RECSIT11中英文对照全文.doc

New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) 新版实体瘤疗效评价标准：修订的RECIST指南（1.1版本）Abstract摘要Background背景介绍Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (6500 patients), simulation studies and literature reviews.临床上评价肿瘤治疗效果最重要的一点就是对肿瘤负荷变化的评估：瘤体皱缩（目标疗效）和病情恶化在临床试验中都是有意义的判断终点。自从2000年RECIST出版以来，许多研究人员、企业团体、行业和政府当局都采纳了这一标准来评价治疗效果。但是，随之涌现出的一些问题导致了本修订版的出版（1.1版）。修正之处（请见各章的专题）源自于对大型数据库（超过6500例患者）、模拟研究以及文献综述的评估。Highlights of revised RECIST 1.11.1版RECIST的重要修订之处Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to 10 mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5 mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes unequivocal progression of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions.主要的修订之处有：病灶数目的判定：为了方便分析，很多小型试验数据库的证据被合并成一个大型数据库。根据该数据库，为判断疗效对肿瘤负荷进行评估所需病灶的总数由原来的最多10个减至现在的5个（每个器官由最多5个减至2个）。病理性淋巴结的判定现在也合并为：短轴值15mm的淋巴结现在也被认为是可检测和评估的目标病灶。计算肿瘤疗效时，（结节性病灶的）短轴值必须包括在病灶（半径的）总和中。结节皱缩至短轴值10mm时可以认为是正常的。疗效的确认因为控制限已用作解释数据的合适均值，试验所必需的疗效最初的终点值在现在的随机化研究中已不再必需。病情恶化根据以下几个方面分类：除了原先的定义目标病灶（半径）的总和增加20%外，若总数很小，为预防过高估计恶化程度，（病灶短轴的）绝对值增加5mm也必须具备。另外，还提供了关于构成不可测量或非目标病灶“明确恶化”的指南即初版RECIST指南中容易混淆的地方。最后还有一节专门介绍新损害的检测，包括解释FDG-PET的扫描结果。影像学指南：修订后的RECIST包含了新的影像学附录，内有更新了的病灶最佳解剖学评估的推荐。Future work 下一步工作A key question considered by the RECIST Working Group in developing RECIST 1.1 was whether it was appropriate to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment with PET or MRI. It was concluded that, at present, there is not sufficient standardisation or evidence to abandon anatomical assessment of tumour burden. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression. As is detailed in the final paper in this special issue, the use of these promising newer approaches requires appropriate clinical validation studies.工作组在修订RECIST 1.1时考虑到的一个关键问题是：评估肿瘤负荷从一维的解剖学评估修改为三维的解剖学评估或用PET和MRI作出的功能评估是否恰当。目前的结论是缺乏足够的标准或证据放弃对肿瘤负荷的解剖学评估。对此唯一的解释是使用FDG-PET成像作为病情恶化判断的辅助手段。正如最后一章的专题中详细讨论的那样，使用这些最新的、前景诱人的技术需要有相应的临床验证研究。 Keywords: Response criteria; Solid tumours; Guidelines关键词：疗效评估标准；实体瘤；指南编译：摘要背景介绍临床上评价肿瘤治疗效果最重要的一点就是对肿瘤负荷变化的评估：瘤体皱缩（目标疗效）和病情恶化在临床试验中都是有意义的判断终点。自从2000年RECIST出版以来，许多研究人员、企业团体、行业和政府当局都采纳了这一标准来评价治疗效果。但是，随之涌现出的一些问题导致了本修订版的出版（1.1版）。修正之处（请见各章的专题）源自于对大型数据库（超过6500例患者）、模拟研究以及文献综述的评估。1.1版RECIST的重要修订之处主要的修订之处有：病灶数目的判定：为了方便分析，很多小型试验数据库的证据被合并成一个大型数据库。根据该数据库，为判断疗效对肿瘤负荷进行评估所需病灶的总数由原来的最多10个减至现在的5个（每个器官由最多5个减至2个）。病理性淋巴结的判定现在也合并为：短轴值15mm的淋巴结现在也被认为是可检测和评估的目标病灶。计算肿瘤疗效时，（结节性病灶的）短轴值必须包括在病灶（半径的）总和中。结节皱缩至短轴值6500 patients with 18,000 target lesions and was utilised to investigate the impact of a variety of questions (e.g. number of target lesions required, the need for response confirmation, and lymph node measurement rules) on response and progression-free survival outcomes. The results of this work, which after evaluation by the RECIST Working Group led to most of the changes in this revised guideline, are reported in detail in a separate paper in this special issue.10 Larry Schwartz and Robert Ford (also co-authors of this guideline) also provided key databases from which inferences have been made that inform these revisions.111.3 RECIST1.1版形成过程RECIST工作组，是由来自于学术研究机构、政府和制药企业的早期药物开发的有经验的临床医生、影像学专家和统计学家组成，他们为RECIST更新定期举行会议，确定对种种变化是否需要做出调整和复习新出现的证据。修订过程中一个最重要的方面是建立一个回顾性的数据库，该数据库的资料来自于工业和学术协作组试验中获得的实体肿瘤相关数据。这个数据库在Jan Bogaerts 和 Patrick Therasse领导下，在EORTC资料中心完成的。该数据库有6500病人，病变器官18000个，被用来调查各种问题（如需要病变的数量、治疗反应确认的需要性，淋巴结测量规则）对治疗反应和无疾病进展生存期的影响。这项工作的结果是由RECIST工作组做出评价后在修改的指南中发生了较大变动，并且在这个专期中做出了具体报道。Larry Schwartz and Robert Ford（该指南的共同作者）也提供了来自于推理的关键的数据库，这些数据库形成了这项修改。The publication of this revised guideline is believed to be timely since it incorporates changes to simplify, optimise and standardise the assessment of tumour burden in clinical trials. A summary of key changes is found in Appendix I. Because the fundamental approach to assessment remains grounded in the anatomical, rather than functional, assessment of disease, we have elected to name this version RECIST 1.1, rather than 2.0.这个修改指南的出版被认为是及时的，因为它将各种变化进行了简化、完美化，使临床试验的肿瘤负荷的评价标准化。关键的变动鉴于附录。由于基本的评价方法仍然是解剖，而不是功能上的，因此我们将这个版本命名为RECIST1.1而不是2.0.1.4. What about volumetric or functional assessment?This raises the question, frequently posed, about whether it is time to move from anatomic unidimensional assessment of tumour burden to either volumetric anatomical assessment or to functional assessment (e.g. dynamic contrast enhanced MRI or CT or (18)F-fluorodeoxyglucose positron emission tomographic (FDG-PET) techniques assessing tumour metabolism). As can be seen, the Working Group and particularly those involved in imaging research, did not believe that there is at present sufficient standardisation and widespread availability to recommend adoption of these alternative assessment methods. The only exception to this is in the use of FDG-PET imaging as an adjunct to determination of progression, as described later in this guideline. As detailed paper in this special issue12, we believe that the use of these promising newer approaches (which could either add to or substitute for anatomical assessment as described in RECIST) requires appropriate and rigorous clinical validation studies. This paper by Sargent et al. illustrates the type of data that will be needed to be able to define endpoints for these modalities and how to determine where and when such criteria/modalities can be used to improve the reliability with which truly active new agents are identified and truly inactive new agents are discarded in comparison to RECIST criteria in phase II screening trials. The RECIST Working Group looks forward to such data emerging in the next few years to allow the appropriate changes to the next iteration of the RECIST criteria.1.4 体积或功能评价怎么样？这就提出了一个问题即是否可以将肿瘤负荷的解剖的一维评价转变为体积评价或功能评价（如动态对比增强MRI或CT或FDG-PET评价肿瘤代谢）。正如大家看到的，工作组特别是那些从事影像学研究者，相信目前还没有完全的标准化和这些推荐的替代评价方法还不能广泛应用。正如指南后面描述的，唯一的例外是FDG-PET作为确定疾病进展的辅助工具。根据此专期的介绍，我们相信这些有希望的新的方法（如RECIST描述中的增加或替代解剖评价）需要适当的和严格的临床评价。Sargent等的文章表明那些将需要确定这些形式的“端点”的资料类型，如何确定这些标准/形式的地点和时间以提高其可靠性，以至于在期筛查试验中通过与RECIST标准比较，确定那些为有活性的新的药物，而哪些不是。RECIST工作组期望明年出现这样的资料，允许在下一版的RECIST标准中做出适当的变动。1 背景1.1 RECIST标准的历史评价肿瘤负荷的改变是癌症治疗的临床评价的一个重要特征。肿瘤缩小（客观反应）和疾病进展的时间都是癌症临床试验中的重要端点。为了筛查新的抗肿瘤药物，肿瘤缩小作为II期试验端点被多年研究的证据所支持。这些研究提示对于多种实体肿瘤来说，促使部分病人肿瘤缩小的药物以后都有可能（尽管不完美）被证实可提高病人的总体生存期或在随机期试验中有进入事件评价的其他机会。目前在期筛查试验中评价治疗效果的指标中，客观反应比任何其他生物标记更可靠。而且，在和期药物试验中，进展期疾病中的临床试验正越来越利用疾病进展的时间（无进展生存）作为得出有治疗效果结论的端点，而这些也是建立在肿瘤大小的基础上。然而这些肿瘤端点、客观反应和疾病进展时间，只有建立在以肿瘤负荷解剖学基础上的广泛接受和容易使用的标准准则上才有价值。1981年世界卫生组织（WHO）首次出版了肿瘤反应标准，主要用于肿瘤反应是主要终点的试验中。WHO标准通过测量病变二维大小并进行合计介绍了肿瘤负荷总体评价的概念，通过评价治疗期间基线的改变而判断治疗的反应。然而，在该标准出版后的十几年中，使用该标准的协作组和制药公司通常对其进行修改以适应新的技术或在原始文献中提出了不清楚的地方，这就导致了试验结果解释的混乱。事实上，各种反应标准的应用导致同一种治疗方法的治疗效果大相径庭。对这些问题的反应是国际工作组于19世纪中期形成，并对反应标准进行了标准化和简化。新的标准，也称为RECIST（实体肿瘤的反应评价标准）于2000年出版。最初的TECIST关键特征包括病变最小大小的确定、对随访病变数目的建议（最多10个；每个器官最大5个）、一维而不是二维的使用、肿瘤负荷的总体评价。这些标准后来被学术团体、协作组和制药工业广泛采用，而该标准的最初端点就是客观反应或疾病进展。另外，当局接受RECIST作为这些评价的合适的标准。1.2 为什么要更新RECIST？自从2000年出版RECIST后，许多研究者在前瞻性研究中证实将以二维测量为基础的标准（甚至是三维测量）替换为一维测量的有效性。但也有例外（如间皮瘤），一维测量标准似乎在实体肿瘤期试验中更好。然而大量问题开始出现需要回答和阐明。如在不影响病人总体预定反应（或试验结束）情况下是否要超过10人才能评估？在随机期试验中，特别当病人没有可测量的病变，而疾病进展，无反应作为主要的端点时，如何应用RECIST？是否或怎样利用新的影像学技术如FDG-PET和MRI？如何评价淋巴结？是否需要确认治疗反应？RECIST在靶向非细胞毒性药物试验中的最大适用范围。RECIST标准的修改包括所有这些问题的更新。1.3 RECIST1.1版形成过程RECIST工作组，是由来自于学术研究机构、政府和制药企业的早期药物开发的有经验的临床医生、影像学专家和统计学家组成，他们为RECIST更新定期举行会议，确定对种种变化是否需要做出调整和复习新出现的证据。修订过程中一个最重要的方面是建立一个回顾性的数据库，该数据库的资料来自于工业和学术协作组试验中获得的实体肿瘤相关数据。这个数据库在Jan Bogaerts 和 Patrick Therasse领导下，在EORTC资料中心完成的。该数据库有6500病人，病变器官18000个，被用来调查各种问题（如需要病变的数量、治疗反应确认的需要性，淋巴结测量规则）对治疗反应和无疾病进展生存期的影响。这项工作的结果是由RECIST工作组做出评价后在修改的指南中发生了较大变动，并且在这个专期中做出了具体报道。Larry Schwartz and Robert Ford（该指南的共同作者）也提供了来自于推理的关键的数据库，这些数据库形成了这项修改。这个修改指南的出版被认为是及时的，因为它将各种变化进行了简化、完美化，使临床试验的肿瘤负荷的评价标准化。关键的变动鉴于附录。由于基本的评价方法仍然是解剖，而不是功能上的，因此我们将这个版本命名为RECIST1.1而不是2.0.1.4 体积或功能评价怎么样？这就提出了一个问题即是否可以将肿瘤负荷的解剖的一维评价转变为体积评价或功能评价（如动态对比增强MRI或CT或FDG-PET评价肿瘤代谢）。正如大家看到的，工作组特别是那些从事影像学研究者，相信目前还没有完全的标准化和这些推荐的替代评价方法还不能广泛应用。正如指南后面描述的，唯一的例外是FDG-PET作为确定疾病进展的辅助工具。根据此专期的介绍，我们相信这些有希望的新的方法（如RECIST描述中的增加或替代解剖评价）需要适当的和严格的临床评价。Sargent等的文章表明那些将需要确定这些形式的“端点”的资料类型，如何确定这些标准/形式的地点和时间以提高其可靠性，以至于在期筛查试验中通过与RECIST标准比较，确定那些为有活性的新的药物，而哪些不是。RECIST工作组期望明年出现这样的资料，允许在下一版的RECIST标准中做出适当的变动。2. Purpose of this guideline2. 该指南的目的This guideline describes a standard approach to solid tumour measurement and definitions for objective assessment of change in tumour size for use in adult and paediatric cancer clinical trials. It is expected these criteria will be useful in all trials where objective response is the primary study endpoint, as well as in trials where assessment of stable disease, tumour progression or time to progression analyses are undertaken, since all of these outcome measures are based on an assessment of anatomical tumour burden and its change on study. There are no assumptions in this paper about the proportion of patients meeting the criteria for any of these endpoints which will signal that an agent or treatment regimen is active: those definitions are dependent on type of cancer in which a trial is being undertaken and the specific agent under study. Protocols must include appropriate statistical sections which define the efficacy parameters upon which the trial sample size and decision criteria are based. In addition to providing definitions and criteria for assessment of tumour response, this guideline also makes recommendations regarding standard reporting of the results of trials that utilise tumour response as an endpoint.该指南描述了一个实体瘤测量和成人、小儿癌症的临床试验中肿瘤大小变化客观评估的规定的标准做法。预计这些标准将有效用于所有以客观响应为主要的研究终点的试验，以及承担稳定疾病评估、肿瘤进展或进展时间分析的试验，因为所有治疗效果的衡量都是基于研究中解剖学肿瘤负荷及其变化的评估。本文中对于达到相应标准-表明试剂或治疗方案有积极作用的终点-的患者的比例没有任何假设：这些定义依赖于试验中癌症的类型以及正在研究中的特殊试剂。协议必须包括适当的统计学章节，介绍如何以实验样本大小和决策标准为基础来界定疗效参数。除了为肿瘤反应评估提供定义和标准外，这一指南也为以肿瘤反应为终点的试验推荐了标准的研究结果报告。While these guidelines may be applied in malignant brain tumour stu