J Clin Oncol 34: by American Society of Clinical Oncology INTRODUCTION

VOLUME 34 NUMBER 16 JUNE 1, 2016 JOURNAL 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 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/16/3416w-1945w/$20.00 DOI: 10.1200/JCO.2015.65.9797 A B S T R A C T Purpose To endorse the European Association of Urology guideline on muscle-invasive (MIBC) and metastatic 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 Association 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 recommended. 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 34:1945-1952. 2016 by American Society of Clinical Oncology INTRODUCTION Worldwide, bladder cancer is the ninth most common cancer. 1 In the United States, there will be an estimated 74,000 new bladder cancer cases and 16,000 related deaths in 2015, 2 and approximately 30% of all newly diagnosed patients present with muscle-invasive bladder cancer (MIBC). 1 In addition to the 5% of patients who present with metastatic disease, roughly 50% of patients with MIBC will ultimately develop distant metastases, demonstrating the lethality of the disease. For these reasons, there is great interest in providing clinicians and patients with guidance on the management of MIBC and metastatic bladder cancer based on the best available evidence. The purpose of this American Society of Clinical Oncology (ASCO) guideline is to endorse theeuropeanassociationofurology(eau)guideline on MIBC and metastatic bladder cancer by Witjes JA et al, which was published in the journal 2016 by American Society of Clinical Oncology 1945

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 cisplatin, 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-cancermuscle-invasive-and-metastatic/. (continued on following page) 1946 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

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 2014 1 and then updated online by the EAU in March 2015 (http://uroweb.org/guideline/bladder-cancer-muscleinvasive-and-metastatic/ with supplementary materials available at: http://uroweb.org/guideline/bladder-cancer-muscle-invasive-andmetastatic/?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 muscleinvasive 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 treatment were examined. A reprint of the original EAU Recommendations (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 guidelines 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) instrument (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,newevidencemayemergebetweenthetimeinformation 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 interventions, 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 givencourseofaction.theuseofwordslike 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 www.jco.org 2016 by American Society of Clinical Oncology 1947

Milowsky et al Table 1. Original EAU and ASCO Endorsement Recommendations and Qualifying Statements EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Recommendations 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. 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. 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. Primary Assessment of Presumably Invasive Bladder Tumors ASCO Endorsement of EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Recommendations With Qualifying Statements (in bold italics) 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. Comorbidity Scales 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. 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, unless the goal is downstaging surgically unresectable tumors. Pre- and Postoperative Radiotherapy Preoperative radiotherapy is not recommended to improve survival. Preoperative radiotherapy is not recommended to improve survival. Preoperative radiotherapy for operable MIBC can result in tumor Not endorsed by ASCO based on the evidence that the EAU reviewed down-staging after 4-6 weeks. Radical Cystectomy and Urinary Diversion Do not delay cystectomy for. 3 months because it increases For patients who are not receiving neoadjuvant chemotherapy, cystectomy for MIBC the risk of progression and cancer-specific mortality. 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. 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). 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. 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 In patients with inoperable locally advanced tumors (T4b), primary radical cystectomy is a radical cystectomy is a palliative option. palliative option. In patients with symptoms palliative cystectomy may be offered. In patients with symptoms palliative cystectomy may be offered. (continued on following page) 1948 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement Table 1. Original EAU and ASCO Endorsement Recommendations and Qualifying Statements (continued) EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Recommendations Transurethral resection of bladder tumor Transurethral resection of bladder tumor (TURB) alone is not a curative treatment option in most patients. External beam radiotherapy (EBRT) Radiotherapy alone is not recommended as primary therapy for localized bladder cancer. Chemotherapy Chemotherapy alone is not recommended as primary therapy for localized bladder cancer. Multimodality bladder-preserving treatment Surgical intervention or multimodality 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, well-informed and compliant patients, especially for whom cystectomy is not an option. Bladder-Sparing Treatments for Localized Disease ASCO Endorsement of EAU Guidelines on Muscle-Invasive and Metastatic Bladder Cancer Original Recommendations With Qualifying Statements (in bold italics) Transurethral resection of bladder tumor (TURB) alone is not a curative treatment option in most patients. Radiotherapy alone is not recommended as primary therapy for localized bladder cancer. Chemotherapy alone is not recommended as primary therapy for localized bladder cancer. Neoadjuvant chemotherapy followed by radical cystectomy or bladder-preserving chemoradiotherapy treatments are the preferred curative therapeutic approaches as they are more effective than radiotherapy alone. Bladder-preserving multimodality treatment could be offered as an alternative to cystectomy in appropriately selected patients, and may be appropriate in some 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, as well as those with 0 or 1 poor Bajorin prognostic factors and impaired renal function, treatment with carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin is indicated. Second-line treatment In patients progressing after platinum-based combination chemotherapy for metastatic disease, vinflunine should be offered. Alternatively, treatment within a clinical trial setting may be offered. For cisplatin-ineligible (unfit) patients, with PS2 or impaired renal function, as well as those with 0 or 1 poor Bajorin prognostic factors and impaired renal function, treatment with carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin is indicated. In patients progressing after platinum-based combination chemotherapy for metastatic disease, entry into a clinical trial is preferred. Alternatively, singleagent 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 contraindications, a continent urinary diversion should be offered. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones for achieving good long-term results. Unless a patient s comorbidities, tumor variables and coping abilities present clear contraindications, a continent urinary diversion should be offered to patients undergoing cystectomy. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones for achieving good long-term 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 alone or in combination. Distant recurrence, poor prognosis Chemotherapy is the first option, and consider individualized cases for metastatectomy in case of unique metastasis site. Secondary urethral tumor: staging and treatment should be done as for primary urethral tumor Local conservative treatment is possible for noninvasive tumor. Staging and treatment should be done as for primary urethral tumor. In isolated invasive disease, urethrectomy should be performed. Staging and treatment should be done as for primary urethral tumor. Urethral washes and cytology are not recommended. Radiotherapy, chemotherapy and possibly surgery are options for treatment, either alone or in combination. Chemotherapy is the first option, and consider individualized cases for metastatectomy when oligometastatic disease is present. Local conservative treatment is possible for noninvasive tumor. Staging and treatment should be done as for primary urethral tumor. In isolated invasive disease, urethrectomy should be performed. Staging and treatment should be done as for primary urethral tumour. Urethral washes and cytology should be considered in high-risk patients. *Available at: http://www.uroweb.org/guidelines/online-guidelines. Theword 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. www.jco.org 2016 by American Society of Clinical Oncology 1949

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 localized disease, adjuvant chemotherapy, metastatic disease, healthrelated 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 publication, and an abbreviated pocket version) was completed independently by two ASCO guideline staff members using the Rigor of Development subscale from the AGREE II instrument. Only the webbased guideline was assessed using the AGREE IIinstrument.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 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 recommendations 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 metastatic 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 chemoradiotherapy; 2) maintains that adjuvant cisplatin-based chemotherapy is an option in high-risk patients who have not received neoadjuvant chemotherapy; and 3) encourages clinical trial participation 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. Implementation 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 combination 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 highrisk disease after cystectomy. Although the recently reported EORTC 30994 open-label randomized phase III trial of immediate versus deferred chemotherapy after radical cystectomy in patients with pt3-pt4 or N1 M0 urothelial carcinoma of the bladder is the largest adjuvant trial published to date, its findings are limited by insufficient statistical power 1950 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Muscle-Invasive and Metastatic Bladder Cancer Guideline Endorsement resulting from under accrual. 3 There was no significant improvement in overall survival; however, immediate treatment significantly prolonged progression-free survival (PFS) compared 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 chemotherapy 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 appropriately 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 combination chemotherapy for metastatic disease. Although singleagent 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 Thepanelacknowledgestheimportanceofsupportivecareinthe 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, placebocontrolled 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 treatment 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 preoperative radiotherapy for operable MIBC can result in tumor downstaging 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 reprint 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 information 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 www.jco.org 2016 by American Society of Clinical Oncology 1951

Milowsky et al REFERENCES 1. Witjes JA, Compérat E, Cowan NC, et al: EAU guidelines on muscle-invasive and metastatic bladder 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 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 nnn 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 1952 2016 by American Society of Clinical Oncology 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 Research Funding: BIND Therapeutics (Inst), Dendreon (Inst), Exelixis (Inst), Johnson & Johnson (Inst), Astellas Pharma (Inst), Mirati Therapeutics (Inst), Pfizer (Inst), Cerulean Pharma (Inst), Merck (Inst), Acerta Pharma (Inst), Tokai Pharmaceuticals (Inst) R. Bryan Rumble Employment: Park Lane Terrace (I) Christopher M. Booth No relationship to disclose Timothy Gilligan Travel, Accommodations, Expenses: WellPoint Libni J. Eapen No relationship to disclose Ralph J. Hauke Honoraria: Best Doctors Research Funding: US Oncology (Inst), Bavarian Nordic (Inst), Bristol- Myers Squibb (Inst), Merck (Inst), Amgen (Inst) Patents, Royalties, Other Intellectual Property: Patent pending for potential immunotherapeutic Other Relationship: American Board of Internal Medicine Subspecialty Board Pat Boumansour No relationship to disclose Cheryl T. Lee Research Funding: Endo Pharmaceuticals www.jco.org 2016 by American Society of Clinical Oncology

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 Matthew I. Milowsky, MD (co-chair) Cheryl T. Lee, MD (co-chair) Christopher M. Booth, MD Timothy Gilligan, MD, MSc Libni J. Eapen, MD Ralph J. Hauke, MD Pat Boumansour (patient representative) Affiliation/Institution University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC University of Michigan, Ann Arbor, MI Queen s University, Kingston, Ontario, Canada Cleveland Clinic, Cleveland, OH Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada Nebraska Cancer Specialists, Omaha, NE 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