with those who had not (HR, 0.94; 95% CI, 0.83–1.07; P = Monotherapy as First-line Treatment, below).
.38).239 This study found that 7% of metastatic urothelial carcinoma
patients were treated with metastasectomy and, on average, patients Genetic alterations are known to be common in bladder cancer, with
treated with metastasectomy were younger, had greater than cT3 data from the Cancer Genome Atlas ranking bladder cancer as the third
disease, had radical surgery on the primary tumor, and received highest mutated cancer.241,242 Supporting this, a study that looked at
systemic therapy. comprehensive genomic profiling of 295 cases of advanced urothelial
carcinoma found that 93% of cases had at least one clinically relevant
Due to the limited and somewhat conflicting evidence supporting genetic alteration, with a mean of 2.6 clinically relevant genetic
metastasectomy for bladder cancer, and the often extensive and difficult alterations per case. The most commonly identified clinically relevant

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genetic alterations were CDKN2A (34%), FGFR3 (21%), PIK3CA is advised, considering the patient’s current performance status, extent
(20%), and ERBB2 (17%).243 of disease, and specific prior therapy.

First-Line Systemic Therapy for Metastatic Disease Surgery or radiotherapy may be feasible in highly select metastatic
The specific systemic therapy regimen recommended partially depends cases for patients who show a major partial response in a previously
on the presence or absence of medical comorbidities, such as cardiac unresectable primary tumor or who have a solitary site of residual
disease, autoimmune disease, peripheral neuropathy, diabetes, and disease that is resectable after chemotherapy. If disease is completely
renal dysfunction, along with the risk classification of the patient based resected, two additional cycles of chemotherapy can be considered,
on disease extent. In general, long-term survival with combination depending on patient tolerance.
platinum-based chemotherapy has been reported only in patients with
Platinum-Based Chemotherapy Regimens (ddMVAC or GC)
more favorable prognosis, defined as those with good performance
GC245,246 and ddMVAC161,187 are commonly used combination
status, no visceral (ie, liver, lung) nor bone disease, and normal alkaline
chemotherapy regimens that have shown clinical benefit. A large,
phosphatase or lactic dehydrogenase levels. Patients with disease with
international, phase III study randomized 405 patients with locally
poor prognostic features, defined as those with poor performance status
advanced or metastatic disease to GC or standard (28-day) MVAC.188
or visceral disease, have consistently shown higher discontinuation
At a median follow-up of 19 months, OS and time to progression were
rates with multiagent platinum-based combination chemotherapy
similar in the two arms. Fewer toxic deaths were recorded among
regimens and few complete remissions, which are prerequisites for
patients receiving GC compared to MVAC (1% vs. 3%), although this
durable responses. An assessment of clinical application is currently
did not reach statistical significance. A 5-year update analysis confirmed
underway to better determine how “platinum-ineligible” may be
that GC was not superior to MVAC in terms of survival (OS, 13.0% vs.
defined.244 Newer combinations with better clinical utility, such as the
15.3%; PFS, 9.8% vs. 11.3%, respectively).246 Another large,
immune checkpoint inhibitors, antibody-drug conjugates, and targeted
randomized, phase III trial compared ddMVAC to standard (28-day)
therapies, provide other treatment options for these patients who are
MVAC.161,187 At a median follow-up of 7.3 years, 24.6% of patients were
not candidates for cisplatin-based chemotherapy.
alive in the ddMVAC cohort compared with 13.2% in the standard
For patients with metastatic disease treated with chemotherapy, MVAC cohort. There was one toxic death in each arm, but less overall
disease status should be re-evaluated after two to three cycles of toxicity was seen in the dose-dense group. From these data, ddMVAC
chemotherapy, and treatment is continued for two more cycles in had improved toxicity and efficacy as compared to standard MVAC;
patients whose disease responds or remains stable. Chemotherapy therefore, standard (28-day) MVAC is no longer used. Both GC and
may be continued for a maximum of six cycles in most cases, ddMVAC with growth factor support are category 1 recommendations
depending on response and tolerance. If no response is noted after two for metastatic disease.
cycles or if significant morbidities are encountered, a change in therapy
The performance status of the patient is a major determinant in the
selection of a regimen and can often limit the use of cisplatin-containing

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NCCN Guidelines Version 5.2024

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regimens such as ddMVAC or GC. Regimens with lower toxicity profiles pembrolizumab.249 The primary endpoint of confirmed ORR was 64.5%
are recommended in patients with compromised liver or renal status or (95% CI, 52.7%–75.1%) for the combination compared to 45.2% (95%
serious comorbid conditions. In patients who are not cisplatin-eligible, CI, 33.5%–57.3%) for enfortumab vedotin monotherapy. The median
carboplatin may be substituted for cisplatin in the metastatic setting for DOR was not reached for the combination and was 13.2 months for the
cisplatin-ineligible patients such as those with a GFR less than 60 monotherapy.
mL/min. A phase II/III study assessed two carboplatin-containing
regimens in medically unfit patients (performance status 2).247 The Subsequently, enfortumab vedotin and pembrolizumab was investigated
overall response rate (ORR) was 42% for gemcitabine plus carboplatin in the phase III EV-302 trial, which randomized 886 patients with
and 30% for methotrexate, carboplatin, and vinblastine. However, the previously untreated locally advanced or metastatic urothelial carcinoma
response rates dropped to 26% and 20%, respectively, with increased to either enfortumab vedotin plus pembrolizumab or gemcitabine in
toxicity among patients who were both unfit and had renal impairment combination with either cisplatin or carboplatin.250 After a median follow-
(GFR <60 mL/min). up of 17.2 months, median PFS was significantly longer with
enfortumab vedotin plus pembrolizumab compared to chemotherapy
Avelumab maintenance therapy is recommended following cisplatin- or (12.5 months vs. 6.3 months; HR, 0.45; 95% CI, 0.38–0.54; P < .001).
carboplatin-based first-line therapy if there is no progression on first-line Median OS was also significantly longer with enfortumab vedotin plus
platinum-containing chemotherapy (see Avelumab Maintenance pembrolizumab (31.5 months vs. 16.1 months; HR, 0.47; 95% CI, 0.38–
Therapy, below). 0.58; < .001). Confirmed ORR was 67.7% and 44.4% for enfortumab
vedotin plus pembrolizumab and chemotherapy, respectively (P < .001),
Pembrolizumab Plus Enfortumab Vedotin-ejfv
with complete responses observed in 29.1% of patients in the
A combination of the immune checkpoint inhibitor, pembrolizumab, with enfortumab vedotin plus pembrolizumab group and 12.5% of those in
the antibody-drug conjugate, enfortumab vedotin, was initially studied in the chemotherapy group. Treatment-related AEs grade ≥3 occurred in
certain cohorts of the phase Ib/II EV103 study, which included cisplatin- 55.9% of patients receiving enfortumab vedotin plus pembrolizumab
ineligible patients with previously untreated, locally advanced or and 69.5% of those receiving chemotherapy.
metastatic urothelial cancer.248,249 Forty-five patients within cohort A
received the combination of enfortumab vedotin and pembrolizumab.248 Based on these results, the combination of pembrolizumab plus
After a median of nine treatment cycles, the confirmed ORR was 73.3%, enfortumab vedotin is the preferred first-line systemic therapy option for
with a complete response rate of 15.6%. The most common treatment- patients with advanced or metastatic urothelial carcinoma, regardless of
related AEs were peripheral sensory neuropathy (55.6%), fatigue whether or not they are eligible for cisplatin. Based on high-level data
(51.1%), and alopecia (48.9%); 64.4% of patients had grade ≥3 from the EV-302 trial, this regimen has been given a category 1
treatment-related AEs and one death was classified as treatment- designation by the panel.
related. Cohort K randomized patients who were ineligible to receive
cisplatin to first-line enfortumab vedotin, alone or in combination with

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Gemcitabine, Cisplatin, and Nivolumab initial analysis with an ORR of 28.6% and a median OS of 11.3
The multinational, phase III CheckMate901 study compared nivolumab months.253 In May 2018, the FDA issued a safety alert for the use of
plus gemcitabine-cisplatin to gemcitabine-cisplatin alone in 608 patients first-line pembrolizumab and atezolizumab, which warned that early
with previously untreated unresectable or metastatic urothelial reviews of data from two clinical trials (KEYNOTE-361 and IMvigor130)
carcinoma.251 Patients who received the nivolumab combination also showed decreased survival for patients receiving pembrolizumab or
received maintenance nivolumab for up to 2 years. After a median atezolizumab as first-line monotherapy compared to those receiving
follow-up of 33.6 months, nivolumab plus gemcitabine-cisplatin showed cisplatin- or carboplatin-based therapy.254 Based on these data, the
longer median OS compared to gemcitabine-cisplatin alone (21.7 vs. pembrolizumab prescribing information was initially amended to restrict
18.9 months; HR, 0.78; 95% CI, 0.63–0.96; P = .02). The median PFS first-line use to patients who either 1) are not eligible for cisplatin-
was similar for the two arms (7.9 vs. 7.6 months; P = .001), but the PFS containing chemotherapy and whose tumors express PD-L1 as
curves separated over time. At 12 months, the PFS was 34.2% with the measured by a combined positive score (CPS) of at least 10; or 2) are
nivolumab combination compared to 21.8% with chemotherapy alone. not eligible for any platinum-containing chemotherapy regardless of PD-
The ORR was 57.6% with the nivolumab combination compared to L1 status.255 Subsequently, the first-line indication was further restricted
43.1% with chemotherapy alone. For those in the nivolumab plus to only patients who were not eligible for any platinum-containing
gemcitabine-cisplatin group, 21.7% had complete responses. Grade ≥3 chemotherapy, removing eligibility for first-line pembrolizumab from the
AEs occurred in 61.8% of those in the nivolumab combination group PD-L1–high, platinum-eligible population.256 This amended indication
and 51.7% of those who received chemotherapy alone. Based on the was granted a full (regular) approval by the FDA.
results from this phase III trial, the NCCN Panel designated the regimen
a category 1 recommendation as first-line therapy. The final approval for pembrolizumab as a first-line therapy for patients
who were not eligible for any platinum-containing chemotherapy was
Checkpoint Inhibitor Monotherapy as First-Line Treatment based on results of the phase III KEYNOTE-361 trial, which randomized
In addition to the combination of pembrolizumab and enfortumab 1010 patients with previously untreated advanced, unresectable, or
vedotin, two checkpoint inhibitors have been tested as monotherapy metastatic urothelial carcinoma to treatment with pembrolizumab plus
first-line options for cisplatin-ineligible patients. platinum-based chemotherapy, pembrolizumab alone, or platinum-
based chemotherapy alone.257 After a median follow-up of 31.7 months,
The single-arm, phase II KEYNOTE-052 trial evaluated pembrolizumab the addition of pembrolizumab to chemotherapy did not significantly
as a first-line therapy in 370 patients with advanced urothelial prolong median PFS or OS compared to chemotherapy alone (8.3 vs.
carcinoma who were ineligible for cisplatin-based therapy. Data from 7.1 months for PFS; P = .0033 and 17.0 vs. 14.3 months for OS; P =
this study showed an ORR of 24%, with 5% of patients achieving a .0407). Additionally, analyses for first-line pembrolizumab versus
complete response. Grade 3 or higher treatment-related AEs occurred chemotherapy alone found that OS was similar both for the total
in 16% of patients treated with pembrolizumab at the time of data population (14.3 vs. 15.6 months) as well as those with high PD-L1
cutoff.252 Long-term outcomes of KEYNOTE-052 were similar to the expression as measured by a CPS of at least 10 (16.1 vs. 15.2 months).

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NCCN Guidelines Version 5.2024

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Data from the two-cohort, multicenter, phase II IMvigor210 trial one-sided P = .027). For the comparison of group B to group C, the
evaluated atezolizumab in patients with metastatic disease. In cohort 1, median OS was 15.7 and 13.1 months, respectively.
atezolizumab was evaluated as a first-line therapy in 119 patients with
locally advanced or metastatic urothelial carcinoma who were ineligible In November 2022 the manufacturer announced that they were
for cisplatin. Data from this study showed an ORR of 23% with 9% of voluntarily withdrawing the first-line bladder cancer indications for
patients showing a complete response. Median OS was 15.9 months. atezolizumab since atezolizumab plus chemotherapy did not meet the
Grade 3 or 4 treatment-related AEs occurred in 16% of patients.258 In co-primary endpoint of OS compared with chemotherapy alone in the
May 2018, the FDA issued a safety alert for the use of first-line IMvigor130 trial.261 Despite this withdrawal, the NCCN Panel has
pembrolizumab and atezolizumab, which warned that early reviews of maintained the inclusion of atezolizumab as a first-line option in patients
data from two ongoing clinical trials (KEYNOTE-361 and IMvigor130) who are not eligible for cisplatin-containing chemotherapy and whose
showed decreased survival for patients receiving pembrolizumab or tumors express PD-L1 or who are not eligible for any platinum-
atezolizumab as first-line monotherapy compared to those receiving containing chemotherapy regardless of PD-L1 expression (both
cisplatin- or carboplatin-based therapy.254 Based on these data, the recommendations are category 2B).
atezolizumab prescribing information was initially amended to restrict
Other Non-Platinum Based Chemotherapy Regimens
first-line use to patients who either 1) are not eligible for cisplatin-
Taxanes have been shown to be active as treatment options for
containing chemotherapy and whose tumors express PD-L1 as
urothelial bladder cancer.262-265 Based on these results, several groups
measured by PD-L1–stained tumor-infiltrating immune cells covering at
are exploring two- and three-drug combinations using these agents,
least 5% of the tumor area; or 2) are not eligible for any platinum-
with and without cisplatin. A randomized phase III trial was conducted to
containing chemotherapy regardless of the level of tumor PD-L1
compare GC and GC plus paclitaxel in 626 patients with locally
expression.259
advanced or metastatic urothelial cancer.266 The addition of paclitaxel to
The IMvigor130 trial was a multicenter phase III trial where 1213 GC resulted in higher response rates and a borderline OS advantage,
patients with previously untreated, locally advanced or metastatic which was not statistically significant in the ITT analysis. Analysis of
urothelial carcinoma were randomized to one of three treatment groups: eligible patients only (92%) resulted in a small (3.2 months) but
atezolizumab plus platinum-based chemotherapy (group A), statistically significant survival advantage in favor of the three-drug
atezolizumab monotherapy (group B), or placebo plus platinum-based regimen (P = .03). There was no difference in PFS. The incidence of
chemotherapy (group C).260 Chemotherapy regimens included neutropenic fever was substantially higher with the three-drug
gemcitabine in combination with either cisplatin or carboplatin. At the combination (13.2% vs. 4.3%; P < .001). Panelists feel that the risk of
time of the analysis, median PFS in the ITT population was 8.2 months adding paclitaxel outweighs the limited benefit reported from the trial.
in group A and 6.3 months in group C. Median OS was 16.0 months for The alternative regimens, including cisplatin/paclitaxel,267
group A compared to 13.4 months for group C (HR, 0.83; 0.69–1.00; gemcitabine/paclitaxel,268 cisplatin/gemcitabine/paclitaxel,269
carboplatin/gemcitabine/paclitaxel,270 and

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cisplatin/gemcitabine/docetaxel,271 have shown modest activity in evidence to guide optimal selection of second- and subsequent-line
patients with bladder cancer in phase I–II trials. therapies following these new first-line regimens.

Although current data are insufficient to recommend the above The FDA has approved the PD-L1 inhibitor avelumab as well as the
alternative regimens as routine first-line options, non– PD-1 inhibitors nivolumab and pembrolizumab for the treatment of
cisplatin-containing regimens may be considered in patients who cannot locally advanced or metastatic urothelial cell carcinoma that has
tolerate cisplatin because of renal impairment or other comorbidities progressed during or after platinum-based chemotherapy or that has
(see Principles of Systemic Therapy in the algorithm). progressed within 12 months of neoadjuvant or adjuvant
platinum-containing chemotherapy, regardless of PD-L1 expression
Avelumab Maintenance Therapy
levels. Pembrolizumab has also been approved in combination with
For patients who show either response or stable disease through their enfortumab vedotin for treatment of adult patients with locally advanced
full course of platinum-based first-line chemotherapy, maintenance or metastatic urothelial carcinoma and as first-line monotherapy for
therapy with the PD-L1 inhibitor, avelumab, is recommended. The patients who are ineligible to receive a platinum-containing regimen.
randomized, phase III JAVELIN Bladder 100 trial showed that avelumab Avelumab has also been approved as maintenance treatment for
significantly prolonged OS in all 700 randomized patients compared to patients with locally advanced or metastatic urothelial carcinoma that
best supportive care alone (median OS, 21.4 vs. 14.3 months; HR, has not progressed with first-line platinum-containing chemotherapy.
0.69; 95% CI, 0.56–0.86; P = .001).272 The OS benefit was observed in See First-Line Systemic Therapy for Metastatic Disease, above, for
all prespecified subgroups, including patients with PD-L1–positive more discussion of these regimens.
tumors. Grade ≥3 AEs were reported in 47.4% of patients treated with
avelumab compared to 25.2% of those with best supportive care alone. Pembrolizumab Monotherapy
Based on these positive OS data in a phase III trial, the NCCN Panel Pembrolizumab is a PD-1 inhibitor that has been evaluated as
has assigned avelumab maintenance therapy a category 1 second-line therapy for patients with bladder cancer who previously
recommendation. received platinum-based therapy and subsequently progressed or
metastasized.273 An open-label, randomized, phase III trial compared
For patients treated with gemcitabine, cisplatin, and nivolumab as first- pembrolizumab to chemotherapy (paclitaxel, docetaxel, or vinflunine) in
line therapy, nivolumab may be used as maintenance therapy. 542 patients with advanced urothelial carcinoma that recurred or
progressed after platinum-based chemotherapy. Data from this trial
Second-Line and Subsequent Therapy for Metastatic Disease
showed a longer median OS for patients treated with pembrolizumab
With the recent changes to first-line treatment options for metastatic compared to chemotherapy (10.3 vs. 7.4 months; P = .002). In addition,
disease, many providers are moving towards immune checkpoint fewer grade 3, 4, or 5 treatment-related AEs occurred in the
inhibitor combinations such as enfortumab vedotin plus pembrolizumab pembrolizumab-treated patients compared to those treated with
as a first-line treatment option. In this evolving paradigm, there is limited chemotherapy (15.0% vs. 49.4%).274 Long-term results (>2 year follow-

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NCCN Guidelines Version 5.2024

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up) from this same phase III trial were consistent with earlier reports, Nivolumab has also been studied for adjuvant therapy of muscle
with longer 1- and 2- year OS and PFS results for pembrolizumab invasive bladder cancer or UTUC after surgery (see section on Adjuvant
compared to chemotherapy.275 The median DOR was not reached for Systemic Therapy under Muscle Invasive Urothelial Bladder Cancer).
pembrolizumab compared to 4.4 months for chemotherapy.
Avelumab
Pembrolizumab also showed lower rates of any grade (62% vs. 90.6%)
and grade ≥3 AEs (16.5% vs. 50.2%) compared to chemotherapy. Avelumab is another PD-L1 inhibitor currently in clinical trials to
Results from this phase 3 trial have led the NCCN Panel to assign evaluate its activity in the treatment of bladder cancer. Results from the
pembrolizumab a category 1 recommendation as a second-line therapy. phase 1b trial for 44 patients with platinum-refractory disease
demonstrated an ORR of 18.2% that consisted of five complete
Pembrolizumab has also been studied as a combination therapy with responses and three partial responses following treatment with
enfortumab vedotin (see Pembrolizumab Plus Enfortumab Vedotin-ejfv, avelumab. The median PFS was 11.6 weeks and the median OS was
above). 13.7 months with a 54.3% OS rate at 12 months. Grade 3 or 4
treatment-related AEs occurred in 6.8% of patients treated with
Nivolumab Monotherapy avelumab.279 A pooled analysis of two expansion cohorts of the same
Data from a phase II trial in patients with locally advanced or metastatic trial reported results for 249 patients with platinum-refractory metastatic
urothelial carcinoma who progressed after at least one urothelial carcinoma or who were ineligible for cisplatin-based
platinum-containing regimen reported an ORR in 52 of 265 patients chemotherapy. Of the 161 post-platinum patients with at least 6 months
(19.6%; 95% CI, 15.0–24.9) following treatment with nivolumab that was of follow-up, the ORR as determined by independent review was 17%,
unaffected by PD-1 tumor status.276 Out of the 270 patients enrolled in with 6% reporting complete responses and 11% reporting partial
the study, grade 3 or 4 treatment-related AEs were reported in 18% of responses. Grade 3 or 4 treatment-related AEs occurred in 8% of
patients. Three patient deaths were the result of treatment.276 The patients and, likewise, 8% of patients had a serious AE related to
median OS was 8.74 months (95% CI, 6.05–not yet reached). Based on treatment with avelumab.280
PD-L1 expression of less than 1% and 1% or greater, OS was 5.95 to
11.3 months, respectively. These data are comparable to the phase I/II Avelumab is also recommended as a maintenance therapy following
data that reported an ORR of 24.4% (95% CI, 15.3%–35.4%) that was first-line platinum-containing treatment. For this setting, see Avelumab
unaffected by PD-1 tumor status. Of the 78 patients enrolled in this Maintenance Therapy, above.
study, two experienced grade 5 treatment-related AEs, and grade 3 or 4
Erdafitinib
treatment-related AEs were reported in 22% of patients.277 An extended
follow-up of this same phase I/II study (minimum follow-up of 37.7 Erdafitinib is a pan-FGFR inhibitor that has been evaluated in a global,
months) reported a similar ORR of 25.6% (95% CI, 16.4%–36.8%) for open-label, phase II trial of 99 patients with a prespecified FGFR
nivolumab monotherapy, with a median DOR of 30.5 months.278 alteration who had either previously received chemotherapy or who
were cisplatin ineligible, chemotherapy naïve. Of these patients, 12%
were chemotherapy naïve and 43% had received two or more prior lines

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NCCN Guidelines Version 5.2024

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of therapy. The confirmed ORR was 40% (95% CI, 31%–50%), to 4.3 months for erdafitinib. Grade 3–4 AEs were reported in 64.7% of
consisting of 3% complete responses and 37% partial responses. patients treated with erdafitinib versus 50.9% treated with
Among patients who had previously received immunotherapy, the pembrolizumab. AEs led to death in 2.9% of patients treated with
confirmed ORR was 59%. Median PFS was 5.5 months and the median erdafitinib and 6.9% of those treated with pembrolizumab.
OS was 13.8 months. Grade ≥3 treatment-related AEs were reported in
46% of patients and 13% of patients discontinued treatment due to Based on the phase III THOR trial results, where all patients had
AEs.281 Upon long-term follow-up (median 24.0 months) of the previously received an immune checkpoint inhibitor, and 89.1% had
aforementioned study, the investigator-assessed ORR was 40% (95% also received at least one line of chemotherapy (cisplatin in 50.8% and
CI, 30–49) and the safety profile remained similar to the primary carboplatin in 29.3%),283 erdafitinib was given a category 1 designation
analysis.282 in the subsequent-line, post-platinum, post-checkpoint inhibitor setting.
Also, since around 11% of patients on the THOR trial had not previously
The phase III THOR trial compared erdafitinib to chemotherapy received platinum-based chemotherapy, erdafitinib is recommended as
(docetaxel or vinflunine) or pembrolizumab in patients with metastatic a preferred regimen in the second-line, post-checkpoint inhibitor setting.
urothelial carcinoma with susceptible FGFR3 or FGFR2 alterations who
had progressed on or after prior treatment. THOR had two cohorts: In January 2024, the FDA amended the indication for erdafitinib that
cohort 1 required one or two prior treatments, at least one of which was previously granted under accelerated approval to provide full
included a checkpoint inhibitor; cohort 2 required one prior treatment approval for adult patients with locally advanced or metastatic urothelial
that did not include a checkpoint inhibitor. For the 266 patients in cohort carcinoma with susceptible FGFR3 genetic alterations, whose disease
1, after a median follow-up of 15.9 months, the median OS was longer has progressed on or after at least one prior line of systemic therapy.285
with erdafitinib compared to chemotherapy (12.1 vs. 7.8 months; HR, Furthermore, the FDA indication notes that erdafitinib is not
0.64; 95% CI, 0.47–0.88; P = .005).283 Median PFS was also longer with recommended for the treatment of patients who are eligible for and
erdafitinib than with chemotherapy (5.6 vs. 2.7 months; P < .001). The have not received prior PD-1 or PD-L1 inhibitor therapy. In response to
incidence of grade ≥3 treatment-related AEs was similar between the the amended FDA indication, the NCCN Panel made the decision to
two groups, with 45.9% reporting in the erdafitinib group compared to match the biomarker requirements and specify susceptible FGFR3
46.4% in the chemotherapy group. Treatment-related AEs that lead to genetic alterations; however, NCCN retains the erdafitinib
death occurred in 0.7% of those treated with erdafitinib and 5.4% of recommendation for second-line therapy, post-platinum or other
those treated with chemotherapy. In the intention-to-treat population of chemotherapy without a checkpoint inhibitor.
351 patients in cohort 2, there was no significant difference between the
Enfortumab Vedotin-ejfv Monotherapy
treatment arms for median OS (10.9 months for erdafitinib vs. 11.1
Enfortumab vedotin is a Nectin-4-directed antibody–drug conjugate that
months for pembrolizumab; HR, 1.18; 95% CI, 0.92–1.51; P = .18).284
was evaluated in a global, phase II, single-arm EV-201 study of 125
ORR was 40% for erdafitinib compared to 21.6% for pembrolizumab,
patients with metastatic urothelial carcinoma who had previously
although pembrolizumab had a longer DOR at 14.4 months, compared
received both a platinum-containing chemotherapy regimen and a PD-

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1/PD-L1 checkpoint inhibitor. The confirmed ORR was 44% (95% CI, enfortumab vedotin post-platinum or other non-platinum chemotherapy
35.1%–53.2%), including 12% complete responses. Similar response are more limited than post-checkpoint inhibitor, although the phase I
rates were seen in subgroups of patients with liver metastases and in EV-101 dose escalation/expansion study included patients with
those with no response to prior checkpoint inhibitor therapy. The pretreated metastatic urothelial carcinoma who had not previously
median DOR was 7.6 months. Grade ≥3 treatment-related AEs were received a checkpoint inhibitor.289 Of the 23 patients in this category,
reported in 54% of patients and treatment-related AEs led to dose 43.5% showed a clinical response to enfortumab vedotin treatment.
reductions or discontinuation of therapy in 32% and 12% of patients, Furthermore, the FDA indication for second-line enfortumab vedotin
respectively.286 Subsequently, an open-label, phase III trial of specifies that the therapy is “indicated for the treatment of adult patients
enfortumab vedotin (EV-301) evaluated the therapy in 608 patients with with locally advanced or metastatic urothelial cancer who are ineligible
advanced urothelial carcinoma who had previously received both a for cisplatin-containing chemotherapy and have previously received one
platinum-containing regimen as well as a checkpoint inhibitor.287 or more prior lines of therapy.”290
Patients were randomized 1:1 to either enfortumab vedotin or the
Sacituzumab Govitecan-hziy
investigator’s choice of chemotherapy (docetaxel, paclitaxel, or
vinflunine). After a median follow-up of 11.1 months, OS was longer Sacituzumab govitecan is another antibody–drug conjugate composed
with enfortumab vedotin than with chemotherapy (12.88 vs. 8.97 of an anti-Trop-2 humanized monoclonal antibody coupled to SN-38,
months; HR, 0.70; 95% CI, 0.56–0.89; P = .001). Median PFS was also the active metabolite of the topoisomerase 1 inhibitor, irinotecan.
longer for enfortumab vedotin (5.55 vs. 3.71 months; HR, 0.62; 95% CI, Sacituzumab govitecan has been evaluated in cohort 1 of TROPHY-U-
0.51–0.75; P < .001). The incidence of grade 3 or greater AEs was 01, a phase II open-label study with 113 patients in cohort 1.291 Patients
similar in both groups, 51.4% with enfortumab vedotin compared to within this cohort had locally advanced, unresectable, or metastatic
49.8% with chemotherapy. urothelial carcinoma that had progressed following prior platinum-based
and PD-1/PD-L1 checkpoint inhibitor therapy and were treated with
Enfortumab vedotin has also been evaluated as a second-line treatment sacituzumab govitecan. At a median follow-up of 9.1 months, ORR was
option. Cohort 2 of the phase II EV-201 study enrolled 91 patients who 27% (95% CI, 19.5%–36.6%) and 77% of participants showed a
had previously been treated with a PD-1 or PD-L1 checkpoint inhibitor decrease in measurable disease. The median DOR was 7.2 months
therapy and were ineligible for a cisplatin-containing regimen.288 Of the (95% CI, 4.7–8.6 months), median PFS was 5.4 months (95% CI, 3.5–
89 patients who received treatment with enfortumab vedotin, the 7.2 months), and median OS was 10.9 months (95% CI, 9.0–13.8
confirmed ORR was 52% (95% CI, 41%–62%) with 20% of patients months). Key grade greater than or equal to three treatment-related
having a complete response. Fifty-five percent of patients had grade 3 AEs were neutropenia (35%), leukopenia (18%), anemia (14%),
or higher AEs, with neutropenia, maculopapular rash, and fatigue being diarrhea (10%), and febrile neutropenia (10%). Six percent of patients in
the most common. Four deaths were considered to be related to the study discontinued treatment as a result of treatment-related AEs.
treatment, caused by acute kidney injury, metabolic acidosis, multiple
organ dysfunction, and pneumonitis. Data supporting second-line use of

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Fam-trastuzumab deruxtecan-nxki (T-DXd) nivolumab. All four of these regimens are supported by category 1 data.
Fam-trastuzumab deruxtecan is a HER2-directed antibody-conjugate A patient who is ineligible for cisplatin, but eligible for carboplatin, may
composed of a HER2 antibody coupled to a topoisomerase inhibitor that receive gemcitabine in combination with carboplatin first-line, although
has been FDA approved for adult patients with unresectable or pembrolizumab plus enfortumab vedotin is the preferred option
metastatic HER2-positive (IHC 3+) solid tumors who have received prior regardless of cisplatin-eligibility. If there is no progression on a first-line
systemic treatment and have no satisfactory alternative treatment platinum-containing chemotherapy, avelumab maintenance therapy is
options.292 Fam-trastuzumab deruxtecan was studied in the open-label preferred (category 1), unless nivolumab was included in the first-line
phase II DESTINY-PanTumor02 trial, which included 267 patients regimen, in which case nivolumab maintenance therapy should be
across 7 tumor cohorts: endometrial, cervical, ovarian, bladder, biliary used.
tract, pancreatic, and other.293 Eligibility for this trial included a HER2-
expressing tumor (IHC 3+/2+ by local or central testing) with locally First-line treatment options that may be useful under certain
advanced or metastatic disease after at least 1 systemic treatment or circumstances for patients who are not eligible for cisplatin-containing
without alternative treatments. In all patients on the study, the ORR was chemotherapy include pembrolizumab for patients who are not eligible
37.1%, median PFS was 6.9 months, and median OS was 13.4 months. for any platinum-containing chemotherapy and atezolizumab for
For the 41 patients with bladder cancer, ORR was 39.0%, median PFS patients whose tumors express PD-L1 or in patients who are not eligible
was 7.0 months, and median OS was 12.8 months. For the 75 patients for any platinum-containing chemotherapy regardless of PD-L1
with HER2 IHC 3+ expression, the ORR was 61.3%, median PFS was expression (both atezolizumab recommendations are category 2B).
11.9 months, and median OS was 21.1 months. For the patients with However, for these patients, enfortumab vedotin plus pembrolizumab
bladder cancer on this study, 65.9% had IHC 3+ HER2 overexpression. should be prioritized if it can be given. Several chemotherapy regimens,
Grade ≥3 drug-related AEs were observed in 40.8% of all patients on including gemcitabine, alone or in combination with paclitaxel, or the
the study, including 10.5% with adjudicated drug-related interstitial lung combination of ifosfamide, doxorubicin, and gemcitabine may also be
disease, of which 3 patients (1.1%) died. appropriate first-line treatment options for some patients.

NCCN Recommendations for Systemic Therapy of Metastatic Clinical trial enrollment is recommended by the NCCN Panel for all
Disease patients when appropriate, but is strongly recommended for second-line
Based on the available data, the NCCN Panel recommends that and subsequent therapies since data for locally advanced or metastatic
patients with metastatic urothelial carcinoma who are eligible for a disease treated with subsequent-line therapy are highly variable. The
cisplatin-containing regimen receive either a cisplatin-based regimen or available second-line options depend on what was given as first-line. If
pembrolizumab in combination with enfortumab vedotin as first-line a chemotherapy regimen, without a checkpoint inhibitor, was given first-
therapy, with pembrolizumab plus enfortumab vedotin being the line, pembrolizumab, nivolumab, avelumab, erdafitinib (if eligible on the
preferred option. First-line cisplatin-based regimens include GC, basis of FGFR3 genetic alteration), or enfortumab vedotin are preferred
ddMVAC with growth factor support, or gemcitabine-cisplatin plus second-line treatment options. Pembrolizumab is supported by category

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1 level data in the post-platinum setting. If PFS was more than 1 year based on negative results from the phase III DANUBE trial.298 DANUBE
following treatment with a platinum-containing regimen, retreatment with evaluated the use of durvalumab, with or without tremelimumab,
platinum may be considered.294 Platinum rechallenge has been studied compared to chemotherapy for first-line treatment of advanced
in the post-platinum and post-checkpoint inhibitor, subsequent-line urothelial carcinoma.299 The trial did not meet its primary endpoints as
setting.295 If a checkpoint inhibitor was given first-line, preferred second- both durvalumab alone and in combination with tremelimumab failed to
line options include enfortumab vedotin, erdafitinib (if eligible on the improve OS compared to chemotherapy.
basis of FGFR3 genetic alteration), or gemcitabine in combination with
carboplatin for those who are cisplatin-ineligible or GC or ddMVAC with Likewise, atezolizumab had initially received accelerated approval for
growth factor support for those who are cisplatin-eligible. Other patients with metastatic urothelial carcinoma post-platinum treatment
regimens may also be appropriate in the second-line setting (see based on early results from the IMvigor210 and IMvigor211 trials.300-302
Principles of Systemic Therapy within the algorithm). The phase IIIb SAUL study and another expanded access study of
atezolizumab also reported similar efficacy and safety results in a real-
For subsequent therapy, after treatment with a platinum-based therapy world population, including those ineligible for IMvigor211.303-305
and a checkpoint inhibitor, if the patient is eligible for these, the However, in March 2021, the makers of atezolizumab voluntarily
preferred regimens are enfortumab vedotin or erdafitinib, if eligible withdrew their indication for patients with locally advanced or metastatic
based on FGFR3 testing results. Both regimens are supported by urothelial carcinoma that was previously treated with a platinum-based
category 1 level data in this setting. A number of chemotherapy chemotherapy.306 This withdrawal was based on the IMvigor211 trial
regimens and the antibody-drug conjugates, sacituzumab govitecan or failing to meet its primary endpoint of improved OS. In November 2022,
fam-trastuzumab deruxtecan (if eligible on the basis of HER2 the remaining bladder cancer indications for atezolizumab were
overexpression), are also recommended options in this setting. withdrawn by the manufacturer based on results from the IMvigor130
trial.261
Targeted Therapies Not Recommended
Early results from a phase I/II multicenter study of durvalumab for 61 In response to these voluntary withdrawals, the NCCN Panel voted to
patients with PD-L1–positive inoperable or metastatic urothelial bladder remove atezolizumab and durvalumab as treatment options for patients
cancer that progressed following a platinum-based regimen showed that with metastatic urothelial carcinoma in the post-platinum setting,
46.4% of patients who were PD-L1 positive had disease that responded although atezolizumab is maintained in the Guidelines as a non-
to treatment; no response was seen in patients who were PD-L1 preferred first-line option for certain patients (see NCCN
negative.296 A 2017 update on this study (N = 191) showed an ORR of Recommendations for Systemic Therapy of Metastatic Disease, above).
17.8% and a median OS of 18.2 months, with 55% of patients surviving
at 1 year.297 In May 2017, the FDA granted accelerated approval to While several ongoing studies are investigating the addition of a
durvalumab based on these initial results. Subsequently, in February targeted therapy agent to chemotherapy for treatment of bladder
2021, the makers of durvalumab voluntarily withdrew this indication cancer, there are no sufficient data to support this approach. The phase
III KEYNOTE-361 trial of pembrolizumab alone or in combination with

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chemotherapy for first-line treatment of advanced urothelial carcinoma histology with localized disease regardless of stage.307-311 In addition, a
showed no improved efficacy compared to chemotherapy and, retrospective analysis has shown that neoadjuvant chemotherapy may
therefore, this combination is not recommended for treatment of have a modest benefit for other variant histologies.312 In patients with
metastatic bladder cancer.257 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 systemic therapy (see NCCN Guidelines for Small Cell Lung
pathologic findings, perioperative chemotherapy may or may not be Cancer) followed by either RT or cystectomy as consolidation, if there is
recommended. The regimens effective for urothelial carcinoma no metastatic disease.313 In addition to the regimens recommended for
histologies have limited efficacy for patients with non-urothelial small cell lung cancer, a regimen alternating ifosfamide plus doxorubicin
carcinomas. with etoposide plus cisplatin has also been tested specifically for small
cell bladder cancer and found to be effective both as neoadjuvant and
These individuals are often treated based on the identified histology. In metastatic therapy.309 The combination of nivolumab plus ipilimumab
general, patients with non-urothelial invasive disease are treated with has also been tested in a phase II trial for advanced rare genitourinary
cystectomy, although those with certain urachal tumors require malignancies, including the BUTCVH cohort of 19 patients with bladder
complete urachal resection (en bloc resection of the urachal ligament or upper tract tumors of variant histology (3 patients with small cell
with the umbilicus) or may be appropriately treated with partial bladder cancer).314 ORR for the BUTCVH cohort was 37%, with two
cystectomy. For example, adenocarcinomas are managed surgically complete responses. Concurrent chemoradiotherapy is also an option
with radical or partial cystectomy and with individualized adjuvant for these patients.315 Primary bladder sarcomas are treated as per the
chemotherapy and radiotherapy for maximum benefit. Pure squamous NCCN Guidelines for Soft Tissue Sarcoma.
cell tumors are treated by cystectomy, chemoradiotherapy, or agents
commonly used for squamous cell carcinoma of other sites such as Upper Tract Urothelial Carcinoma
5-FU or taxanes. However, overall experience with chemotherapy in Upper tract tumors, including those that originate in the renal pelvis or in
non-urothelial carcinomas is limited. the ureter, are relatively uncommon.316 The treatment recommendations
discussed in this section are based on the most common histology of
Data are limited to support perioperative chemotherapy for upper tract tumors, urothelial carcinoma.
non-urothelial carcinomas; however, neoadjuvant chemotherapy may
benefit patients with small cell carcinoma of the bladder and is
recommended by the panel for any patient with small-cell component

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NCCN Guidelines Version 5.2024

Bladder Cancer

Renal Pelvis Tumors Well-differentiated tumors of low grade may be managed with a
Tumors that develop in the renal pelvis may be identified during nephroureterectomy with a bladder cuff with or without perioperative
evaluation of hematuria or a renal mass. In the latter case, renal pelvic intravesical chemotherapy. Several prospective, randomized, clinical
tumors must be distinguished from the more typical adenocarcinomas trials have shown a reduction of risk of bladder recurrence following
that originate in the renal parenchyma. These tumors may also be nephroureterectomy when a single postoperative intravesical instillation
detected during an assessment to pinpoint the source of a positive of chemotherapy was administered.318-320 While the studies have
cytology in a negative cystoscopy with a retrograde ureteropyelography. generally looked at early instillation (within 24–48 hours of
surgery),319,320 some centers are delaying intravesical instillation of
Workup chemotherapy by up to 1 week to administer a cystogram confirming
The evaluation of a patient with a suspected renal pelvic tumor should there is no perforation. While mitomycin is most commonly used,
include cystoscopy and imaging of the upper tract collecting system with gemcitabine is an option for select patients. As an alternate to
CT or MR urography; renal ultrasound or CT without contrast with nephroureterectomy, a nephron-sparing procedure through a
retrograde ureteropyelography; or ureteroscopy with biopsy; or transureteroscopic approach or a percutaneous approach may be used,
percutaneous biopsy; and/or selective washings. A chest radiograph or with or without postsurgical intrapelvic chemotherapy or BCG (see
CT can help evaluate for possible metastasis and assess for any Endoscopic Management of UTUC).
comorbid diseases. Urine cytology obtained from a urine sample or
during a cystoscopy may help identify carcinoma cells. Hematologic, High-grade tumors or those that are large and/or invade the renal
renal, and hepatic function should also be evaluated. Additional imaging parenchyma are managed through nephroureterectomy with a bladder
studies, such as a renal scan or bone scan, may be needed if indicated cuff and regional lymphadenectomy with or without perioperative
by the test results or by the presence of specific symptoms. Recent intravesical chemotherapy. Decline in renal function following surgery
evidence has suggested a high prevalence of Lynch syndrome in may preclude adjuvant therapy. Hence, in selected patients, cisplatin-
patients with UTUC.8,317 Therefore, it is recommended to take a based neoadjuvant chemotherapy is recommended. The data
thorough family history for all patients with UTUC and consider supporting the use of neoadjuvant chemotherapy for UTUC are more
evaluation for Lynch syndrome for those who are at high risk (see limited than for urothelial bladder cancer, although a growing body of
NCCN Guidelines for Genetic/Familial High-Risk Assessment: evidence suggests that this approach may be beneficial to certain
Colorectal for information on the criteria and strategies for evaluation of patients. A phase II trial demonstrated the safety and activity of
Lynch syndrome). accelerated MVAC as neoadjuvant therapy for high-grade UTUC with a
pathologic complete response rate of 14% and a final pathologic stage
Primary Treatment of ypT1 or less in more than 60% of patients.321 Systematic reviews and
In general, the primary form of treatment for renal pelvic tumors is meta-analyses have also reported that neoadjuvant chemotherapy may
surgery. also improve outcomes compared to no perioperative treatment,
although more prospective data are needed.322-325

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NCCN Guidelines Version 5.2024

Bladder Cancer

If metastatic disease is documented, or comorbid conditions that do not low-grade noninvasive UTUC with at least one measurable papillary
allow for surgical resection are present, treatment should include tumor above the ureteropelvic junction who were scheduled to receive 6
systemic therapy with regimens similar to those used for metastatic weekly instillations of mitomycin ureteral gel via retrograde catheter to
urothelial bladder tumors. the renal pelvis and calyces.331 Of the 71 patients who received at least
one dose of mitomycin gel, 59% showed a complete response at the
In positive upper tract cytology but negative imaging and biopsy studies, primary disease evaluation visit (95% CI, 47%–71%; P < .0001).
treatment remains controversial and appropriate management is Durability of response was estimated at 84.2% 12 months after the
currently poorly defined. Frequent monitoring for disease is necessary primary disease evaluation, with a median time to recurrence of 13
for these patients. months. The most common all-cause AEs in this study were ureteric
stenosis, urinary tract infections, hematuria, flank pain, and nausea.
Endoscopic Management of UTUC
Based on these data, the NCCN Panel recommends mitomycin gel be
Nephron-sparing endoscopic treatment is a treatment option for certain
considered for use in this setting, with the caveat that complete or near
patients with UTUC, depending on clinical and pathologic criteria and/or
complete endoscopic resection or ablation is recommended prior to gel
comorbid conditions that may contraindicate nephroureterectomy.
application. Treatment with mitomycin gel is most appropriate for
Favorable clinical and pathologic criteria for nephron preservation
patients with a solitary residual, low-grade, UTUC tumor that is low
include a papillary, unifocal, low-grade tumor, and size less than 1.5 cm,
volume (eg, 5–15 mm) and who are not candidates for or are not
where cross-sectional imaging shows no concern for invasive
seeking nephroureterectomy as a definitive treatment. Long-term follow-
disease.316,326 Although there are no randomized controlled trials,
up of OLYMPUS showed a durable response to mitomycin ureteral gel
systematic reviews of retrospective studies have shown that nephron-
in those who had a complete response to induction therapy (56%
sparing approaches show similar outcomes compared to
remained in complete response after 12 months).332 Fifty percent of
nephroureterectomy for these patients.327,328 In addition, patients with
those who did not receive any maintenance instillations of mitomycin gel
bilateral disease, solitary functional or anatomic kidney, chronic kidney
and 59% of those who received at least one maintenance instillation
disease, or renal insufficiency are contraindicated from
remained in complete response at 12 months.
nephroureterectomy and should receive nephron-sparing
treatment.316,329 Long-term surveillance (>5 years), including urine Adjuvant Treatment and Follow-up
cytology and cross-sectional urography or endoscopic visualization, is Subsequent management is dictated by the extent of disease at
required following nephron-sparing treatment due to a high risk of surgery. Tumors that are pT0 or pT1 should be followed up with serial
disease recurrence.316 cystoscopies at 3-month intervals for the first year and, if negative, at
longer intervals. Cytology may also be considered at similar intervals for
Mitomycin for pyelocalyceal solution (also called UGN-101 or mitomycin
high-grade tumors. Tumors that are pT0 or pT1 and were treated with
gel) has been FDA-approved for treatment of adult patients with low-
nephron-sparing surgery should also be followed up with ureteroscopy
grade UTUC.330 This approval was based on OLYMPUS, a single-arm,
and upper tract imaging at 3- to 12-month intervals.
multicenter, phase 3 trial of patients with treatment-naïve or recurrent

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NCCN Guidelines Version 5.2024

Bladder Cancer

While a previous retrospective study of 1544 patients with pT2–4 or opportunity to delay recurrence, and who accept the risk of side effects,
node-positive UTUC showed no difference in OS between adjuvant even if the chance for cure was not improved in this situation. Follow-up
chemotherapy and observation following radical nephroureterectomy,333 should be the same as pT0/pT1 disease with the addition of chest
the more recent phase III POUT trial has demonstrated benefit of imaging and a stronger recommendation for cytology.
adjuvant therapy for these patients.334 POUT randomized 261 patients
with pT2–4 or pN1–3, M0 UTUC after nephroureterectomy to either There have been some data on the use of adjuvant RT or
surveillance or adjuvant chemotherapy. Chemotherapy consisted of chemoradiotherapy following nephroureterectomy for UTUC. One study
gemcitabine, in combination with either cisplatin or carboplatin. Adjuvant reported on local recurrence patterns and risk factors in 389 patients
therapy significantly improved DFS (HR, 0.45; 95% CI, 0.30–0.68; P = with UTUC who were treated with radical nephroureterectomy.335 This
.0001) after a median follow-up of 30.3 months. Three-year event-free study found that adjuvant RT reduced local recurrence rates (HR,
estimates were 71% for those who received adjuvant chemotherapy 0.177; 95% CI, 0.064–0.493; P = .001). However, another retrospective
and 46% for surveillance. Forty-four percent of those who started study of 198 patients with pT3, N0, M0 UTUC found no significant
chemotherapy had grade 3 or higher treatment-emergent AEs differences in 2-year OS, DSS, or RFS for those who received adjuvant
compared to 4% with surveillance. Nivolumab has also been RT compared to those who did not.336 In addition, a retrospective review
investigated for adjuvant treatment of UTUC as the above-mentioned of 31 patients with UTUC who were treated with RT, with or without
CheckMate 274 trial included 21% of patients with UTUC (96 renal concurrent chemotherapy, following attempted curative resection found
pelvis and 53 ureter).185 Results from the full trial population are detailed that 5-year actuarial OS and DSS were longer in the patients who
in the section on Adjuvant Systemic Therapy under Muscle Invasive received adjuvant cisplatin-based chemoradiotherapy compared to
Urothelial Bladder Cancer, above. While the authors note that the those who received RT alone.337 In this study, 5-year actuarial OS was
analysis shows the possibility of a larger effect size for bladder 27% for RT alone compared to 67% for chemoradiotherapy (P = .01)
compared to UTUC, they caution that the trial was designed to measure and DSS was 41% for RT compared to 76% for chemotherapy (P =
the entire trial population and that further analyses are planned to test .06). Based on the lack of data supporting this approach for UTT,
the effects on these subgroups. adjuvant RT is not recommended.

Based on these data, adjuvant therapy should be discussed for patients Urothelial Carcinoma of the Ureter
with pT3–4 or nodal disease. If no platinum-based neoadjuvant Ureteral tumors may develop de novo or in patients who have
treatment was given, adjuvant treatment with a platinum-based regimen undergone successful treatment for superficial tumors that originate in
should be discussed. Alternatively, adjuvant nivolumab may be the bladder. The presentation varies as a function of disease extent.
considered (category 2B). If platinum-based neoadjuvant therapy was Ureteral tumors may be identified in patients who have a positive
given and the disease was determined to be ypT2–4 or ypN+ after cytology with a negative cystoscopy in whom selective catheterization of
surgery, adjuvant nivolumab may be considered, although adjuvant the ureters is performed. More extensive lesions may result in pain or
therapy would be most appropriate for patients who value the obstruction.

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NCCN Guidelines Version 5.2024

Bladder Cancer

Workup lymphadenectomy. Neoadjuvant chemotherapy can be considered in

The evaluation is similar to that outlined for tumors that originate in the select patients.
renal pelvis.
Distal ureteral tumors may be managed with a distal ureterectomy and
Primary Treatment regional lymphadenectomy if high grade followed by reimplantation of
For resectable ureteral tumors, the primary management is surgery (see the ureter (preferred if clinically feasible), with or without perioperative
Endoscopic Management of UTUC within the Renal Pelvis Tumors intravesical chemotherapy. Other primary treatment options include
section of this Discussion for more discussion of nephron-sparing endoscopic resection for low-grade tumors, or, in some cases, a
approaches), with or without perioperative intravesical chemotherapy. nephroureterectomy with a bladder cuff, and regional lymphadenectomy
The specific procedure required varies depending on the location of the if high grade. Neoadjuvant chemotherapy can be considered for select
tumor (upper, mid, or distal location) and disease extent. Neoadjuvant patients with distal ureteral tumors following distal ureterectomy or the
chemotherapy may be considered in selected patients, such as when nephroureterectomy with bladder cuff.
the degree of invasiveness is established before definitive surgery.322,338
Follow-up
Tumors that originate in the upper ureter occasionally can be managed The final pathologic stage is used to guide subsequent management, as
endoscopically, if low-grade, but more commonly are treated with is the case for tumors that originate in other sites. No adjuvant therapy
nephroureterectomy with a bladder cuff, with or without perioperative is advised for lesions that are pT1 or less, but serial follow-up of the
intravesical chemotherapy, plus regional lymphadenectomy for urothelial tracts or remaining unit (as previously described under Renal
high-grade tumors. Neoadjuvant chemotherapy should be considered in Pelvis Tumors) is recommended.
select patients, including patients with retroperitoneal lymphadenopathy;
bulky (>3 cm) high-grade tumor; sessile histology; or suspected Patients with more extensive disease are advised to consider adjuvant
parenchymal invasion. A portion of the bladder is removed to ensure treatment, depending on the disease stage, whether neoadjuvant
complete removal of the entire intramural ureter. treatment was given, and patient preference. Please see Adjuvant
Treatment and Follow-up for Renal Pelvis Tumors, above, for more
Tumors that originate in the mid portion may also be managed discussion of the recommendations and data on adjuvant therapy for
differently depending on grade. Low-grade tumors may be managed by UTUC.
endoscopic resection or excision, with or without perioperative
intravesical chemotherapy, followed by ureteroureterostomy, or Urothelial Carcinomas of the Prostate
segmental or complete ureterectomy, or ileal ureter interposition may Urothelial (transitional cell) carcinomas of the prostate represent a
also be an option in highly selected patients. High-grade lesions are distinct entity with a unique staging system. In this respect, they must
generally managed with nephroureterectomy with a bladder cuff, with or be distinguished from urothelial carcinomas of bladder origin that invade
without perioperative intravesical chemotherapy, and regional into the prostate through the bladder wall. Urothelial carcinomas of the
prostate may occur de novo or, more typically, concurrently or after

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NCCN Guidelines Version 5.2024

Bladder Cancer

treatment of bladder cancer. Similar to tumors originating in other sites patients with only ductal and acini invasion. Local recurrences in
of the urothelium, management of prostate urothelial carcinomas is patients undergoing TURP and BCG therapy are treated with
based on the extent of disease with particular reference to the urethra, cystoprostatectomy with or without urethrectomy.
duct, acini, and stroma.
Primary Carcinoma of the Urethra
Workup Primary carcinoma that arises in the urethra is rare. Unlike for bladder
The evaluation of a suspected urothelial carcinoma of the prostate cancer, squamous cell carcinoma is the most common histologic
includes a digital rectal examination (DRE), cystoscopy with bladder subtype for urethral cancer.340 The 5-year OS is 42%.341,342 Stage and
biopsy, and TURP that includes the prostatic stroma. Prostate-specific disease location are the most important prognostic factors for male
antigen testing should be performed. Multiple stromal biopsies are patients, while tumor size and histology are prognostically significant for
advised and, if the DRE is abnormal, additional needle biopsies may be female patients.340,342 Unfortunately, there is a lack of robust,
required in selected patients to exclude primary adenocarcinoma of the prospective data to support treatment decisions due to disease rarity.
prostate. Upper tract collecting system imaging is also recommended. Treatment recommendations typically encompass all of the respective
histologies (ie, squamous, transitional, adenocarcinomas) with the
Primary Treatment
treatment approach based on location (ie, proximal vs. distal urethral
Pending histologic confirmation, tumors that are limited to the mucosal
tumors).
prostatic urethra with no acinar or stromal invasion can be managed
with TURP and intravesical BCG, with follow-up similar to that for Workup
superficial disease of the bladder. A systematic review and meta- A cystourethroscopy should be performed if carcinoma of the urethra is
analysis of intravesical BCG for treatment of noninvasive urothelial suspected. This includes EUA and transurethral or transvaginal biopsy.
carcinoma of the prostate found that the complete response rate for Chest x-ray or CT and MRI of the pelvis are recommended to evaluate
prostatic disease was 88% (95% CI, 0.81–0.96).339 If local recurrence is the extent of the disease.
seen, cystoprostatectomy with or without urethrectomy is
recommended. Patients with tumors that invade the ducts, acini, or If palpable inguinal lymph nodes are present, a chest/abdomen/pelvis
stroma should undergo an additional workup with chest radiograph or CT and lymph node biopsy should be performed.
CT, and abdominal/pelvic CT if necessary, to exclude metastatic
disease, and then a cystoprostatectomy with or without urethrectomy Treatment
should be performed. Based on data extrapolated from bladder cancer Patients with CIS, Ta, or T1 disease should have a repeat transurethral
therapy, neoadjuvant chemotherapy is recommended in patients with or transvaginal resection. In select cases, TURBT is followed by
stromal invasion.153-155 Adjuvant chemotherapy may be advised for intraurethral therapy with BCG, mitomycin, or gemcitabine. A total
stromal invasion after primary treatment if neoadjuvant therapy was not urethrectomy may be considered if the patient has undergone a radical
given. Alternatively, TURP and intravesical BCG may be offered to cystectomy and cutaneous diversion.

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NCCN Guidelines Version 5.2024

Bladder Cancer

Treatment for T2 disease is based on patient anatomy and tumor receiving chemoradiation alone (54%). If systemic therapy is used, the
location. For patients assigned male at birth with pendulous urethra, a choice of regimen should be based on histology.
distal urethrectomy or partial penectomy are viable options. Patients
may consider neoadjuvant chemotherapy (category 2B) or Patients with T3 or T4 disease but no clinical nodes should receive
chemoradiation (category 2A) before a urethrectomy. Patients who have neoadjuvant chemotherapy (if urothelial carcinoma) followed by
positive margins may undergo additional surgery or radiation, preferably consolidative surgery or, if ineligible for standard systemic
with chemotherapy. At recurrence, options include systemic therapy, chemotherapy, radiation or chemoradiation with or without consolidative
total penectomy, radiation, or a combination. Patients with T2 tumors in surgery. Surgery alone is an option for non-urothelial histologies. If
the bulbar urethra should undergo urethrectomy with or without node-positive, chemoradiation is the preferred treatment for squamous
cystoprostatectomy. Adjuvant chemotherapy or chemoradiation may be cell carcinoma. Systemic therapy or chemoradiotherapy with or without
considered if pT3, pT4, or nodal disease is found. Recurrent cases may consolidative surgery are also treatment options. At recurrence, the
be treated with systemic therapy and/or radiation. patient may undergo pelvic exenteration (category 2B) with or without
ilioinguinal lymphadenectomy and/or chemoradiotherapy. Pelvic
Initial treatment options for patients assigned female at birth with T2 exenteration for T3 urethral cancer consists of urethrectomy,
tumors include chemoradiation or urethrectomy with cystectomy, with cystectomy, and either a prostatectomy or anterior vaginectomy with
organ-sparing approaches used when feasible in appropriately selected hysterectomy, as applicable. For highly local advanced T4 tumors, the
cases.139,140 Partial urethrectomy is possible in a minority of cases, posterior vagina and rectum may also need to be removed en bloc with
depending on tumor location, and has been associated with a high local the specimen. Systemic therapy is a category 2B option.
recurrence rate.343 At recurrence, the patient may receive systemic
therapy or chemoradiotherapy (both category 2A) or pelvic exenteration Patients with distant metastases should receive similar treatment as
(category 2B). Pelvic exenteration for T2 urethral cancer consists of en metastatic bladder cancer. Systemic therapies include chemotherapy
bloc removal of the urethra, bladder, and anterior vagina. and targeted therapies as subsequent-line options. However, it should
be noted that checkpoint inhibitors have only been evaluated in patients
A multimodal treatment approach (ie, surgery, systemic therapy, with urothelial histology.
radiation) is common for advanced disease. A cohort study reported a
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.344 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.345 Patients undergoing 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

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NCCN Guidelines Version 5.2024

Bladder Cancer

recurrences are non-muscle invasive and can be treated

endoscopically. Within each category of disease, more refined methods
to determine prognosis and guide management, based on molecular
staging, are under development with the goal of optimizing each
patient’s likelihood of cure and chance for organ preservation.

For patients with more extensive disease, newer treatments typically

involve combined modality approaches using recently developed
surgical procedures or three-dimensional treatment planning for more
precise delivery of RT. Although these are not appropriate in all cases,
they offer the promise of an improved quality of life and prolonged
survival.

Within the category of metastatic disease, several new agents and

combination regimens have been studied and seem to be superior to
those that were previously considered standard therapies. In particular,
immune checkpoint inhibitors, antibody-drug conjugates, and targeted
therapies have emerged as new options for the treatment of metastatic
bladder cancer. Experts surmise that the treatment of urothelial tumors
will evolve rapidly over the next few years, with improved outcomes
across all disease stages.

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Bladder Cancer

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