title: Definitions, End Points, and Clinical Trial Designs for Non-Muscle-Invasive Bladder Cancer: Recommendations From the International Bladder Cancer Group.
abstract: To provide recommendations on appropriate clinical trial designs in non-muscle-invasive bladder cancer (NMIBC) based on current literature and expert consensus of the International Bladder Cancer Group.
  
  
  
  We reviewed published trials, guidelines, meta-analyses, and reviews and provided recommendations on eligibility criteria, baseline evaluations, end points, study designs, comparators, clinically meaningful magnitude of effect, and sample size.
  
  
  
  NMIBC trials must be designed to provide the most clinically relevant data for the specific risk category of interest (low, intermediate, or high). Specific eligibility criteria and baseline evaluations depend on the risk category being studied. For the population of patients for whom bacillus Calmette-Guérin (BCG) has failed, the type of failure (BCG unresponsive, refractory, relapsing, or intolerant) should be clearly defined to make comparisons across trials feasible. Single-arm designs may be relevant for the BCG-unresponsive population. Here, a clinically meaningful initial complete response rate (for carcinoma in situ) or recurrence-free rate (for papillary tumors) of at least 50% at 6 months, 30% at 12 months, and 25% at 18 months is recommended. For other risk levels, randomized superiority trial designs are recommended; noninferiority trials are to be used sparingly given the large sample size required. Placebo control is considered unethical for all intermediate- and high-risk strata; therefore, control arms should comprise the current guideline-recommended standard of care for the respective risk level. In general, trials should use time to recurrence or recurrence-free survival as the primary end point and time to progression, toxicity, disease-specific survival, and overall survival as potential secondary end points. Realistic efficacy thresholds should be set to ensure that novel therapies receive due review by regulatory bodies.
  
  
  
  The International Bladder Cancer Group has developed formal recommendations regarding definitions, end points, and clinical trial designs for NMIBC to encourage uniformity among studies in this disease.
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands. akamat@mdanderson.org.
authors.forename: Ashish M
authors.initials: AM
authors.lastname: Kamat
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sylvester
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Böhle
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Joan
authors.initials: J
authors.lastname: Palou
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Donald L
authors.initials: DL
authors.lastname: Lamm
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Brausi
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Soloway
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Raj
authors.initials: R
authors.lastname: Persad
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Roger
authors.initials: R
authors.lastname: Buckley
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: Marc
authors.initials: M
authors.lastname: Colombel
authors.affiliation: Ashish M. Kamat, University of Texas MD Anderson Cancer Center, Houston, TX; Richard J. Sylvester, European Organisation for Research and Treatment of Cancer, Brussels, Belgium; Andreas Böhle, HELIOS Agnes Karll Hospital, Bad Schwartau, Germany; Joan Palou, Fundació Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Donald L. Lamm, University of Arizona and BCG Oncology, Phoenix, AZ; Maurizio Brausi, Azienda Unità Sanitaria Locale di Modena, Modena, Italy; Mark Soloway, University of Miami School of Medicine, Miami, FL; Raj Persad, Bristol Royal Infirmary and Bristol Urological Institute, Bristol, United Kingdom; Roger Buckley, North York General Hospital, Toronto, Ontario, Canada; Marc Colombel, Claude Bernard University, Hôpital Edouard Herriot, Lyon, France; and J. Alfred Witjes, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
authors.forename: J Alfred
authors.initials: JA
authors.lastname: Witjes
mesh_terms: D001500:BCG Vaccine / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D023381:Endpoint Determination; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000628:therapy; D012107:Research Design; D018401:Sample Size; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
chemical_list: D001500:BCG Vaccine
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