质子治疗的物理与生物学基础

近几十年来质子治疗在临床上取得了巨大成就,这是因为质子束在物理学和生物学上具有独特的优势。在肿瘤治疗学上质子比常规射线(^60Co、X射线、电子)有两个主要优势：(1)可根据肿瘤在体内的深度,使质子束精确地定位在肿瘤病灶处,以使肿瘤受到最大的照射剂量而不伤害健康组织,从而达到适形治疗。(2)可根据肿瘤的形状改变质子在微观尺度能量沉积的形状,实现辐射生物学效应的改变。基于此,对于形状较复杂的大实体瘤,质子治疗比常规治疗有更高的精度。质子的这些在治疗学上特异的可能性是由其剂量学和辐射生物学特性决定的。剂量学的性质与能量在宏观尺度的沉积特征有关,作为带电粒子,质子在介质中有确定的射程和相对小的散射歧离,此外在射程前端剂量相对较小,而到射程末端剂量达到最大,形成一个尖锐的Bragg峰,基于这屿特点使得肿瘤受到高剂量的照射而周围的健康组织受到很小的伤害;相对生物学效应与能量在微观尺度的沉积特征有关,与重离子相比虽然质子属于低LET射线,但就其能量在微观尺度沉积的性质与常规射线相比质子足致密电离辐射,因此目前已有实验证实质子治疗比常规射线治疗增加了相对生物学效应,然而目前对能量的微观沉积与生物学效应关系的原理仍需要进一步从理论上和实验上研究证明。文中分析了质子与介质的作用过程、以及传能线密度(LET)、相对生物学效应(RBE)、氧增比(OER)等放射治疗学的一般概念,讨论了质子用于肿瘤治疗的物理学与生物学性质。     

调强型多叶光栅

０简介随着放射治疗技术的飞速发展,对病灶靶区实施精确的剂量照射已成为现代放疗技术发展的主要方向。在此要求的基础上,人们提出了适形放射治疗的理论：即由医用电子直线加速器照射病人后在患者体内产生的剂量分布与患者肿瘤的形状尽可能地接近,同时尽量降低肿瘤周围...     

用剂量梯度法作放射治疗设计

放射治疗设计就是根据病人的个体特征,布置照射野,得到一个最适合于该病人的剂量在体内的分布。要求(一)靶区(肿瘤及有关的淋巴结)剂量均匀。(二)保证放射敏感器官受到的剂量不超过它的耐受量。(三)受到照射的一切正常组织的总剂量不很大。此外,不允许体内某些部位剂量特别大(热点),肿瘤边沿某处剂量特别小(冷点)以及靶区剂量对入口处剂量的比值较大。满足这些要求的剂量分布称最佳分布,该种布     

医用直线加速器输出剂量稳定性分析

目的：分析医用直线加速器输出剂量稳定性及其影响因素。方法：采用SPSS15.0统计分析软件,统计2009年每日治疗病人前监测6 MV、15 MVX射线,和9 MeV、12 MeV电子线输出剂量数据,分析医用直线加速器不同能量输出剂量的稳定性及其影响因素,提出加速器输出剂量质量保证的相关措施。结果：4档能量中的3档能量（9 MeV,12 MeV,15MV）输出剂量K-S检测双尾渐进概率P值分别为0.428、0.933、0.355均大于显著性水平0.05,符合正态分布。由于加速器微波源输出不稳定,6 MV输出剂量1月到3月,从98.4%连续不断漂移上升到102.5%。6 MV K-S检测双尾渐进概率P值是0.012小于显著性水平0.05,不符合正态分布。结论：直线加速器输出剂量的稳定性是肿瘤放射治疗治疗质量保证的重要方面。每日治疗肿瘤病人前监测和直线加速器输出剂量,分析直线加速器输出剂量的稳定性,有助于降低加速器系统误差,提高患者治疗剂量的精度。     

高能X射线肿瘤照射靶区的生物剂量验证的可行性研究

目的:研究MM50加速器高能X射线放疗患者时光核反应产生的正电子发射核在PET/CT的显象技术及显象信息,探讨用该信息对照射的肿瘤靶区准确度和剂量分布进行活体的生物学验证。材料与方法:当用高能光子线照射肿瘤时,其与人体的主要组成元素碳C、氧O、氮N等进行光核反应,在照射区会产生可发射正电子的11C,15O,13N等核素,用正电子发射断层扫描仪PET/CT立即扫描照射后的病人,11C,15O,13N等发射的正电子即可在功能影像或分子生物学影像设备PET/CT上显像。根据显像的位置和强度便可分析推断和验证肿瘤照射的生物学位置和生物学剂量,从而真正意义上实现精确的生物适形放疗和验证。用与人体组成类似的有机玻璃头模实验,按常规放射治疗程序,先在PET/CT进行肿瘤的CT定位,之后用治疗计划系统TPS设计三野照射计划,按计划在MM50加速器上用三组不同能量(10MV,25MV,50MV)和剂量为1Gy～10Gy的X射线进行照射。由于碳C、氧O是人体最主要的组成元素,所以我们只研究11C,15O等核素的显像。对11C和15O,PET/CT上分别扫描20min或2min～5min获取正电子核素显像及显像位置、强度分布等信息。MM50是IBA公司医用跑道式电子回旋加速器,束流能量范围10MeV～50MeV,三维治疗计划设计系统是核通公司的3D治疗计划系统TPP3.2,美国GE公司的Discovery LSⅡ PET/CT,用于肿瘤定位和核医学图像扫描及数据处理。结果:10MV X射线,放疗后不能产生光核反应;25MV X射线可产生光核反应,但需要较大的照射剂量,方能获得有意义的信息。对50MV X射线,2Gy～4Gy的常规放疗剂量即可获得11C,15O的正电子显像图及强度分布等信息,10Gy的剂量即可清楚获得15O和11C的正电子显像图及强度分布等信息。结论:MM50加速器50MV X射线放疗病人时光核反应产生正电子发射核可在PET/CT上显像,显像的位置和强度分布可用来对射线照射肿瘤靶区的准确度和照射剂量进行生物学验证,但要获得定量关系还需做大量工作。     

宫颈癌调强放疗和三维适形放疗剂量对比研究

目的:研究宫颈癌调强放疗(IMRT)和三维适形放疗(3D-CRT)时靶区及其周围正常组织受照剂量的差异.材料方法:用拓能公司生产的WiMRT三维适形调强放疗计划系统分别进行6～9个照射角度的3D-CRT和IMRT计划设计,肿瘤量45Gy,计算出正常组织和靶区的剂量—体积直方图以及所需照射的总跳数.用Siemens生产的Primart电子直线加速器(X射线能量6MV,MLC叶片29对)实施放疗计划,测量出10 cm×10cm射野外漏射线和散射线剂量率,估算放疗时正常组织所受辐射剂量随距离的变化关系.结果:照射野数和照射角度一致,IMRT时膀胱、直肠、阴道所受平均剂量分别只有3D-CRT时的19.5％(29.3/150.3)、64.5％(538.0/833.0)和61.0％(1553.6/2546.3),靶区平均受照剂量略高于3D-CRT.IMRT病人正常组织所受散射线和漏射线剂量约为3D-CRT病人的1.5倍.结论:宫颈癌IMRT剂量分布优于3D-CRT.     

射束强度受调节的适形放射治疗

射束强度受调节的适形放疗法是一种先进的放射治疗方法，它使用一组强度可独立控制的笔射束。通过旋转或多野静态照射肿瘤靶，使射野内高剂量分布开头在三维方向上与肿瘤靶的形状一致。同时尽可能地减少了靶区周围健康组织的照射剂量，从而大大提高放射治疗的治疗增益比，促进肿瘤的局部控制。     

射束强度受调节的适形放射治疗

射束强度受调节的适形放疗法是一种先进的放射治疗方法，它使用一组强度可独立控制的笔射束，通过旋转或多野静态照射肿瘤靶，使射野内高剂量分布形状在三维方向上与肿瘤靶的形状一致，同时尽可能地减少了靶区周围健康组织的照射剂量，从而大大提高放射治疗的治疗增益比，促进肿瘤的局部控制。本文系统地阐述了强度受调节的适形放疗的优势与治疗计划理论。     

脑室肿瘤放射治疗的剂量分布测量

放射治疗的根本目标在于给肿瘤区域足够的精确治疗剂量，而使周围正常组织和器官受照射量最小。提高肿瘤的局部控制率，减少正常组织的放射并发症，而实现这个目标的关键是取决于治疗剂量的精确实施和脑剂量分布的优劣。本工作根据临床常用的三种治疗方案，用ＴＬＤ剂量元件和剂量胶片，利用人体等效非均匀头模，检验治疗计划系统剂量分布理论计算结果     

用多叶准直器实现适形放射治疗

适形放射疗法是一种先进的放射疗法。它通过旋转照射或静态多射野照射使得高剂量区剂量分布的形状在三维方向上与靶区（病灶）的实际形状一致，而尽可能地降低靶区周围健康组织的照射量，从而大大提高放射治疗的治疗增益比，提高单次照射所能给出的处方剂量，达到更好的治疗效果。本文系统地阐述了用多叶准直器实现适形放疗的理论与技术。     

质子治疗技术的发展及其挑战

质子治疗有显著的剂量学优势,布拉格峰的迅速跌落可保证肿瘤在接受相同照射剂量的同时,大大减少肿瘤周围正常组织受照射剂量,降低放疗并发症。但是质子剂量学优势能否充分转化为临床患者的获益仍然存在一定的争议。本文综述了质子治疗的历史、基础原理及其技术发展历程,并分析了质子治疗的优势和面临的挑战。     

Characteristics of proton beams after field shaping at PMRC

The proton irradiation control system was developed for cancer radiotherapy at the Proton Medical Research Center, with the extension of a beam line connected to a synchrotron at the High Energy Physics Laboratory. The initial energy of the 500 MeV proton beam supplied by the accelerator is degraded down to 243 MeV after passing through a graphited rod. In the control system, a proton beam is scattered to form a large field, its Bragg peak width is spread out, and its energy is degraded to the optimum value with a range covering tumour depth. The characteristics of the devices required for these procedures have been investigated from the viewpoint of the relationship between dose rate and field flatness, taking the setting-up geometry of these devices into consideration.     

基于临床质子加速器的DeepPlan笔形束模型构建

目的:基于佛罗里达大学质子放疗中心（University of Florida Health Proton Therapy Institute, UFHPTI）质子加速器在笔形束扫描模式下的临床实验数据,在DeepPlan中构建相应模型,验证模型构建的准确性并初步应用于临床前列腺癌的剂量计算。方法:在DeepPlan质子模块中建立UFHPTI质子加速器的笔形束计算模型,并将剂量计算结果与临床实验数据进行对比,包括30组积分深度剂量（Integrated Depth Dose, IDD）、30组空气中质子束斑发散大小、1组多能量多点照射下的纵向扩展布拉格峰（Spread Out Bragg Peak, SOBP）和横向剂量分布,以此验证模型构建的准确性。最后以UFHPTI的两个前列腺癌临床放疗计划为指导,将DeepPlan计算结果与商用放疗计划系统RayStation计算结果通过PTW公司的VeriSoft软件进行gamma分析。结果:DeepPlan质子模块计算产生的30组IDD与UFHPTI加速器的临床实验数据平均相对误差为0.01%,最大相对误差为0.23%;30组空气质子束斑发散大小与临床实验数据平均相对误差为0.15%,最大相对误差为1.14%。在多能量多点照射下,DeepPlan质子模块计算产生的SOBP与临床实验数据平均相对误差为1.07%,最大相对误差为3.91%;横向剂量分布和临床实验数据平均相对误差为1.92%,最大相对误差为4.09%。针对两个前列腺癌的放疗计划,DeepPlan质子模块与RayStation计算的三维剂量结果在以3 mm/3%的标准下每个子野的gamma通过率都达到95%以上,其中病例1两个子野（270°和90°方向）的gamma通过率分别为96.4%和97.5%,病例2两个子野（270°和90°方向）的gamma通过率分别为99.3%和98.9%。结论:在DeepPlan中构建了与UFHPTI质子加速器相匹配的笔形束模型,该模型可初步应用于临床前列腺癌的剂量计算。     

A prototype beam delivery system for the proton medical accelerator at Loma Linda.

A variable energy proton accelerator was commissioned at Fermi National Accelerator Laboratory for use in cancer treatment at the Loma Linda University Medical Center. The advantages of precise dose localization by proton therapy, while sparing nearby healthy tissue, are well documented [R. R. Wilson, Radiology 47, 487 (1946); M. Wagner, Med. Phys. 9, 749 (1982); M. Goitein and F. Chen, Med. Phys. 10, 831 (1983)]. One of the components of the proton therapy facility is a beam delivery system capable of delivering precise dose distributions to the target volume in the patient. To this end, a prototype beam delivery system was tested during the accelerator's commissioning period. The beam delivery system consisted of a beam spreading device to produce a large, uniform field, a range modulator to generate a spread out Bragg peak (SOBP), and various beam detectors to measure intensity, beam centering, and dose distributions. The beam delivery system provided a uniform proton dose distribution in a cylindrical volume of 20-cm-diam area and 9-cm depth. The dose variations throughout the target volume were found to be less than +/- 5%. Modifications in the range modulator should reduce this considerably. The central axis dose rate in the region of the SOBP was found to be 0.4 cGy/spill with an incident beam intensity of 6.7 x 10(9) protons/spill. With an accelerator repetition rate of 30 spills/min and expected intensity of 2.5 x 10(10) protons/spill for patient treatment, this system can provide 50 cGy/min for a 20-cm-diam field and 9-cm range modulation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incorporating partial shining effects in proton pencil-beam dose calculation

A range modulator wheel (RMW) is an essential component in passively scattered proton therapy. We have observed that a proton beam spot may shine on multiple steps of the RMW. Proton dose calculation algorithms normally do not consider the partial shining effect, and thus overestimate the dose at the proximal shoulder of spread-out Bragg peak (SOBP) compared with the measurement. If the SOBP is adjusted to better fit the plateau region, the entrance dose is likely to be underestimated. In this work, we developed an algorithm that can be used to model this effect and to allow for dose calculations that better fit the measured SOBP. First, a set of apparent modulator weights was calculated without considering partial shining. Next, protons spilled from the accelerator reaching the modulator wheel were simplified as a circular spot of uniform intensity. A weight-splitting process was then performed to generate a set of effective modulator weights with the partial shining effect incorporated. The SOBPs of eight options, which are used to label different combinations of proton-beam energy and scattering devices, were calculated with the generated effective weights. Our algorithm fitted the measured SOBP at the proximal and entrance regions much better than the ones without considering partial shining effect for all SOBPs of the eight options. In a prostate patient, we found that dose calculation without considering partial shining effect underestimated the femoral head and skin dose.     

Nuclear interactions in proton therapy: dose and relative biological effect distributions originating from primary and secondary particles

The dose distribution delivered in charged particle therapy is due to both primary and secondary particles. The secondaries, originating from non-elastic nuclear interactions, are of interest for three reasons. First, if fast Monte Carlo treatment planning is envisaged, the question arises whether all nuclear interaction products deliver a significant contribution to the total dose and, hence, need to be tracked. Second, there could be an enhanced relative biological effectiveness (RBE) due to low energy and/or heavy secondaries. Third, neutrons originating from nuclear interactions may deliver dose outside the target volume. The particle yield from different nuclear interaction channels as a function of proton penetration depth was studied theoretically for different proton beam energies. Three-dimensional dose distributions from primary and secondary particles were simulated for an unmodulated 160 MeV proton beam with and without including a slice of bone material and for a spread-out Bragg peak (SOBP) of 3 x 3 x 3 cm3 in water. Secondary protons deliver up to 10% of the total dose proximal to the Bragg peak of an unmodulated proton beam and they affect the flatness of the SOBP. Furthermore, they cause a dose build-up due to forward emission of secondary particles from nuclear interactions. The dose deposited by d, t, 3He and alpha-particles was found to contribute less than 0.1% of the total dose. The dose distal to the target volume caused by liberated neutrons was studied for four proton beam energies in the range of 160-250 MeV and found to be below 0.05% (2 cm distal to SOBP) of the prescribed target dose for a 3 x 3 x 3 cm3 target. RBE values relative to 60Co were calculated proximal to and within the SOBP. The RBE proximal to the Bragg peak (100% dose) is influenced by secondary particles (mainly protons and a-particles) with a strong dose dependency resulting in RBE values up to 1.2 (2 Gy; inactivation of V79). Depending on the endpoint considered, secondary particles cause a shift in RBE by up to 8% at 2 Gy. In contrast, the RBE in the Bragg peak is almost entirely determined by primary protons due to a decreasing secondary particle fluence with depth. RBE values up to 1.3 (2 Gy; inactivation of V79) at 1 cm distal to the Bragg peak maximum were found. The inactivations of human skin fibroblasts and mouse lymphoma cells were also analysed and reveal a substantial tissue dependency of the total RBE. The outcome of this study shows that elevated RBE values occur not only at the distal edge of the SOBP. Although the variations are modest, and in most cases might have no observable clinical effect, they might have to be considered in certain treatment situations. The biological effect downstream of the target caused by neutrons was analysed using a radiation quality factor of 10. The biological dose was found to be below 0.5% of the prescribed target dose (for a 3 x 3 x 3 cm3 SOBP) but depends on the size of the SOBP. This dose should not be significant with respect to late effects, e.g. cancer induction.     

Dose error analysis for a scanned proton beam delivery system

All particle beam scanning systems are subject to dose delivery errors due to errors in position, energy and intensity of the delivered beam. In addition, finite scan speeds, beam spill non-uniformities, and delays in detector, detector electronics and magnet responses will all contribute errors in delivery. In this paper, we present dose errors for an 8 × 10 × 8 cm(3) target of uniform water equivalent density with 8 cm spread out Bragg peak and a prescribed dose of 2 Gy. Lower doses are also analyzed and presented later in the paper. Beam energy errors and errors due to limitations of scanning system hardware have been included in the analysis. By using Gaussian shaped pencil beams derived from measurements in the research room of the James M Slater Proton Treatment and Research Center at Loma Linda, CA and executing treatment simulations multiple times, statistical dose errors have been calculated in each 2.5 mm cubic voxel in the target. These errors were calculated by delivering multiple treatments to the same volume and calculating the rms variation in delivered dose at each voxel in the target. The variations in dose were the result of random beam delivery errors such as proton energy, spot position and intensity fluctuations. The results show that with reasonable assumptions of random beam delivery errors, the spot scanning technique yielded an rms dose error in each voxel less than 2% or 3% of the 2 Gy prescribed dose. These calculated errors are within acceptable clinical limits for radiation therapy.     

Dose-volume delivery guided proton therapy using beam on-line PET system

Proton therapy is one form of radiotherapy in which the irradiation can be concentrated on a tumor using a scanned or modulated Bragg peak. Therefore, it is very important to evaluate the proton-irradiated volume accurately. The proton-irradiated volume can be confirmed by detection of pair annihilation gamma rays from positron emitter nuclei generated by the target nuclear fragment reaction of irradiated proton nuclei and nuclei in the irradiation target using a positron emission tomography (PET) apparatus, and dose-volume delivery guided proton therapy (DGPT) can thereby be achieved using PET images. In the proton treatment room, a beam ON-LINE PET system (BOLPs) was constructed so that a PET apparatus of the planar-type with a high spatial resolution of about 2 mm was mounted with the field of view covering the isocenter of the beam irradiation system. The position and intensity of activity were measured using the BOLPs immediately after the proton irradiation of a gelatinous water target containing 16O nuclei at different proton irradiation energy levels. The change of the activity-distribution range against the change of the physical range was observed within 2 mm. The experiments of proton irradiation to a rabbit and the imaging of the activity were performed. In addition, the proton beam energy used to irradiate the rabbit was changed. When the beam condition was changed, the difference between the two images acquired from the measurement of the BOLPs was confirmed to clearly identify the proton-irradiated volume.     

Depth absorbed dose and LET distributions of therapeutic 1H, 4He, 7Li, and 12C beams

The depth absorbed dose and LET (linear energy transfer) distribution of different ions of clinical interest such as 1H, 4He, 7Li, and 12C ions have been investigated using the Monte Carlo code SHIELD-HIT. The energies of the projectiles correspond to ranges in water and soft tissue of approximately 260 mm. The depth dose distributions of the primary particles and their secondaries have been calculated and separated with regard to their low and high LET components. A LET value below 10 eV/nm can generally be regarded as low LET and sparsely ionizing like electrons and photons. The high LET region may be assumed to start at 20 eV/nm where on average two double-strand breaks can be formed when crossing the periphery of a nucleosome, even though strictly speaking the LET limits are not sharp and ought to vary with the charge and mass of the ion. At the Bragg peak of a monoenergetic high energy proton beam, less than 3% of the total absorbed dose is comprised of high LET components above 20 eV/nm. The high LET contribution to the total absorbed dose in the Bragg peak is significantly larger with increasing ion charge as a natural result of higher stopping power and lower range straggling. The fact that the range straggling and multiple scattering are reduced by half from hydrogen to helium increases the possibility to accurately deposit only the high LET component in the tumor with negligible dose to organs at risk. Therefore, the lateral penumbra is significantly improved and the higher dose gradients of 7Li and 12C ions both longitudinally and laterally will be of major advantage in biological optimized radiation therapy. With increasing charge of the ion, the high LET absorbed dose in the beam entrance and the plateau regions where healthy normal tissues are generally located is also increased. The dose distribution of the high LET components in the 7Li beam is only located around the Bragg peak, characterized by a Gaussian-type distribution. Furthermore, the secondary particles produced by high energy 7Li ions in tissuelike media have mainly low LET character both in front of and beyond the Bragg peak.     

Density heterogeneities and the influence of multiple Coulomb and nuclear scatterings on the Bragg peak distal edge of proton therapy beams

Density heterogeneities in the path of proton beams are known to cause degradation of the Bragg peak and, thus, widening of its distal fall-off. Inadequate accounting for this effect may lead to unwanted dose delivered to normal tissue distal to the target volume. In low-density regions, such as the thorax, this may lead to large volumes of healthy tissue receiving unnecessary dose. Although it is known that multiple Coulomb scattering within the density heterogeneities is the main cause of Bragg peak degradation, no systematic attempt has been made to quantify the contribution of multiple Coulomb scattering and nuclear scattering. Through a systematic study using a 220 MeV proton beam, we show that nuclear scattering contributes to about 5% of the distal fall-off width and is only slightly dependent on heterogeneity complexity. Furthermore, we also show that the energy spectra of the proton fluence downstream of various heterogeneity volumes are well correlated with the Bragg peak distal fall-off widths. Based on this correlation, a novel method for predicting distal fall-offs is suggested. This method is tested for three clinical setups of a voxelized model of a human head based on computer tomography data. Results are within 3% of the distal fall-off values obtained using Monte Carlo simulations.