Published Ahead of Print on March 21, 2016 as 10.1200/JCO.2015.65.
9797
The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2015.65.9797
JOURNAL OF CLINICAL ONCOLOGY
Matthew I. Milowsky, University of North
Carolina Lineberger Comprehensive
Cancer Center, Chapel Hill, NC; R. Bryan
Rumble, American Society of Clinical
Oncology, Alexandria, VA; Christopher M.
Booth, Queen’s University, Kingston;
Libni J. Eapen, Ottawa Hospital Cancer
Centre, Ottawa, Ontario, Canada; Timothy
Gilligan, Cleveland Clinic, Cleveland, OH;
Ralph J. Hauke, Nebraska Cancer
Specialists, Omaha, NE; Pat Boumansour,
Patient Representative, Palm Coast, FL;
and Cheryl T. Lee, University of Michigan,
Ann Arbor, MI.
Published online ahead of print at
www.jco.org on March 21, 2016.
Clinical Practice Guideline Committee
approval: January 4, 2016.
Editor’s note: This American Society of
Clinical Oncology clinical practice
guideline endorsement provides
recommendations based on the review
and analysis of the relevant literature on
guidelines for muscle-invasive and
metastatic bladder cancer. Additional
information, which may include a
methodology supplement, data
supplements, slide sets, patient versions,
frequently asked questions, and other
clinical tools and resources, is available at
www.asco.org/endorsements/MIBC and
www.asco.org/guidelineswiki.
Authors’ disclosures of potential conflicts
of interest are found in the article online at
www.jco.org. Author contributions are
found at the end of this article.
Reprint requests: 2318 Mill Rd, Suite 800,
Alexandria, VA 22314; e-mail: guidelines@
asco.org.
Corresponding author: American Society
of Clinical Oncology, 2318 Mill Rd, Suite
800, Alexandria, VA 22314; e-mail:
guidelines@asco.org.
© 2016 by American Society of Clinical
Oncology
0732-183X/16/3499-1/$20.00
DOI: 10.1200/JCO.2015.65.9797
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Copyright 2016 by American Society of Clinical Oncology
A S C O S P E C I A L A R T I C L E
Guideline on Muscle-Invasive and Metastatic Bladder Cancer
(European Association of Urology guideline): American
Society of Clinical Oncology Clinical Practice
Guideline Endorsement
Matthew I. Milowsky, R. Bryan Rumble, Christopher M. Booth, Timothy Gilligan, Libni J. Eapen, Ralph J. Hauke,
Pat Boumansour, and Cheryl T. Lee
A B S T R A C T
Purpose
To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and meta-
static bladder cancer. The American Society of Clinical Oncology (ASCO) has a policy and set of
procedures for endorsing clinical practice guidelines that have been developed by other professional
organizations.
Methods
The guideline on MIBC and metastatic bladder cancer was reviewed for developmental rigor by
methodologists. The ASCO Endorsement Panel then reviewed the content and recommendations.
Results
The ASCO Endorsement Panel determined that the recommendations from the European Asso-
ciation of Urology guideline on MIBC and metastatic bladder cancer, published online in March 2015,
are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses the guideline
on MIBC and metastatic bladder cancer and has added qualifying statements, including highlighting
the use of chemoradiotherapy for select patients with MIBC and recommending a preference for
clinical trials in the treatment of metastatic disease in the second-line setting.
Recommendations
Multidisciplinary care for patients with MIBC and metastatic bladder cancer is critical. The standard
treatment of MIBC (cT2-T4a N0M0) is neoadjuvant cisplatin-based combination chemotherapy
followed by radical cystectomy. In cisplatin-ineligible patients, radical cystectomy alone is rec-
ommended. Adjuvant cisplatin-based chemotherapy may be offered to high-risk patients who have
not received neoadjuvant therapy. Chemoradiotherapy may be offered as an alternative to cystectomy
in appropriately selected patients with MIBC and in some patients for whom cystectomy is not an
option. Metastatic disease should be treated with cisplatin-containing combination chemotherapy or
with carboplatin combination chemotherapy or single agents in patients ineligible for cisplatin.
Additional information is available at http://www.asco.org/endorsements/MIBC and www.asco.org/
guidelineswiki.
J Clin Oncol 34. © 2016 by American Society of Clinical Oncology
distant metastases, demonstrating the lethality of
INTRODUCTION
the disease. For these reasons, there is great
interest in providing clinicians and patients with
Worldwide, bladder cancer is the ninth most
guidance on the management of MIBC and
common cancer.1 In the United States, there will
be an estimated 74,000 new bladder cancer cases metastatic bladder cancer based on the best
and 16,000 related deaths in 2015,2 and ap- available evidence.
proximately 30% of all newly diagnosed patients The purpose of this American Society of
present with muscle-invasive bladder cancer Clinical Oncology (ASCO) guideline is to endorse
(MIBC).1 In addition to the 5% of patients who the European Association of Urology (EAU) guide-
present with metastatic disease, roughly 50% of line on MIBC and metastatic bladder cancer by
patients with MIBC will ultimately develop Witjes JA et al, which was published in the journal
© 2016 by American Society of Clinical Oncology 1
 Milowsky et al

THE BOTTOM LINE

Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology guideline):
American Society of Clinical Oncology Clinical Practice Guideline Endorsement

Target Population
Patients with muscle-invasive (MIBC) or metastatic bladder cancer

Target Audience
Primary care providers, urologists, radiation and medical oncologists, and other providers

Methods
An ASCO Endorsement Panel was convened to consider endorsing the EAU guideline on MIBC and metastatic bladder cancer
recommendations that were based on a systematic review of the medical literature. The ASCO Endorsement Panel considered the
methodology used in the EAU guideline by considering the results from the AGREE II review instrument. The ASCO Endorsement
Panel carefully reviewed the EAU guideline content to determine appropriateness for ASCO endorsement.

ASCO Key Recommendations for MIBC and Metastatic Bladder Cancer

Table 1 lists the EAU recommendations and ASCO-endorsed guidelines with qualifying statements (in bold italics).
1. Multidisciplinary input via tumor board discussions and/or directed consultations is critical to the optimal
management of patients with MIBC and metastatic bladder cancer (eg, referral to a medical oncologist should be
made for a discussion of neoadjuvant chemotherapy and referral to a radiation oncologist for a discussion of bladder
preservation in patients with muscle-invasive disease). Implementation of these guidelines requires the integration of
urology and medical and radiation oncology expertise to provide the highest level of care to patients.
2. Neoadjuvant chemotherapy is recommended for T2-T4a, cN0M0 bladder cancer and should always be cisplatin-based
combination therapy.
3. Neoadjuvant chemotherapy is not recommended in patients who are ineligible for cisplatin-based combination
chemotherapy, unless the goal is downstaging surgically unresectable tumors.
4. Any decision regarding bladder-sparing or radical cystectomy in elderly/geriatric patients with invasive bladder cancer
should be based on tumor stage, bladder function, and the ability to tolerate major surgery, radiotherapy, and/or
chemotherapy.
5. Radical cystectomy is recommended in T2-T4a, N0M0 and high-risk non-MIBC. Chemoradiotherapy-based organ
preservation treatment may be offered to select patients with MIBC.
6. In patients being treated with bladder-preservation therapy with curative intent, combined chemoradiotherapy is
superior to, and is recommended over, radiotherapy alone.
7. Although neoadjuvant chemotherapy is recommended, adjuvant chemotherapy may be offered to high-risk patients
who have not received neoadjuvant treatment.*
8. First-line treatment of fit patients with metastatic disease: Use cisplatin-containing combination chemotherapy with
gemcitabine plus carboplatin, MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), or high-dose MVAC
with granulocyte colony-stimulating factor.
9. First-line treatment in patients ineligible (unfit) for cisplatin: use carboplatin combination chemotherapy or single
agents.
10. In patients experiencing progression after platinum-based combination chemotherapy for metastatic disease, entry into
a clinical trial is preferred. Alternatively, single-agent therapy may be offered (eg, paclitaxel, docetaxel, or vinflunine
where available).

Additional Resources
More information that may include a Data Supplement, a Methodology Supplement, slide sets, and clinical tools and resources is
available at www.asco.org/endorsements/MIBC and www.asco.org/guidelineswiki. Patient information is available at www.cancer.net.
A link to the guideline on MIBC and metastatic bladder cancer can be found at http://uroweb.org/guideline/bladder-cancer-
muscle-invasive-and-metastatic/.
(continued on following page)

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 Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement

THE BOTTOM LINE (CONTINUED)

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should
have the opportunity to participate.

*The word “offered” should be interpreted as having a detailed discussion with the patient about the risks and benefits of adjuvant chemotherapy. The discussion
should include a thorough review of the absolute risk of recurrence in light of the pathologic findings, acknowledging the limitations of the data in the adjuvant
setting.

European Urology in 20141 and then updated online by the EAU in
March 2015 (http://uroweb.org/guideline/bladder-cancer-muscle-
invasive-and-metastatic/ with supplementary materials available at:
http://uroweb.org/guideline/bladder-cancer-muscle-invasive-and-
metastatic/?type=appendices-publications) (note that a 2016
update is currently in development). This ASCO endorsement
reinforces the recommendations offered in the guideline on MIBC
and metastatic bladder cancer and acknowledges the effort put
forth by the EAU to produce an evidence-based guideline
informing practitioners who care for patients with muscle-
invasive or metastatic disease. The issues addressed in the
original guideline as well as this endorsement cover a broad
range of options around MIBC and metastatic bladder cancer,
from pathology and classification to treatment to follow-up. For
this endorsement, only the recommendations relevant to treat-
ment were examined. A reprint of the original EAU Recom-
mendations (which also appear online at: http://uroweb.org/
guideline/bladder-cancer-muscle-invasive-and-metastatic/) along
with the ASCO Endorsed Recommendations and qualifying
statements appear in Table 1.
OVERVIEW OF ASCO GUIDELINE ENDORSEMENT PROCESS
ASCO has policies and procedures for endorsing practice guide-
lines that have been developed by other professional organizations.
The goal of guideline endorsement is to increase the number
of high-quality, ASCO-vetted guidelines available to the ASCO
membership. The ASCO endorsement process involves an
assessment by ASCO staff of candidate guidelines for methodologic
quality using the Rigour of Development subscale of the Appraisal
of Guidelines for Research and Evaluation II (AGREE II) instru-
ment (Methodology Supplement provides more detail).
Disclaimer
The clinical practice guideline and other guidance published
herein are provided by ASCO to assist providers in clinical decision
making. The information herein should not be relied on as being
complete or accurate, nor should it be considered as inclusive
of all proper treatments or methods of care or as a statement
of the standard of care. With the rapid development of scientific
knowledge, new evidence may emerge between the time in-
formation is developed and when it is published or read. The
information is not continually updated and may not reflect the
most recent evidence. The information addresses only the topics
specifically identified herein and is not applicable to other inter-
ventions, diseases, or stages of disease. This information does not
mandate any particular course of medical care. Furthermore, the
information is not intended to substitute for the independent
professional judgment of the treating provider, because the
information does not account for individual variation among
patients. Recommendations reflect high, moderate, or low
confidence that the recommendation reflects the net effect of a
given course of action. The use of words like “must,” “must
not,” “should,” and “should not” indicates that a course of
action is recommended or not recommended for either most or
many patients, but there is latitude for the treating physician to select
other courses of action in individual cases. In all cases, the selected
course of action should be considered by the treating provider in the
context of treating the individual patient. Use of the information is
voluntary. ASCO provides this information on an as-is basis and
makes no warranty, express or implied, regarding the information.
ASCO specifically disclaims any warranties of merchantability or
fitness for a particular use or purpose. ASCO assumes no
responsibility for any injury or damage to persons or property
arising out of or related to any use of this information or for any
errors or omissions.
Guideline and Conflicts of Interest
The Expert Panel (Appendix Table A1, online only) was
assembled in accordance with ASCO’s Conflict of Interest Policy
Implementation for Clinical Practice Guidelines (“Policy,” found at
http://www.asco.org/rwc). All members of the panel completed the
ASCO disclosure form, which requires disclosure of financial and
other interests that are relevant to the subject matter of the
guideline, including relationships with commercial entities that are
reasonably likely to experience direct regulatory or commercial impact
as a result of promulgation of the guideline. Categories for disclosure
include employment; leadership; stock or other ownership; honoraria;
consulting or advisory role; speaker’s bureau; research funding;
patents, royalties, other intellectual property; expert testimony; travel,
accommodations, expenses; and other relationships. In accordance
with the policy, the majority of the members of the panel did not
disclose any relationships constituting a conflict under the Policy.
CLINICAL QUESTIONS AND TARGET POPULATION
The EAU guideline did not disclose specific research questions but
instead presented recommendations according to the following

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 Milowsky et al

Table 1. Original EAU and ASCO Endorsement Recommendations and Qualifying Statements
ASCO Endorsement of EAU Guidelines on Muscle-Invasive and
EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Metastatic Bladder Cancer Original Recommendations With Qualifying
Recommendations Statements (in bold italics)

Primary Assessment of Presumably Invasive Bladder Tumors

Cystoscopy should describe all macroscopic features of the tumor
(site, size, number and appearance) and mucosal abnormalities.
A bladder diagram is recommended.
Biopsy of the prostatic urethra is recommended for cases of bladder
neck tumor, when bladder CIS is present or suspected, when there is
positive cytology without evidence of tumor in the bladder, or when abnormalities
of the prostatic urethra are visible.
If biopsy is not performed during the initial procedure, it should be
completed at the time of the second resection.
In women undergoing subsequent orthotopic neobladder construction, procedural
information is required (including histological evaluation) of
the bladder neck and urethral margin, either before or at the time of
cystoscopy.
The pathological report should specify the grade, depth of tumor
invasion, and whether the lamina propria and muscle tissue are present
in the specimen.
Comorbidity Scales
The decision regarding bladder-sparing or radical cystectomy in
elderly/geriatric patients with invasive bladder cancer should be based
on tumor stage and comorbidity best quantified by a validated score,
such as the Charlson Comorbidity Index.
The ASA score does not address comorbidity and should not be used
in this setting.
Treatment Failure of Non–Muscle-Invasive Bladder Cancer
In all T1 tumors at high risk of progression (ie, high grade,
multifocality, CIS, and tumor size, as outlined in the EAU guidelines
for non–muscle-invasive bladder cancer*), immediate radical treatment
is an option.
In all T1 patients failing intravesical therapy, radical treatment should be
offered.
Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is recommended for T2-T4a, cN0M0
bladder cancer and should always be cisplatin-based combination
therapy.
Neoadjuvant chemotherapy is not recommended in patients who are
ineligible for cisplatin-based combination chemotherapy.
Pre- and Postoperative Radiotherapy
Preoperative radiotherapy is not recommended to improve survival.
Preoperative radiotherapy for operable MIBC can result in tumor
down-staging after 4-6 weeks.
Radical Cystectomy and Urinary Diversion
Do not delay cystectomy for . 3 months because it increases
the risk of progression and cancer-specific mortality.
Before cystectomy, the patient should be fully informed about the
benefits and potential risks of all possible alternatives, and the final
decision should be based on a balanced discussion between patient and surgeon.
An orthotopic bladder substitute or ileal conduit diversion should be
offered to male and female patients lacking any contraindications and
who have no tumor in the urethra or at the level of urethral dissection.
Preoperative radiotherapy is not recommended in subsequent
cystectomy with urinary diversion.
Preoperative bowel preparation is not mandatory. “Fast track”
measurements may reduce the time of bowel recovery.
Radical cystectomy is recommended in T2-T4a, N0 M0, and high-risk
non-MIBC (as outlined above).
Lymph node dissection should be an integral part of cystectomy.
The urethra can be preserved if margins are negative. If no bladder
substitution is attached, the urethra must be checked regularly.
Laparoscopic cystectomy and robot-assisted laparoscopic cystectomy
are both management options. However, current data have not sufficiently
proven the advantages or disadvantages for oncological and functional
outcomes.
Nonresectable Tumors: Palliative Cystectomy for Muscle-Invasive Bladder Carcinoma
In patients with inoperable locally advanced tumors (T4b), primary
radical cystectomy is a palliative option.
In patients with symptoms palliative cystectomy may be offered.
(continued on following page)
Cystoscopy should describe all macroscopic features of the tumor (site, size, number and
appearance) and mucosal abnormalities. A bladder diagram is recommended when
feasible.
Biopsy of the prostatic urethra is recommended when there is positive cytology without
evidence of tumor in the bladder, or when abnormalities of the prostatic urethra are
visible. Additionally, prostatic urethral biopsy should be considered for cases of
bladder neck tumor or when bladder CIS is present or suspected.
If biopsy is not performed during the initial procedure, it should be completed at the time
of the second resection.
In women undergoing subsequent orthotopic neobladder construction, procedural
information is required (including histological evaluation) of the bladder neck and
urethral margin, either before or at the time of cystectomy.
The pathological report should specify the grade, histology, depth of tumor invasion, and
whether the lamina propria and muscle tissue are present in the specimen.
Any decision regarding bladder-sparing or radical cystectomy in elderly/geriatric patients
with invasive bladder cancer should be based on tumor stage, bladder function, and
the ability to tolerate major surgery, radiotherapy and/or chemotherapy.
The ASA score does not address comorbidity and should not be used in this setting.
In all T1 tumors at high risk of progression (ie, high grade, multifocality, CIS, and tumor
size, as outlined in the EAU guidelines for non–muscle-invasive bladder cancer*),
immediate radical treatment is an option.
In all T1 patients failing intravesical therapy, radical treatment should be offered.
Neoadjuvant chemotherapy is recommended for T2-T4a, cN0M0 bladder cancer and
should always be cisplatin-based combination therapy.
Neoadjuvant chemotherapy is not recommended in patients who are ineligible for
cisplatin-based combination chemotherapy, unless the goal is downstaging surgically
unresectable tumors.
Preoperative radiotherapy is not recommended to improve survival.
Not endorsed by ASCO based on the evidence that the EAU reviewed
For patients who are not receiving neoadjuvant chemotherapy, cystectomy for MIBC
should be performed within 3 months of diagnosis to lower the risk of progression and
cancer- specific mortality.
Before cystectomy, the patient should be fully informed about the benefits and potential
risks of all possible alternatives, and the final decision should be based on a balanced
discussion between patient and surgeon.
In addition to ileal conduit diversion, an orthotopic bladder substitute should be offered
to male and female patients lacking any contraindications and who have no tumor in the
urethra or at the level of urethral dissection.
Preoperative radiotherapy is not recommended for patients undergoing cystectomy with
urinary diversion.
Preoperative bowel preparation is not mandatory. “Fast track” measurements may
reduce the time of bowel recovery.
Radical cystectomy is recommended in T2-T4a, N0 M0, and high-risk non-MIBC (as
outlined above). Chemoradiation-based organ preservation treatment may be offered
to select patients with MIBC
Lymph node dissection should be an integral part of cystectomy.
The urethra can be preserved if margins are negative. If no bladder substitution is
attached, the urethra must be surveyed regularly in males.
Laparoscopic cystectomy and robot-assisted laparoscopic cystectomy are both
management options. However, current data have not sufficiently proven the advantages
or disadvantages for oncological and functional outcomes.
In patients with inoperable locally advanced tumors (T4b), primary radical cystectomy is a
palliative option.
In patients with symptoms palliative cystectomy may be offered.

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 Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement

Table 1. Original EAU and ASCO Endorsement Recommendations and Qualifying Statements (continued)
ASCO Endorsement of EAU Guidelines on Muscle-Invasive and
EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Metastatic Bladder Cancer Original Recommendations With Qualifying
Recommendations Statements (in bold italics)

Bladder-Sparing Treatments for Localized Disease

Transurethral resection of bladder tumor
Transurethral resection of bladder tumor (TURB) alone is not a curative Transurethral resection of bladder tumor (TURB) alone is not a curative treatment option in
treatment option in most patients. most patients.
External beam radiotherapy (EBRT)
Radiotherapy alone is not recommended as primary therapy for localized Radiotherapy alone is not recommended as primary therapy for localized bladder cancer.
bladder cancer.
Chemotherapy
Chemotherapy alone is not recommended as primary therapy for localized Chemotherapy alone is not recommended as primary therapy for localized bladder
bladder cancer. cancer.
Multimodality bladder-preserving treatment
Surgical intervention or multimodality treatments are the preferred curative Neoadjuvant chemotherapy followed by radical cystectomy or bladder-preserving
therapeutic approaches as they are more effective than radiotherapy alone. chemoradiotherapy treatments are the preferred curative therapeutic approaches as
they are more effective than radiotherapy alone.
Multimodality treatment could be offered as an alternative in selected, Bladder-preserving multimodality treatment could be offered as an alternative to
well-informed and compliant patients, especially for whom cystectomy is cystectomy in appropriately selected patients, and may be appropriate in some
not an option. patients for whom cystectomy is not an option.
Adjuvant Chemotherapy
Adjuvant cisplatin based combination chemotherapy may be offered Adjuvant cisplatin based combination chemotherapy may be offered to patients
to patients with pT3/4 and/or pN1 disease if no neoadjuvant chemotherapy with pT3/4 and/or or pN1) disease if no neoadjuvant chemotherapy has been
has been given. given.
While neoadjuvant chemotherapy is recommended, adjuvant chemotherapy may
be offered to high-risk patients who did not receive neoadjuvant treatment†
Metastatic Disease
First-line treatment for fit patients
Use cisplatin-containing combination chemotherapy with GC, PCG, MVAC, First-line treatment for fit patients: use cisplatin-containing combination chemotherapy
preferably with G-CSF, or HD-MVAC with G-CSF. with GC, MVAC, or HD-MVAC with G-CSF.
Carboplatin and nonplatinum combination chemotherapy is not recommended. Carboplatin and nonplatinum combination chemotherapy is not recommended.
First-line treatment in patients ineligible (unfit) for cisplatin
Use carboplatin combination chemotherapy or single agents. Use carboplatin combination chemotherapy or single agents.
For cisplatin-ineligible (unfit) patients, with PS2 or impaired renal function, For cisplatin-ineligible (unfit) patients, with PS2 or impaired renal function, as well as
as well as those with 0 or 1 poor Bajorin prognostic factors and impaired those with 0 or 1 poor Bajorin prognostic factors and impaired renal function,
renal function, treatment with carboplatin-containing combination chemotherapy, treatment with carboplatin-containing combination chemotherapy, preferably
preferably with gemcitabine/carboplatin is indicated. with gemcitabine/carboplatin is indicated.
Second-line treatment
In patients progressing after platinum-based combination chemotherapy for In patients progressing after platinum-based combination chemotherapy for
metastatic disease, vinflunine should be offered. Alternatively, treatment within metastatic disease, entry into a clinical trial is preferred. Alternatively, single-
a clinical trial setting may be offered. agent therapy may be offered (e.g. paclitaxel, docetaxel, or vinflunine where
available).
Zoledronic acid or denosumab is recommended for treatment of bone metastases. Zoledronic acid or denosumab may be offered for treatment of bone metastases†
Biomarkers
Currently, no biomarkers can be recommended in daily clinical practice because they Currently, no biomarkers can be recommended in daily clinical practice because
have no impact on predicting outcome, treatment decisions, or monitoring they have no impact on predicting outcome, treatment decisions, or monitoring
therapy in muscle-invasive bladder cancer. therapy in muscle-invasive bladder cancer.
Health-Related Quality of Life
The use of validated questionnaires is recommended to assess HRQoL in patients The use of validated questionnaires is recommended to assess HRQoL in patients
with MIBC. with MIBC.
Unless a patient’s comorbidities, tumor variables and coping abilities present clear Unless a patient’s comorbidities, tumor variables and coping abilities present clear
contraindications, a continent urinary diversion should be offered. contraindications, a continent urinary diversion should be offered to patients
undergoing cystectomy.
Preoperative patient information, patient selection, surgical techniques, and careful Preoperative patient information, patient selection, surgical techniques, and careful
postoperative follow-up are the cornerstones for achieving good long-term postoperative follow-up are the cornerstones for achieving good long-term
results. results.
Patients should be encouraged to take active part in the decision-making process. Patients should be encouraged to take active part in the decision-making process.
Clear and exhaustive information on all potential benefits and side-effects should Clear and exhaustive information on all potential benefits and side-effects should
be provided, allowing them to make informed decisions. be provided, allowing them to make informed decisions.
Follow-Up
Local recurrence, poor prognosis: treatment should be individualized depending
on the local extent of tumor
Radiotherapy, chemotherapy and possibly surgery are options for treatment, either Radiotherapy, chemotherapy and possibly surgery are options for treatment, either
alone or in combination. alone or in combination.
Distant recurrence, poor prognosis
Chemotherapy is the first option, and consider individualized cases for Chemotherapy is the first option, and consider individualized cases for
metastatectomy in case of unique metastasis site. metastatectomy when oligometastatic disease is present.
Secondary urethral tumor: staging and treatment should be done as for primary
urethral tumor
Local conservative treatment is possible for noninvasive tumor. Local conservative treatment is possible for noninvasive tumor.
Staging and treatment should be done as for primary urethral tumor. In isolated Staging and treatment should be done as for primary urethral tumor. In isolated
invasive disease, urethrectomy should be performed. invasive disease, urethrectomy should be performed.
Staging and treatment should be done as for primary urethral tumor. Urethral Staging and treatment should be done as for primary urethral tumour. Urethral
washes and cytology are not recommended. washes and cytology should be considered in high-risk patients.

*Available at: http://www.uroweb.org/guidelines/online-guidelines.

†The word “offered” should be interpreted as having a detailed discussion with the patient about the risks and benefits and limitations of the available data to facilitate
shared decision making.

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 Milowsky et al
domains: primary assessment of presumably invasive bladder
tumors, classification of MIBC, treatment failure in non-MIBC,
neoadjuvant chemotherapy, comorbidity scales, radical cystectomy
and urinary diversion, nonresectable tumors and palliative care,
preoperative radiotherapy, bladder-sparing treatments for local-
ized disease, adjuvant chemotherapy, metastatic disease, health-
related quality of life, and follow-up. The complete set of
recommendations is reprinted in Table 1. The target population for
the EAU guideline is patients with MIBC or metastatic bladder
cancer.
SUMMARY OF EAU GUIDELINE ON MIBC AND METASTATIC
BLADDER CANCER GUIDELINE DEVELOPMENT METHODOLOGY
The EAU guideline panel was composed of an international
multidisciplinary group of experts representing urology, pathology,
radiology, and oncology. The literature search strategy was not
described in any detail, although it was stated that evidence from
the previous 10 years was searched using multiple databases.
The EAU guideline panel reviewed evidence on the diagnosis,
pathology, and treatment of MIBC and metastatic bladder cancer.
The panel relied on both the available evidence as well as expert
consensus opinion to formulate the recommendations.
RESULTS OF ASCO METHODOLOGY REVIEW
The methodology review of the EAU guideline (which comprises
several modalities including a web-based guideline, a journal pub-
lication, and an abbreviated pocket version) was completed inde-
pendently by two ASCO guideline staff members using the Rigor of
Development subscale from the AGREE II instrument. Only the web-
based guideline was assessed using the AGREE II instrument. Detailed
results of the scoring for this guideline are available on request to
guidelines@asco.org. Overall, the EAU guideline on MIBC and
metastatic bladder cancer itself scored 4.5 of 7, along with a score of
65% on the Rigor of Development subscale, because the methodology
for arriving at the body of supporting evidence, the strengths and
limitations of that evidence, and the methods used to arrive at the
final recommendations were not described in detail in the actual
guideline (Methodology Supplement Fig 2). However, the preliminary
ASCO content reviewers of the EAU guideline MIBC and metastatic
bladder cancer, as well as the ASCO Endorsement Panel, found the
recommendations well supported in the original guideline. Each
section, including the introduction, summary, and recommendations
themselves, was clear and well referenced from the systematic review.
This is the most recent information as of the publication date.
For updates, the most recent information, and to submit new
evidence, please visit http://www.asco.org/endorsements/MIBC or
the ASCO Guidelines Wiki (http://www.asco.org/guidelineswiki).
METHODS AND RESULTS OF ASCO UPDATED
LITERATURE REVIEW
ASCO guidelines staff updated the EAU guideline on MIBC and
metastatic bladder cancer literature search. To identify additional
6 © 2016 by American Society of Clinical Oncology
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evidence, MEDLINE was searched on March 26, 2015 and was
updated in December 2015. The search was restricted to articles
published in English and to systematic reviews, meta-analyses, and
randomized controlled trials.
The updated search yielded 382 records. After a title and
abstract review, 20 articles were ordered for full-text review, and
five of these were retained for inclusion in this endorsement.
Additional articles were also retained for discussion.
RESULTS OF THE ASCO CONTENT REVIEW
The ASCO Endorsement Panel reviewed the EAU guideline on
MIBC and metastatic bladder cancer and concurs that the rec-
ommendations are clear, thorough, based on the most relevant
scientific evidence in this content area, and present options that
will be acceptable to patients. Overall, the ASCO Endorsement
Panel agrees with the recommendations as stated in the guideline,
with the minor qualifications presented under Discussion.
DISCUSSION
The ASCO Endorsement Panel has highlighted and qualified
certain statements from the EAU guideline on MIBC and meta-
static bladder cancer to better clarify the roles for systemic
chemotherapy– and chemoradiotherapy-based organ preservation
treatment in patients with MIBC. In particular, the panel: 1)
emphasizes that radiotherapy alone is inferior to chemo-
radiotherapy; 2) maintains that adjuvant cisplatin-based chemo-
therapy is an option in high-risk patients who have not received
neoadjuvant chemotherapy; and 3) encourages clinical trial par-
ticipation for those patients with metastatic disease who experience
progression after platinum-based combination chemotherapy.
Finally, given the lethality of MIBC and metastatic bladder cancer
and their severe impact on patient quality of life, the importance of
multidisciplinary care (eg, the importance of referral to a medical
oncologist for a discussion of neoadjuvant chemotherapy) in the
management of this disease cannot be overemphasized. Imple-
mentation of this guideline requires the integration of urology and
medical and radiation oncology expertise to provide the highest
level of care to patients.
In the United States, radical cystectomy with pelvic lymph
node dissection is the standard management for patients with
MIBC (cT2-T4a N0M0), and neoadjuvant cisplatin-based com-
bination chemotherapy is associated with a survival benefit.
Increasingly, bladder-sparing chemoradiotherapy after radical
transurethral resection is being used in this treatment context
and may be considered in appropriately selected patients with
MIBC. Unfortunately, incomplete clinical trials of adjuvant
cisplatin-based combination chemotherapy have limited the
standard use of adjuvant chemotherapy in patients with high-
risk disease after cystectomy. Although the recently reported
EORTC 30994 open-label randomized phase III trial of
immediate versus deferred chemotherapy after radical cys-
tectomy in patients with pT3-pT4 or N1 M0 urothelial car-
cinoma of the bladder is the largest adjuvant trial published to
date, its findings are limited by insufficient statistical power
JOURNAL OF CLINICAL ONCOLOGY
 Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement
resulting from under accrual. 3 There was no significant im-
provement in overall survival; however, immediate treatment
significantly prolonged progression-free survival (PFS) com-
pared with deferred treatment (hazard ratio, 0.54; 95% CI, 0.4 to
0.73; P ,.001), with 5-year PFS of 47.6% (95% CI, 38.8 to 55.9)
in the immediate group and 31.8% (95% CI, 24.2 to 39.6) in the
deferred treatment group. The median PFS was 3.11 years (95% CI,
1.84 to 7.77) in the immediate treatment group compared with 0.99
years (95% CI, 0.63 to 1.49) in the deferred treatment group (hazard
ratio, 0.54; 95% CI, 0.40 to 0.73; P , .001). Incorporating the
European Organisation for Research and Treatment of Cancer trial
into the adjuvant literature published to date, the panel felt that
adjuvant chemotherapy may be offered to high-risk patients who
have not received neoadjuvant chemotherapy; however, the panel
clarified that “offered” should be interpreted as having a detailed
discussion with the patient about the risks and benefits of adjuvant
chemotherapy to facilitate shared decision making. The discussion
should include a thorough review of the absolute risk of recurrence
in light of the pathologic findings, acknowledging the limitations of
the data in the adjuvant setting. Similar to the neoadjuvant che-
motherapy setting, there are insufficient data to consider the use of
non–cisplatin-containing chemotherapy in the adjuvant setting.
Several statements related to bladder-preservation therapy
were clarified by the panel to acknowledge the importance of
bladder-preserving treatment as a potential management strategy
for MIBC. Specifically, bladder-preserving trimodality treatment
could be offered as an alternative to cystectomy in appropriately
selected patients, as well as in some patients for whom cystectomy
is not an option. The clinical criteria generally used to appro-
priately select patients for a bladder-preserving approach include
small tumor size, early stage, absence of carcinoma in situ, absence
of multifocality, complete transurethral resection of the bladder
tumor (as is safely possible), absence of ureteral obstruction, and
no evidence of pelvic lymph node metastasis.4 In addition, the
panel clarified the superiority of chemoradiotherapy as compared
with radiotherapy alone in bladder-preservation treatment.
Metastatic bladder cancer is an incurable disease for almost all
patients, with many patients unfit for first-line cisplatin-containing
chemotherapy. A uniform definition of “unfit” for cisplatin-based
chemotherapy has been proposed, with unfit patients meeting at
least one of the following criteria: Eastern Cooperative Oncology
Group performance status of 2, creatinine clearance less than
60 mL/min, grade 2 or worse hearing loss, grade 2 or worse
neuropathy, and/or New York Heart Association class III heart
failure.5 Carboplatin-based combination chemotherapy in these
unfit patients is associated with inferior survival outcomes.6 There
is no US Food and Drug Administration–approved therapy for
patients who experience progression after platinum-based com-
bination chemotherapy for metastatic disease. Although single-
agent chemotherapy may be offered, the panel supports entry into
a clinical trial as the preferred strategy for these patients. Recent
advances in the understanding of the genetic underpinnings of
bladder cancer through The Cancer Genome Atlas and other
efforts has led to promising molecular targets and clinical trials of
novel targeted therapeutics.7 Several recent studies have also
demonstrated the promise of immunotherapy with checkpoint
inhibitors, including antibodies targeting both programmed cell
death 1 and programmed death-ligand 1.8
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The panel acknowledges the importance of supportive care in the
management of patients with advanced bladder cancer but had concerns
regarding a standard recommendation for zoledronic acid or denosumab
for treatment of bone metastases in metastatic bladder cancer. Although
there are studies supporting the use of both agents in patients with
advanced solid tumors with skeletal metastases,9,10 there are limited data
specific to bladder cancer. A prospective, randomized, placebo-
controlled trial of zoledronic acid in bony metastatic bladder cancer did
demonstrate a decrease in skeletal-related events and an improvement in
1-year survival; however, the study was limited by the small number of
patients (N 5 40) and median follow-up of 24 weeks.11 On the basis of
the limitations of the data, the panel revised the recommendation by
stating that zoledronic acid or denosumab “may be offered” for treat-
ment of bone metastases in metastatic bladder cancer and clarified that
“offered” should be interpreted as having a detailed discussion with the
patient about the risks and benefits and limitations of the available data
to facilitate shared decision making. The panel removed one statement
because of insufficient evidence to support a formal recommendation.
Specifically, the panel did not support the recommendation that pre-
operative radiotherapy for operable MIBC can result in tumor down-
staging after 4 to 6 weeks. Furthermore, the panel agreed that there is
insufficient evidence to support a role for the use of preoperative
radiotherapy in the management of MIBC.
Overall, the panel commends the EAU on the development of
its guideline on MIBC and metastatic bladder cancer and intends to
disseminate it broadly to specialists and generalists in the United
States who provide care for these patients.
ENDORSEMENT RECOMMENDATION
ASCO endorses all but one of the recommendations in the EAU
guideline on MIBC and metastatic bladder cancer, by Witjes et al in
2015, with minor qualifying statements (see Table 1).
ADDITIONAL RESOURCES
Additional information, including a Data Supplement with a re-
print of all EAU recommendations on MIBC and metastatic bladder
cancer (of the original guideline), a Methodology Supplement, slide
sets, and clinical tools and resources, is available at www.asco.org/
endorsements/MIBC and www.asco.org/guidelineswiki. Patient infor-
mation is available at www.cancer.net. Visit www.asco.org/guidelineswiki
to provide comments on the guideline or to submit new evidence.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Disclosures provided by the authors are available with this article at
www.jco.org.
AUTHOR CONTRIBUTIONS
Administrative support: R. Bryan Rumble
Manuscript writing: All authors
Final approval of manuscript: All authors
© 2016 by American Society of Clinical Oncology 7

REFERENCES
1. Witjes JA, Compérat E, Cowan NC, et al: EAU
guidelines on muscle-invasive and metastatic blad-
der cancer: Summary of the 2013 guidelines. Eur Urol
65:778-792, 2014
2. Siegel RL, Miller KD, Jemal A: Cancer
statistics, 2015. CA Cancer J Clin 65:5-29,
2015
3. Sternberg CN, Skoneczna I, Kerst JM, et al:
Immediate versus deferred chemotherapy after
radical cystectomy in patients with pT3-pT4 or N1
M0 urothelial carcinoma of the bladder (EORTC
30994): An intergroup, open-label, randomised phase
3 trial. Lancet Oncol 16:76-86, 2015
4. Rödel C, Weiss C: Organ-sparing multimodality
treatment for muscle-invasive bladder cancer: Can we
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Milowsky et al
continue to ignore the evidence? J Clin Oncol 32:
3787-3788, 2014
5. Galsky MD, Hahn NM, Rosenberg J, et al:
Treatment of patients with metastatic urothelial
cancer “unfit” for cisplatin-based chemotherapy.
J Clin Oncol 29:2432-2438, 2011
6. De Santis M, Bellmunt J, Mead G, et al:
Randomized phase II/III trial assessing gemcitabine/
carboplatin and methotrexate/carboplatin/vinblastine in
patients with advanced urothelial cancer who are unfit
for cisplatin-based chemotherapy: EORTC study
30986. J Clin Oncol 30:191-199, 2012
7. Cancer Genome Atlas Research Network:
Comprehensive molecular characterization of
urothelial bladder carcinoma. Nature 507:315-322,
2014
8. Powles T, Eder JP, Fine GD, et al: MPDL3280A
(anti-PD-L1) treatment leads to clinical activity in
n n n
metastatic bladder cancer. Nature 515:558-562,
2014
9. Henry DH, Costa L, Goldwasser F, et al:
Randomized, double-blind study of denosumab versus
zoledronic acid in the treatment of bone metastases in
patients with advanced cancer (excluding breast and
prostate cancer) or multiple myeloma. J Clin Oncol 29:
1125-1132, 2011
10. Rosen LS, Gordon D, Tchekmedyian S, et al:
Zoledronic acid versus placebo in the treatment of
skeletal metastases in patients with lung cancer and
other solid tumors: A phase III, double-blind, randomized
trial—The Zoledronic Acid Lung Cancer and Other Solid
Tumors Study Group. J Clin Oncol 21:3150-3157, 2003
11. Zaghloul MS, Boutrus R, El-Hossieny H, et al:
A prospective, randomized, placebo-controlled trial of
zoledronic acid in bony metastatic bladder cancer. Int
J Clin Oncol 15:382-389, 2010
JOURNAL OF CLINICAL ONCOLOGY
 Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Guideline on Muscle-Invasive and Metastatic Bladder Cancer (European Association of Urology guideline): American Society of Clinical Oncology
Clinical Practice Guideline Endorsement
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are
self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more
information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc.
Matthew I. Milowsky Ralph J. Hauke
Research Funding: BIND Therapeutics (Inst), Dendreon (Inst), Exelixis Honoraria: Best Doctors
(Inst), Johnson & Johnson (Inst), Astellas Pharma (Inst), Mirati Research Funding: US Oncology (Inst), Bavarian Nordic (Inst), Bristol-
Therapeutics (Inst), Pfizer (Inst), Cerulean Pharma (Inst), Merck (Inst), Myers Squibb (Inst), Merck (Inst), Amgen (Inst)
Acerta Pharma (Inst), Tokai Pharmaceuticals (Inst) Patents, Royalties, Other Intellectual Property: Patent pending for
potential immunotherapeutic
R. Bryan Rumble Other Relationship: American Board of Internal Medicine Subspecialty
Employment: Park Lane Terrace (I) Board
Christopher M. Booth Pat Boumansour
No relationship to disclose No relationship to disclose
Timothy Gilligan Cheryl T. Lee
Travel, Accommodations, Expenses: WellPoint Research Funding: Endo Pharmaceuticals
Libni J. Eapen
No relationship to disclose

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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
 Milowsky et al

Acknowledgment

The American Society of Clinical Oncology (ASCO) Endorsement Panel thanks Christina Lacchetti for assisting with the methodology
review, Supriya Mohile and Eric Mininberg, and the rest of the ASCO Clinical Practice Guideline Committee for their thoughtful reviews
and insightful comments on this guideline endorsement. The panel also thanks both the EAU and the original authors of the EAU guideline
for their contribution to this effort.

Appendix

Table A1. EAU Guideline on Muscle-Invasive and Metastatic Bladder Cancer: ASCO Clinical Practice Guideline Endorsement Panel
Member Affiliation/Institution
Matthew I. Milowsky, MD (co-chair) University of North Carolina Lineberger Comprehensive Cancer
Center, Chapel Hill, NC
Cheryl T. Lee, MD (co-chair) University of Michigan, Ann Arbor, MI
Christopher M. Booth, MD Queen’s University, Kingston, Ontario, Canada
Timothy Gilligan, MD, MSc Cleveland Clinic, Cleveland, OH
Libni J. Eapen, MD Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
Ralph J. Hauke, MD Nebraska Cancer Specialists, Omaha, NE
Pat Boumansour (patient representative) Palm Coast, FL

NOTE. ASCO staff: R. Bryan Rumble, MSc.

Abbreviations: ASCO, American Society of Clinical Oncology; EAU, European Association of Urology.

© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.