Kamat Ashish M, Sylvester Richard J, Böhle Andreas, Palou Joan, Lamm Donald L, Brausi Maurizio, Soloway Mark, Persad Raj, Buckley Roger, Colombel Marc, Witjes J Alfred
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.
J Clin Oncol. 2016 Jun 1;34(16):1935-44. doi: 10.1200/JCO.2015.64.4070. Epub 2016 Jan 25.
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.
基于当前文献及国际膀胱癌小组的专家共识，为非肌层浸润性膀胱癌（NMIBC）的适当临床试验设计提供建议。
我们回顾了已发表的试验、指南、荟萃分析和综述，并就纳入标准、基线评估、终点、研究设计、对照、具有临床意义的效应量和样本量提供了建议。
NMIBC试验的设计必须为特定风险类别（低、中或高）提供最具临床相关性的数据。具体的纳入标准和基线评估取决于所研究的风险类别。对于卡介苗（BCG）治疗失败的患者群体，应明确失败类型（BCG无反应、难治、复发或不耐受），以使不同试验间的比较可行。单臂设计可能适用于BCG无反应的人群。在此，建议6个月时具有临床意义的初始完全缓解率（原位癌）或无复发生存率（乳头状肿瘤）至少为50%，12个月时为30%，18个月时为25%。对于其他风险水平，建议采用随机优效性试验设计；鉴于所需样本量较大，非劣效性试验应谨慎使用。对于所有中高危分层，安慰剂对照被认为是不道德的；因此，对照组应包括当前指南推荐的针对相应风险水平的标准治疗。一般而言，试验应以复发时间或无复发生存作为主要终点，以进展时间、毒性、疾病特异性生存和总生存作为潜在的次要终点。应设定切实可行的疗效阈值，以确保新疗法能得到监管机构的适当审查。
国际膀胱癌小组已就NMIBC的定义、终点和临床试验设计制定了正式建议，以促进该疾病研究的一致性。
