由SABR再论放射敏感性

随着现代放射治疗技术进步,放疗已由过去二维时代进入三维和四维时代,治疗精度大幅度提高,分割模式也发生了深刻变革。从传统放射治疗发展到以三维适形放射治疗（3D-CRT）和调强放射治疗（IMRT）为代表的聚焦照射,提高了肿瘤靶区剂量,减少了正常组织的损伤。同时随着影像引导技术进步,治疗机与影像引导结合,每次治疗前通过影像扫描技术获得肿瘤靶区位置信息,或用4D影像引导技术精确地将射线投射到目标靶点,达到立体定向体部放射治疗（stereotactic body radiation therapy,SBRT）/立体定向消融放疗（stereotactic ablative radiotherapy,SABR）的目的,放射治疗完全进入精准、高效和低毒时代。高剂量、大分割照射已经取得令人信服和可喜的疗效,传统放射生物学理论已无法解释这种照射模式抗肿瘤细胞作用机制。传统放疗认为,肿瘤有敏感与不敏感之分,但是,进入SABR时代,肿瘤对其治疗均反应良好,放射治疗学迫切需要建立新的放射生物学学说和体系,在传统放射生物学理论基础上,更好地阐明新技术原理、作用机制,并建立与传统放射生物学内在联系,为临床普及和推广消融放疗技术奠定理论基础。     

The radiobiology of targeted radiotherapy

Targeted radiotherapy consists of biologically selective irradiation of malignant cells by means of radionuclides attached to tumour-seeking molecules. A variety of clinical strategies for targeted radiotherapy may be used, for which different normal tissues will be critical. A large number of radionuclides exist, emitting nuclear particles with a range of path lengths from nanometres to millimetres. An important feature of normal-tissue radiobiology is the dose-rate effect, which is especially marked for late-responding tissues. Radiobiological calculations imply that tolerance dose for targeted radiotherapy using low-LET emitters will depend strongly on the effective half-life of the radionuclide, which will be affected by pharmacokinetics and may vary between patients. Some strategies designed to improve the therapeutic radio (e.g. accelerated clearance of radionuclide) may have modulating effects on the tolerance dose. Tumour response will be governed by the 'four Rs' (repair, repopulation, reoxygenation, redistribution) as well as by mechanisms peculiar to targeted radiotherapy. Analysis based on the extended linear quadratic model predicts that dose-rate effects will be of major importance for only a minority of tumours. Most of the radiation dose to tumour will usually be delivered over a time-scale of a few days. This might give insufficient time for tumour reoxygenation, making the use of hypoxic sensitizers appropriate. A special feature of targeted radiotherapy is the complex relationship between tumour curability and tumour size for different radionuclides. For long-range beta-emitters, microscopic tumours may be operationally resistant because of inefficient absorption of radionuclide disintegration energy in small volumes. Short-range emitters will be more efficient in sterilization of micrometastases but sterilization of larger tumours may require an unattainable degree of homogeneity of radionuclide distribution. Optimal use of targeted radiotherapy may require it to be combined with external-beam irradiation or chemotherapy. Experimental studies will be necessary to investigate those features of targeted radiotherapy which differ from external-beam irradiation. Future directions may include targeted radiotherapy of minimal numbers of tumour cells detected by use of molecular probes. Such applications call for use of short-range alpha-emitters and Auger emitters whose radiobiology will become increasingly important.     

Estimation of linear energy transfer distribution for broad-beam carbon-ion radiotherapy at the National Institute of Radiological Sciences,Japan

A treatment of carbon-ion radiotherapy (CIRT) is generally evaluated using the dose weighted by relative biological effectiveness (RBE) while ignoring the radiation quality varying in the patient. In this study, we have developed a method of estimating linear energy transfer (LET) from the RBE in an archived treatment plan to represent the radiation quality of the treatment. The LET in a beam database was associated with the RBE by two fitting functions per energy, one for the spread-out Bragg peak (SOBP) and the other for shallower depths, to be differentiated by RBE per energy per modulation. The estimated LET was generally consistent with the original calculation within a few keV/μm, except for the overkill region near the distal end of SOBP. The knowledge of experimental radiobiology can thereby be associated with CIRT treatments through LET, which will potentially contribute to deeper understanding of clinical radiobiology and further optimization of CIRT.     

颅内生殖细胞瘤的放射治疗

放射治疗在颅内生殖细胞瘤的治疗中起重要作用,但传统放疗并发症较多。随着放疗技术的进步,降低颅内生殖细胞瘤并发症的发生率提高治愈率已成为可能,近年也不乏大宗、长时间观察病例报道,澄清了一些该病在放疗方面有争议的和处理不规范的问题。     

Review: Total Doses in Fractionated Radiotherapy—Implications of New Radiobiological Data

Summary

The total dose in radiotherapy has been adjusted in the past for different fractionation schedules by the use of empirical formulae such as NSD, TDF and CRE. It is now appropriate to consider fractionation factors which include more biological insight in their formulation than was possible earlier.

It has become clear, from both clinical and experimental animal data, that the total dose in multi-fraction irradiations depends more critically on size of dose-per-fraction for late than for early damage to normal tissues. This difference has been interpreted as due to different shapes of the underlying dose—response curves. The late reactions respond with more curvature in the dose—response curve, i.e. with more repair capability at very low doses per fraction, than the early tissue reactions. A linear-quadratic relationship for the dose—response curves has been found to fit experimental data well, with few exceptions. This paper reviews this interpretation and explores some of its implications for radiotherapy and for radiobiology applied to therapy. Of many repair factors that have been suggested, the ratio α/β (of the linear to the quadratic coefficients) is one that should be independent of the level of damage assayed. Values of α/β of about 10 Gy have been reported for a number of early tissue responses but a range of values from about 1 to 5 or 6 Gy for late responses. It is a current challenge to radiobiology to explain why this difference occurs.

Once such values are known for different tissues—and the dangers of premature assumptions are emphasized—calculations are possible which might be useful in radiotherapy as an alternative to NSD, TDF, CRE etc. Some data are presented on the magnitude of differences from these previously used empirical formulae, with a discussion about how easily detected the discrepancies might be in clinical practice. Applications to hypofractionation, hyperfractionation and accelerated fractionation are illustrated.     

Ability to repair DNA double-strand breaks related to cancer susceptibility and radiosensitivity

Traditional radiobiology has aimed at elucidating the mechanism of radiosensitivity of cancer cells and normal cells. Because the mechanism of DNA double-strand break (DSB) repair, which is inherently important to radiosensitivity, was unknown, it has been difficult to obtain results applicable to clinical radiotherapy from traditional radiobiology research. Today, however, the molecular mechanism of DNA DSB repair has been elucidated because of the rapid advances in molecular biology. In DNA DSB repair, at least two major repair mechanisms, homologous recombination and nonhomologous end joining (NHEJ) have been reported. In the NHEJ pathway, DSBs are directly, or after processing of the DNA ends, rejoined at an appropriate chromosomal end. DNA-dependent protein kinase (DNA-PK) plays an important role in DNA DSB repair by NHEJ. We have investigated how the ability of repair of DNA DSB influences cancer susceptibility and the radiosensitivity of tumors and normal tissues by focusing on the activity of DNA-PK. In the near future, research on DNA DSB repair mechanism will be able to be applied to research on carcinogenesis, prediction of radiosensitivity of tumors and normal cells, and sensitization of tumor cells.     

BOPPPS模式在放射生物学线上教学活动中的效果分析

目的 利用BOPPPS模式,包括导入（bridge-in）、学习目标（outcome）、前测（pre-test）、参与式学习（participation）、后测（post-test）、总结（summary）,探讨肿瘤放疗从业人员线上学习放射生物学相关知识的效果。方法 选取细胞存活曲线、细胞周期和放射敏感性为例,以多个大学附属医院放疗从业人员为研究对象,开展了一项多中心前瞻随机对照研究。所有学员采用分类随机分组的方式,分为BOPPPS组和对照组。BOPPPS组是将课程设计为网上课堂,分为课前准备、网络授课以及课后阶段3个环节。网络授课阶段包含视频观看、基础知识学习、文献探讨及分组讨论等多种形式。对照组即为传统的教学模式。采用χ²检验比较两组一般情况的一致性,采用非参检验比较两组或者多组间成绩的差异。结果 课前摸底测试为（58.56±0.99）分。课后BOPPPS组平均分为（85.48±0.85）分,对照组为（77.79±1.10）分,与对照组相比,BOPPPS组平均分升高7.69分（Z=5.31,P < 0.001）。BOPPPS组和对照组的平均答题时间分别为（296.62±15.40）和（386.41±21.27） s,BOPPPS组缩短了89.79 s （Z=3.34,P=0.001）。亚组分析发现,学员不论是否学过放射生物学课程,BOPPPS组的成绩均有显著性提高,且在未学过的学员中,成绩提升幅度更大。从不同岗位情况分析,发现BOPPPS组和对照组相比均有提高,特别是对于医师、副主任医师和技师成绩的提高差异有统计学意义（Z=3.98、3.53、2.32,P<0.05）;不同学位之间成绩也有差异,本科和博士学员的成绩有显著提高（Z=3.64、4.18,P< 0.001）。结论 将BOPPPS教学模式灵活应用于放射生物学等枯燥的学科的线上教育中,对于提高放疗科医技人员的理论基础具有重要意义。     

MR-guided radiotherapy for prostate cancer: state of the art and future perspectives

Advances in radiotherapy technology have increased precision of treatment delivery and in some tumour types, improved cure rates and decreased side effects. A new generation of radiotherapy machines, hybrids of an MRI scanner and a linear accelerator, has the potential to further transform the practice of radiation therapy in some cancers. Facilitating superior image quality and the ability to change the dose distribution online on a daily basis (termed “daily adaptive replanning”), MRI-guided radiotherapy machines allow for new possibilities including increasing dose, for hard to treat cancers, and more selective sparing of healthy tissues, where toxicity reduction is the key priority.These machines have already been used to treat most types of cancer, although experience is still in its infancy. This review summarises the potential and current evidence for MRI-guided radiotherapy, with a predominant focus on prostate cancer. Current advantages and disadvantages are discussed including a realistic appraisal of the likely potential to improve patient outcomes. In addition, horizon scanning for near-term possibilities for research and development will hopefully delineate the potential role for this technology over the next decade.     

Personalized radiotherapy: concepts,biomarkers and trial design

In the past decade, and pointing onwards to the immediate future, clinical radiotherapy has undergone considerable developments, essentially including technological advances to sculpt radiation delivery, the demonstration of the benefit of adding concomitant cytotoxic agents to radiotherapy for a range of tumour types and, intriguingly, the increasing integration of targeted therapeutics for biological optimization of radiation effects. Recent molecular and imaging insights into radiobiology will provide a unique opportunity for rational patient treatment, enabling the parallel design of next-generation trials that formally examine the therapeutic outcome of adding targeted drugs to radiation, together with the critically important assessment of radiation volume and dose-limiting treatment toxicities. In considering the use of systemic agents with presumed radiosensitizing activity, this may also include the identification of molecular, metabolic and imaging markers of treatment response and tolerability, and will need particular attention on patient eligibility. In addition to providing an overview of clinical biomarker studies relevant for personalized radiotherapy, this communication will highlight principles in addressing clinical evaluation of combined-modality-targeted therapeutics and radiation. The increasing number of translational studies that bridge large-scale omics sciences with quality-assured phenomics end points—given the imperative development of open-source data repositories to allow investigators the access to the complex data sets—will enable radiation oncology to continue to position itself with the highest level of evidence within existing clinical practice.     

A purpose-built iodine-125 irradiation plaque for low dose rate low energy irradiation of cell lines in vitro

The phenomenon of hyper-radiosensitivity (HRS) to very low acute single doses of radiation has been demonstrated in several cell lines in vitro and in vivo, and has been studied in theory and in practice. The theory suggests a similar hypersensitivity when cells are continuously exposed to radiation at very low dose rates. These low dose rates are used when radioactive seed (iodine-125 or palladium-103) implants of the prostate are used as an alternative to surgery or external beam radiotherapy. To investigate the radiobiology of hypersensitivity of this type on various cell lines in vitro, an iodine-125 seed irradiator has been designed and built for safe use in the Gray Laboratory. In practice, the calculated dose rate has been used for consistency. Discrepancies between calculated and measured dose rates are discussed.     

Molecular radiobiology meets clinical radiation oncology

Background:?The 2nd Langendorff Congress in Freiburg in Breisgau (Germany) gathered basic and translational scientists as well as clinicians interested in recent developments in molecular and clinical radiobiology. The topics ranged from the most recent insight into the organisation of the DNA damage response and radiotherapeutically relevant cell death mechanisms to biological imaging for treatment planning and advances in the understanding of the molecular biological effects of particle beams. Clinical aspects of stem cell and tumour stem cell biology as well as of angiogenesis and hypoxia, the search for novel molecular radiosensitisers and potential strategies for exploitation of the immune system to further improve tumour radiotherapy were also discussed.

Results and conclusion:?This report surveys the presentations at the meeting, considering their significance in light of the literature, and documents the increasing importance of molecular radiobiology for clinical radiooncology.     

Biochemical indicators of whole-body gamma-radiation effects in the pig

PURPOSE: Validation of the pig as an experimental animal model for dose assessment after ionizing irradiation. MATERIALS AND METHODS: The evolution of haematological and biochemical parameters was followed for up to 7 days after irradiation in pigs exposed to whole-body 60Co gamma-radiation at doses between O and 6 Gy. RESULTS: Some biochemical indicators showed significant variations: amylase, LDH, alkaline and acid phosphatases, ALT and iron. None of the studied parameters alone presents a reliable dose-effect relationship; however, there was evidence that the combination of lymphocyte and neutrophil counts and the determination of LDH, ALT, AST and urea levels allowed some dose determination, independent of time, if blood samples were taken within 7 days post-irradiation. CONCLUSION: The results confirm the main problems of biochemical dosimetry. However, the pig model could represent a useful alternative to the non-human primate in radiobiology research, especially in the case of partial-body exposure. A multiparametric approach to dose assessment seems to be possible in the pig model. Confirmation should be carried out using blood samples from patients undergoing radiotherapy treatment.     

闪速放射治疗(FLASH)技术对机房屏蔽设计带来的挑战

与常规放疗技术相比, FLASH治疗技术在保护正常组织方面具有优势, 但剂量率提升100倍以上。如果按照现有标准对机房进行屏蔽设计, 将显著提升改造成本, 且仍有可能无法满足标准要求, 导致FLASH治疗技术无法开展。通过调研国内外标准及文献, 分析了FLASH治疗技术对机房屏蔽设计带来的挑战, 并着重对比了不同国家在放疗机房屏蔽设计时采用的剂量率控制标准。部分国家屏蔽设计时采用考虑实际治疗工况下的平均剂量率;我国主要采用考虑居留因子条件下的瞬时剂量率方法进行控制。如果在我国开展FLASH治疗技术, 瞬时剂量率的要求将很难满足。为了提高FLASH等高剂量率放射治疗技术, 在管理目标限值不变的前提下, 建议考虑对现有标准进行修订, 采用一定时间内的平均剂量率限值进行控制, 或增加FLASH治疗条件下的控制标准。     

超高剂量率放疗在恶性肿瘤中的应用

放疗作为一种局部治疗手段,在肿瘤治疗中扮演重要的角色。在过去数十年间,放疗技术取得了进步,适形性、均质性不断增强,放疗效率提高,结果令人鼓舞。尽管如此,正常组织最大耐受剂量成为制约肿瘤区域放疗剂量进一步提升的瓶颈。如果能够减轻正常组织不良反应,则可给予肿瘤病灶较高的放疗剂量,从而取得更好的疗效。近年来,超高剂量率放疗（FLASH-RT）诱导的FLASH效应,使得保持相同的抗肿瘤效果的同时,对正常组织能够降低放疗诱发的不良反应。因此,成为国内外放疗界热门研究领域。目前,部分学者倾向于采用急性氧消耗学说解释FLASH效应,但FLASH-RT的正常组织保护作用仍有待阐明。此外,FLASH-RT的临床研究已初步展开,结果令人期待。本文基于现有的证据,对FLASH-RT在恶性肿瘤治疗中的研究进行了阐述,以期为该项新技术的临床转化应用提供参考。     

中医药防治放射性皮肤损伤的研究进展

放射性皮肤损伤是指放射线对皮肤照射所引起的急慢性皮肤损伤。核灾难、放射性事故、放射性治疗、职业暴露等都有可能造成放射性皮肤损伤的发生。大约95%接受放射治疗的患者最终会在治疗过程中或治疗过程后发展为辐射诱发性皮炎,因此如何正确防治放射性皮肤损伤具有重要的现实意义。中医认为,放射性皮肤损伤属于火热毒邪,阻滞气血,损伤肌表,影响体内气血津液布散,损伤脏腑机能。本文综述放射性皮肤损伤中医理论的认识与发展,及中医内治法和外治法的研究进展,为中医药防治放射性皮肤损伤研究及治疗提供依据。     

Molecular biology: the key to personalised treatment in radiation oncology?

We know considerably more about what makes cells and tissues resistant or sensitive to radiation than we did 20 years ago. Novel techniques in molecular biology have made a major contribution to our understanding at the level of signalling pathways. Before the “New Biology” era, radioresponsiveness was defined in terms of physiological parameters designated as the five Rs. These are: repair, repopulation, reassortment, reoxygenation and radiosensitivity. Of these, only the role of hypoxia proved to be a robust predictive and prognostic marker, but radiotherapy regimens were nonetheless modified in terms of dose per fraction, fraction size and overall time, in ways that persist in clinical practice today. The first molecular techniques were applied to radiobiology about two decades ago and soon revealed the existence of genes/proteins that respond to and influence the cellular outcome of irradiation. The subsequent development of screening techniques using microarray technology has since revealed that a very large number of genes fall into this category. We can now obtain an adequately robust molecular signature, predicting for a radioresponsive phenotype using gene expression and proteomic approaches. In parallel with these developments, functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) can now detect specific biological molecules such as haemoglobin and glucose, so revealing a 3D map of tumour blood flow and metabolism. The key to personalised radiotherapy will be to extend this capability to the proteins of the molecular signature that determine radiosensitivity.Molecular biology developments have, over the past 20 years, provided us with a remarkable array of techniques, enhancing our understanding of how tumour and normal tissues respond to radiation damage. As these techniques grow increasingly sophisticated, their application should, in theory, present opportunities to improve the effectiveness of radiotherapy.However, as we look at how radiotherapy is performed today we see a discipline founded on 100 years of practice-based, empirical development, recently enhanced by impressive advances in dose delivery and image-guided procedures. These developments have brought us to a point where dose deposition is already highly tailored, to a tolerance of ∼2% for most tissues of the body, which is much more accurate than any pharmaceutical agent. Yet, are we really delivering dose where it needs to go for maximal therapeutic gain?     

解毒疏络法对肺癌放疗减毒作用的临床研究

 目的 观察解毒疏络法对肺癌放疗不良反应的影响.方法 设立单纯放疗组(简称对照组)53例,放疗加解毒疏络法组(以下简称治疗组)55例.以放疗后血象、肝肾功能、免疫功能、放射性肺损伤的评定及分级、放射治疗毒性反应、中医疗效评定标准为指标进行临床疗效观察.结果 治疗组血象、肝肾功能、免疫功能、放射性肺损伤的评定及分级、放射治疗毒性反应、中医疗效评定标准优于对照组(P＜0.05).结论 解毒疏络法可一定程度地减轻放疗的不良反应.     

纳米粒子在协同光动力放射治疗中的作用

重点阐述了一种全新的治疗手段:利用纳米粒子将放射治疗同光动力治疗相结合。该方法不仅可以解决光动力治疗仅适用于体表疾病的局限,从而提高光动力治疗的疗效;还可以在保证治疗效果的同时降低放疗剂量,有效地控制放疗后并发症的发生,为肿瘤治疗开辟新的篇章。     

PI3K/Akt与胶质瘤辐射抗性

恶性脑胶质瘤的术后治疗是患者预后生存期延长的关键,如何提高肿瘤组织的辐射敏感性,增强正常组织的辐射抗性是当前肿瘤放射生物学及临床放疗研究的热点。研究资料表明,PI3K/Akt抗细胞凋亡通路的激活提高了部分细胞的辐射抗性,特别在表皮细胞受紫外线照射的研究中提示,辐射产生的活性氧可能是该通路激活的原因之一;电离辐射可能诱导相关的细胞因子通过激活PI3K/Akt通路介导胶质瘤细胞的辐射抗性;PI3K及其相关酶可能通过DNA修复途径发挥抗辐射作用。PI3K/Akt通路的研究可为放射治疗胶质瘤提供新型的增敏药。     

电离辐射与细胞动力学

细胞对电离辐射的反应取决于DNA的损伤程度及细胞对此损伤的修复能力,损伤后修复能力和损伤性质因细胞周期而异。因此,细胞动力学改变是影响放射治疗效果的重要因素。随着放射生物学研究的进展,细胞动力学改变与修复的分子基础逐渐被揭示出来,并表现出许多明显的共同点。近年来有关放射治疗的分子生物学研究成果,展示了放射生物学几个重要因素之间的内在联系。