QUANTEC目录

ACCURATE ACCUMULATION OF DOSE FOR IMPROVED UNDERSTANDING OF RADIATION EFFECTS IN NORMAL TISSUE（最没把握的翻译）

精确累积剂量以提高对正常组织放疗反应的理解

The actual distribution of radiation dose accumulated in normal tissues over the complete course of radiation therapy is, in general, poorly quantified. Differences in the patient anatomy between planning and treatment can occur gradually (e.g., tumor regression, resolution of edema) or relatively rapidly (e.g., bladder filling, breathing motion) and these undermine the accuracy of the planned dose distribution. Current efforts to maximize the therapeutic ratio require models that relate the true accumulated dose to clinical outcome. The needed accuracy can only be achieved through the development of robust methods that track the accumulation of dose within the various tissues in the body. Specific needs include the development of segmentation methods, tissue-mapping algorithms, uncertainty estimation, optimal schedules for image-based monitoring, and the development of

informatics tools to support subsequent analysis. These developments will not only improve radiation outcomes modeling but will address the technical demands of the adaptive radiotherapy paradigm. The next 5 years need to see academia and industry bring these tools into the hands of the clinician and the clinical scientist. 在整个放疗过程中正常组织的累积剂量通常是难以精确定量的。在计划和治疗之间病人的解剖会逐渐产生不同（如肿瘤退缩，水肿消散）或相对进展（如膀胱充盈，呼吸运动），这些对计划剂量的精确分布产生破坏。当前使治疗率最大化的作用，要求真正精确剂量与临床结果相关的模型。对精确的需求只能从健全的方法中沿着体内不同组织累计剂量而获得。特殊需求包括以下的发展，节段方法，组织海藻地图，不确定的评价，以影像为基础的管理优化流程，以及支持顺序分析的信息工具发展。这些发展不仅会促进放射结果模型的发展，也会成为技术要求适应放疗的典范。将来的5来需要看到学术界和工业界把这些工具带给临床学家和临床科学家的手里。

BIOMARKERS AND SURROGATE ENDPOINTS FOR NORMAL-TISSUE EFFECTS OF RADIATION THERAPY THE IMPORTANCE OF DOSE–VOLUME EFFECTS

放疗正常组织反应的生物标志和替代终点—剂量体积效应的提高 Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed.

生物标志是预测和监测正常组织放射毒性的有趣因素。分子生物学的进展提供了标志物引入寻找在临床上应用的有充分敏感性和特异性正常组织生物标志。本文综述了生物标志作为放疗副反应的预测标志、疗效标志或surrogate终点标志的研究例子。在候选基因和全基因组背景下简要地讨论与单核苷酸多态性相关的研究。调整正常组织中的剂量分布的重要性，生物标志研究见下文。最后，确定和讨论这个领域的研究重点。

GUEST EDITOR’S INTRODUCTION TO QUANTEC A USERS GUIDE

客座编辑介绍QUANTEC—使用者指南

IMAGING FOR ASSESSMENT OF RADIATION-INDUCED NORMAL TISSUE EFFECTS

评价放射所致正常组织效应的影像

Imaging can provide quantitative assessment of radiation-induced

normal tissue effects. Identifying an early sign of normal tissue damage with imaging would have the potential to predict organ dysfunction, thereby allowing reoptimization of treatment strategies based on

individual patients’ risks and benefits. Early detection with noninvasive imaging may enable interventions to mitigate therapy-associated injury before its clinical manifestation. Furthermore, successive imaging may provide an objective assessment of the impact of such mitigation therapies. However, many problems make application of imaging to normal tissue assessment challenging, and further work is required to

establish imaging biomarkers as surrogate endpoints of clinical outcome. The performance of clinical trials in which normal tissue injury is a clearly defined endpoint would greatly aid in realization of these goals.

影像学可以对放射引起的正常组织效应进行定量评价。确定一个早期的正常组织损伤影像具有预测组织功能损伤的的潜力，从而允许基于个体化病人的风险和受益的治疗分类再优化。早期非侵入性的影像检测，使减轻治疗相关损伤在临床症状出现之前通过干预得到减轻成为可能。进而成功的影像可能对这个减症治疗的影响提供一个客观的评价。但是很多问题使对正常组织影像学评价的应用成为一个挑战。进一步的的工作要求确立影像生物标志作为临床结果的替代终点。明确界定终点的临床试验将大大地有助于对这些目的的认识。

IMPROVING NORMALTISSUE COMPLICATION PROBABILITYMODELS THE NEEDTO ADOPT A ‘‘DATA-POOLING’’ CULTURE

改进正常组织并发症概率模型---适应数据汇总教育

Clinical studies of the dependence of normal tissue response on dose-volume factors are often confusingly inconsistent, as the QUANTEC reviews demonstrate. A key opportunity to accelerate progress is to begin storing high-quality datasets in repositories. Using available technology, multiple repositories could be conveniently queried, without divulging protected health information, to identify relevant sources of data for further analysis. After obtaining

institutional approvals, data could then be pooled, greatly enhancing the capability to construct predictive models that are more widely applicable and better powered to accurately identify key predictive factors (whether dosimetric, image-based, clinical, socioeconomic, or biological). Data pooling has already been carried out effectively in a few normal tissue complication probability studies and should become a common strategy.

如QUANTEC所确定的那样，正常组织反应与剂量体积因素的依赖关系临床研究通常的模糊的和不恒定。加速研究进展的关键机会是开始建立高质量的数据库。应用可获取的技术，容易获得的多个数据库，无洩密保护的健康信息，以识别相关的数据来源作为进一步

的分析。通过获得研究机构的批准，采集的数据可以大大地增强构建对关键因素(如剂量测定，影像基础，临床，社会经济学或生物学)准确界定的能广泛应用和更有效力的数学模型。数个正常组织并发症概率研究的数据汇总已经在进行，并将成为通用策略。

QUANTITATIVE ANALYSES OF NORMAL TISSUE EFFECTS IN THE CLINIC(QUANTEC) AN INTRODUCTION TO THE SCIENTIFIC ISSUES

临床中对正常组织效应定量分析(QUANTEC)介绍科学文件 Advances in dose–volume/outcome (or normal tissue complication probability, NTCP) modeling since the seminal Emami paper from 1991 are reviewed. NTCPThere has been some progress with an increasing number of studies on large patient samples with

three-dimensional dosimetry. Nevertheless, NTCP models are not ideal. Issues related to the grading of side effects, selection of appropriate statistical methods, testing of internal and external model validity, and quantification of predictive power and statistical uncertainty, all limit the usefulness of much of the published literature. Synthesis (meta-analysis) of data from multiple studies is often impossible because of suboptimal primary analysis, insufficient reporting and

variations in the models and predictors analyzed. Clinical limitations to the current knowledge base include the need for more data on the effect of patient-related cofactors, interactions between dose distribution and cytotoxic or molecular targeted agents, and the effect of dose fractions and overall treatment time in relation to nonuniform dose distributions. Research priorities for the next 5–10 years are proposed.

自从1991年the seminal Emami paper 的综述开始了剂量-体积/结果(或正常组织并发症概率，NTCP)模型的发展。随着不断增长的大宗病例研究数的出现，三维剂量学有了一些进展。然而，NTCP模型还不是最理想的。大部份现有文献有实用性都受到以下因素的限制，副反应分级、选择合适的统计学方法，检验内照射及外照射模型的有效性、定量分析预测效力及统计学不确定性。来自多个研究数据的Meta分析通常是不可能的，其原因在于不合适的初始分析、以及报告、模型中的变量和预测因子分析的不准确性。当前的基础知识的临床限制包括对病人相关的协变量的效应需要更多的数据、

剂量分布与细胞毒或分子靶向药物的相互作用、剂量分割的作用、总治疗时间和不均匀剂量分布。并提出未来5-10年的研究目标。

QUANTITATIVE ANALYSES OF NORMAL TISSUE EFFECTS IN THE CLINIC

临床中对正常组织效应定量分析(QUANTEC)介绍科学文件的介绍 RADIATION ASSOCIATED BRAINSTEM INJURY 放射相关脑损伤

RADIATION DOSE VOLUME EFFECTS IN THE SPINAL CORD 脊髓的放射剂量体积效应

Dose–volume data for myelopathy in humans treated with radiotherapy (RT) to the spine is reviewed, along with pertinent preclinical data. Using conventional fractionation of 1.8–2 Gy/fraction to the

full-thickness cord, the estimated risk of myelopathy is <1% and <10% at 54 Gy and 61 Gy, respectively, with a calculated strong dependence on dose/fraction (a/b = 0.87 Gy.) Reirradiation data in animals and humans suggest partial repair of RT-induced subclinical damage

becoming evident about 6 months post-RTand increasing over the next 2 years. Reports of myelopathy from stereotactic radiosurgery to spinal lesions appear rare (<1%) when the maximum spinal cord dose is

limited to the equivalent of 13 Gy in a single fraction or 20 Gy in three fractions. However, long-term data are insufficient to calculate a dose–volume relationship for myelopathy when the partial cord is treated with a hypofractionated regimen.

我们分析了脊髓经过放射治疗的脊髓病人的剂量体积数据与临床前数据。使用常规分割，1.8-2.0Gy/次照射全层脊髓，剂量54Gy和61Gy其脊髓病预计风险分别为小于1%和小于10%，与剂量/分割(α/β=0.87Gy)显著相关。动物和人类的再放疗数据明确表明放射引起的亚临床损伤的部份修复时间从放疗后6个月开始并延伸到此后2年。来自脊髓节段立体放射外科的脊髓病报导显得很少(<1%)，当最大脊髓剂量限制到单次分割当量为13Gy或三次分割20Gy。但是，当部分脊髓以高分割方案治疗时脊髓病的剂量体积关系的长期数据就难以准确计算了。