Monte Carlo role in radiobiological modelling of radiotherapy outcomes

Radiobiological models are essential components of modern radiotherapy. They are increasingly applied to optimize and evaluate the quality of different treatment planning modalities. They are frequently used in designing new radiotherapy clinical trials by estimating the expected therapeutic ratio of new protocols. In radiobiology, the therapeutic ratio is estimated from the expected gain in tumour control probability (TCP) to the risk of normal tissue complication probability (NTCP). However, estimates of TCP/NTCP are currently based on the deterministic and simplistic linear-quadratic formalism with limited prediction power when applied prospectively. Given the complex and stochastic nature of the physical, chemical and biological interactions associated with spatial and temporal radiation induced effects in living tissues, it is conjectured that methods based on Monte Carlo (MC) analysis may provide better estimates of TCP/NTCP for radiotherapy treatment planning and trial design. Indeed, over the past few decades, methods based on MC have demonstrated superior performance for accurate simulation of radiation transport, tumour growth and particle track structures; however, successful application of modelling radiobiological response and outcomes in radiotherapy is still hampered with several challenges. In this review, we provide an overview of some of the main techniques used in radiobiological modelling for radiotherapy, with focus on the MC role as a promising computational vehicle. We highlight the current challenges, issues and future potentials of the MC approach towards a comprehensive systems-based framework in radiobiological modelling for radiotherapy.     

Intra-fraction dose delivery timing during stereotactic radiotherapy can influence the radiobiological effect

The sequence of incremental dose delivery during a radiotherapy fraction can potentially influence the radiobiological effect. This would be most noticeable during the long fractions characteristic of hypo-fractionated stereotactic radiotherapy and radiosurgery. We demonstrate here the spatio-temporal variation of dose delivery by the CyberKnife to a lung tumor and propose strategies to reduce and/or correct for any resultant dose-time cytotoxic effects.     

Statistical methods for clinical verification of dose-response parameters related to esophageal stricture and AVM obliteration from radiotherapy

The purpose of this work is to provide some statistical methods for evaluating the predictive strength of radiobiological models and the validity of dose-response parameters for tumour control and normal tissue complications. This is accomplished by associating the expected complication rates, which are calculated using different models, with the clinical follow-up records. These methods are applied to 77 patients who received radiation treatment for head and neck cancer and 85 patients who were treated for arteriovenous malformation (AVM). The three-dimensional dose distribution delivered to esophagus and AVM nidus and the clinical follow-up results were available for each patient. Dose-response parameters derived by a maximum likelihood fitting were used as a reference to evaluate their compatibility with the examined treatment methodologies. The impact of the parameter uncertainties on the dose-response curves is demonstrated. The clinical utilization of the radiobiological parameters is illustrated. The radiobiological models (relative seriality and linear Poisson) and the reference parameters are validated to prove their suitability in reproducing the treatment outcome pattern of the patient material studied (through the probability of finding a worse fit, area under the ROC curve and chi2 test). The analysis was carried out for the upper 5 cm of the esophagus (proximal esophagus) where all the strictures are formed, and the total volume of AVM. The estimated confidence intervals of the dose-response curves appear to have a significant supporting role on their clinical implementation and use.     

利用放射生物学模型比较周围型肺癌立体定向放射治疗中的3种剂量方案

目的:利用放射生物学模型比较周围型肺癌立体定向放射治疗（SBRT）中3种常见剂量方案3×15 Gy、4×12 Gy和3×18 Gy在肿瘤局部控制率（TCP）、放射性肺炎（RIP）、胸壁疼痛（CWP）和肋骨骨折（RIRF）发生概率方面的差异。方法:收集20例周围型早期肺癌的CT图像资料,分别采用3种剂量方案设计放射治疗计划,利用放射生物学模型计算每种剂量方案的TCP、RIP、CWP和RIRF概率值。结果:3种剂量方案对TCP没有显著影响;4×12 Gy剂量方案的放疗毒性最低,3×15 Gy放疗毒性稍有增高,而3×18 Gy的毒性最高;3×18 Gy剂量方案的RIP、CWP和RIRF发生概率均明显高于其它两种剂量方案。结论:3种剂量方案的TCP数值没有显著差别,4×12 Gy剂量方案的放疗毒性最低,3×18 Gy剂量方案显著增加RIP、CWP和RIRF的发生概率,建议临床治疗前应根据肿瘤与危及器官的毗邻关系选择合适的剂量方案,实施个体化治疗策略。     

Herpes simplex encephalitis occurring after chemotherapy, surgery, and stereotactic radiotherapy for medulloblastoma

Reactivation of latent herpes simplex virus (HSV) in the trigeminal ganglion most commonly gives rise to recurrent herpes labialis and rarely to herpes simplex encephalitis. The mechanisms underlying reactivation of latent trigeminal HSV are complex. Here we report the case history of a 25-year-old woman who developed a fatal, bilateral necrotizing destructive temporal lobe lesion following surgical removal of a cerebellar medulloblastoma and combined radiotherapy and chemotherapy for recurrent tumor. Neuropathologic examination of the brain revealed minimal inflammatory changes, but immunohistochemistry was positive for HSV protein, and HSV deoxyribonucleic acid (DNA) was recovered from formalin-fixed paraffin-embedded brain tissue. The temporal proximity of the surgery, chemotherapy, and radiotherapy to the onset of disease suggests that these factors may have acted as triggers that precipitated conversion of latent HSV to overt HSV.     

Three-year clinical and optical coherence tomography follow-up after stereotactic radiotherapy for neovascular age-related macular degeneration

PurposeThe long-term clinical outcome of adjuvant stereotactic radiotherapy (SRT) in neovascular age-related macular degeneration (nAMD) patients was evaluated.MethodsThis case-control study included patients with unilateral nAMD, who underwent SRT complementary to standard anti-VEGF treatment. Only patients with monthly follow-up over at least three years were considered. Number of intravitreal injections, visual acuity (VA), central retinal thickness (CRT), and subfoveal choroidal thickness (SFCT) were evaluated and compared to baseline as well as to an age- and gender-matched control group, who received anti-VEGF monotherapy.ResultsTwenty patients were irradiated and had complete follow-up. Cumulatively, SRT patients needed significantly less injections than non-irradiated ones over three years (14 vs. 18, p ​= ​0.014), while median VA did not show statistically significant changes (0.4 logMAR at baseline to 0.65 logMAR at final follow-up, p ​= ​0.061). CRT remained steady, but SFCT showed a continuous thinning of almost 50 ​μm (p ​= ​0.031) in irradiated patients over three years. Multiple linear regression analysis revealed that SFCT and VA at time of irradiation are significant prognostic factors of VA change in SRT patients over the following three years (F(2,17) ​= ​23.946, p<0.001, R² of 0.738).ConclusionsSRT significantly reduced the cumulative anti-VEGF treatment burden over three years, however, this was mainly driven by the results of the first year after irradiation. A thinner SFCT at time of irradiation was associated with poorer visual outcome. While further research and investigation are warranted to elucidate the underlying pathogenesis, SFCT could be a potential biomarker when evaluating a patient’s suitability for SRT.     

一种新的头颈部常规放疗立体定位装置及其使用方法

目的：介绍一种新的自行 地头颈部肿瘤常规放射治疗的立体定位装置及其使用方法。方法：本装置为附加在患者体外的一个带有三维坐标系的框架结构,在ＣＴ影像上构成建立坐标系的标志呈“Ｖ”型,采用义量法确定扫描范围内任一点相对于该坐标系的空间位置。据此可求出靶中心坐标、不同Ｇａｎｔｒｙ角野的大小及形状等各项放疗参数。应用本装置和方法对一模拟靶的各放疗参数进行确定,并应用模拟定位机对其进行验证。结果：通过本装置     

Monte Carlo verification of gel dosimetry measurements for stereotactic radiotherapy

The quality assurance of stereotactic radiotherapy and radiosurgery treatments requires the use of small-field dose measurements that can be experimentally challenging. This study used Monte Carlo simulations to establish that PAGAT dosimetry gel can be used to provide accurate, high-resolution, three-dimensional dose measurements of stereotactic radiotherapy fields. A small cylindrical container (4 cm height, 4.2 cm diameter) was filled with PAGAT gel, placed in the parietal region inside a CIRS head phantom and irradiated with a 12-field stereotactic radiotherapy plan. The resulting three-dimensional dose measurement was read out using an optical CT scanner and compared with the treatment planning prediction of the dose delivered to the gel during the treatment. A BEAMnrc/DOSXYZnrc simulation of this treatment was completed, to provide a standard against which the accuracy of the gel measurement could be gauged. The three-dimensional dose distributions obtained from Monte Carlo and from the gel measurement were found to be in better agreement with each other than with the dose distribution provided by the treatment planning system's pencil beam calculation. Both sets of data showed close agreement with the treatment planning system's dose distribution through the centre of the irradiated volume and substantial disagreement with the treatment planning system at the penumbrae. The Monte Carlo calculations and gel measurements both indicated that the treated volume was up to 3 mm narrower, with steeper penumbrae and more variable out-of-field dose, than predicted by the treatment planning system. The Monte Carlo simulations allowed the accuracy of the PAGAT gel dosimeter to be verified in this case, allowing PAGAT gel to be utilized in the measurement of dose from stereotactic and other radiotherapy treatments, with greater confidence in the future.     

Monte Carlo dosimetry for synchrotron stereotactic radiotherapy of brain tumours

A radiation dose enhancement can be obtained in brain tumours after infusion of an iodinated contrast agent and irradiation with kilovoltage x-rays in tomography mode. The aim of this study was to assess dosimetric properties of the synchrotron stereotactic radiotherapy technique applied to humans (SSR) for preparing clinical trials. We designed an interface for dose computation based on a Monte Carlo code (MCNPX). A patient head was constructed from computed tomography (CT) data and a tumour volume was modelled. Dose distributions were calculated in SSR configuration for various energy beam and iodine content in the target volume. From the calculations, it appears that the iodine-filled target (10 mg ml(-1)) can be efficiently irradiated by a monochromatic beam of energy ranging from 50 to 85 keV. This paper demonstrates the feasibility of stereotactic radiotherapy for treating deep-seated brain tumours with monoenergetic x-rays from a synchrotron.     

Characterization of a dynamic multi-leaf collimator for stereotactic radiotherapy applications

The Apex? dynamic mini-multileaf collimator has recently been released by Elekta and attaches directly to the linear accelerator head. This paper details the work and results obtained in characterizing this mini-MLC for stereotactic usage within our department. A range of mechanical and dosimetric characteristics were investigated which included inter and intra leaf leakage, light/radiation field congruence, leaf position reproducibility, radiation penumbra, total scatter factors and mechanical rotational stability with the additional mini-MLC weight.     

网格精度对肝癌立体定向放射治疗计划的剂量学影响

目的:研究不同网格精度对肝癌立体定向放射治疗（SBRT）计划的剂量学影响,为临床肝癌SBRT计划的设计提供 合适的网格精度。方法:回顾性分析湖北省肿瘤医院2017~2020年间采用VMAT-SBRT治疗方式的肝癌患者10例,在相 同函数配置和参数设置条件下,分别采用1.0、2.0、3.0、4.0、5.0 mm网格精度设计治疗计划。比较靶区D95%、Dmean、适形度指 数、梯度指数,危及器官中肝脏Dmean、正常肝脏的V10、V20、V30,脊髓的Dmax以及计划的计算时间,分析在3 %/3 mm和2%/2 mm标准下Gamma通过率。结果:采用Eclipse系统AAA算法下对网格大小进行更改,结果显示靶区D95%随着网格值增 大呈下降趋势,GI随着网格值增大呈增长趋势;在Dmean和适形度指数上,网格值对其产生的影响未见显著差异;在危及器 官保护方面,1.0 mm网格表现出更优异的计算结果;在计算时间方面,随着网格大小减小,剂量计算时间呈大幅度增长;在 计划验证通过率方面,随着网格大小增大,两种标准（2%/2 mm和3%/3 mm）下的通过率不断减小。结论:随着计算网格 大小的改变,靶区和危及器官的剂量受量以及计算时间和Gamma通过率都有不同程度的改变。综合计划剂量优化结果 以及计算时间和验证通过率,建议在肝癌SBRT计划设计中使用2.0 mm大小的计算网格。     

The reproducibility of polyacrylamide gel dosimetry applied to stereotactic conformal radiotherapy

The reproducibility of polyacrylamide gel (PAG) dosimetry has been evaluated when used to verify two radiotherapy treatment plans of increasing complexity. The plans investigated were a three-field coplanar arrangement, using the linac jaws for field shaping, and a four-field, conformal, non-coplanar plan using precision-cast lead alloy shielding blocks. Each treatment was performed three times using phantoms and calibration gels manufactured in-house. Two phantoms were specially designed for this work to aid accurate positioning of the gels for irradiation and imaging. All gels were imaged post-irradiation using a Siemens Vision 1.5T MR scanner. T2 relaxation images were calibrated to absorbed dose distributions using a number of smaller calibration vessels to produce distribution maps of relative dose. The relative dose distributions were found to be reproducible, with the standard deviation on the mean areas enclosed by the > or = 50% isodose lines measured in three orthogonal planes being 6.4% and 4.1% for the coplanar and non-coplanar plans respectively. The measured distributions were also consistent with those planned, with isodose lines generally agreeing to within a few millimetres. However, the measured absolute doses were on average 23.5% higher than those planned. Although the polyacrylamide gel dosimetry technique has some limitations, particularly when calibrating distributions to absolute dose, the ability to resolve sharp dose gradients in three dimensions with millimetre precision is invaluable when verifying complex conformal treatment plans, where avoidance of proximal, critical structures is a treatment criterion.     

Monte Carlo modelling of external radiotherapy photon beams

An essential requirement for successful radiation therapy is that the discrepancies between dose distributions calculated at the treatment planning stage and those delivered to the patient are minimized. An important component in the treatment planning process is the accurate calculation of dose distributions. The most accurate way to do this is by Monte Carlo calculation of particle transport, first in the geometry of the external or internal source followed by tracking the transport and energy deposition in the tissues of interest. Additionally, Monte Carlo simulations allow one to investigate the influence of source components on beams of a particular type and their contaminant particles. Since the mid 1990s, there has been an enormous increase in Monte Carlo studies dealing specifically with the subject of the present review, i.e., external photon beam Monte Carlo calculations, aided by the advent of new codes and fast computers. The foundations for this work were laid from the late 1970s until the early 1990s. In this paper we will review the progress made in this field over the last 25 years. The review will be focused mainly on Monte Carlo modelling of linear accelerator treatment heads but sections will also be devoted to kilovoltage x-ray units and 60Co teletherapy sources.     

基于kV-CBCT图像验证非小细胞肺癌立体定向放疗的照射剂量

目的:基于千伏级锥形束CT（kV-CBCT）图像验证非小细胞肺癌（NSCLC）立体定向放疗（SBRT）的照射剂量。方法:收集20例行SBRT的NSCLC患者的100张CBCT图像。采用形变配准和非形变配准两种方法在CBCT图像上对单次照射剂量分布进行重新计算。使用剂量体积直方图对计划剂量和重新计算的照射剂量进行比较。结果:患者内靶区的平均覆盖率（V100%）相对差异较小;计划之间的适形度指数和梯度指数表现出很好的一致性。对于危及器官,在计划剂量和照射剂量之间仅在一名患者中发现有明显差异（P<0.05）。结论:CBCT图像能用来验证NSCLC的SBRT剂量,并提供相关的3D执行剂量的信息。     

Targeting accuracy of an image guided gating system for stereotactic body radiotherapy

Recently, a commercial system capable of x-ray image guided patient positioning and respiratory gated delivery has become available. Here we describe the operational principles of this system and investigate its geometric targeting accuracy under controlled conditions. The system tracks breathing via infrared (IR) detection of reflective markers located on the patient's abdomen. Localization kilovoltage (kV) x-rays are triggered from within the gated delivery window portion of the breathing trace and after positioning, the tumour will cross the linac isocentre during gated delivery. We tested geometric accuracy of this system by localizing and delivering gated fields to a moving phantom. Effects of phantom speed, gating window location, timing errors and phantom rotations on positioning and gating accuracy were investigated. The system delivered gated fields to both a moving and static phantom with equal accuracy. The position of the gating window affects accuracy only to the extent that an asymmetric breathing motion could affect dose distribution within its boundaries. Positioning errors were found to be less then 0.5 +/- 0.2 mm for phantom rotations up to 5 degrees. We found and corrected a synchronization error caused by a faulty x-ray duration setting and detected a 60 +/- 20 ms time delay in our linear accelerator.     

SRS MapCHECK与EDOSE在立体定向放疗计划剂量验证中的对比

目的:使用SRS MapCHECK和EDOSE对立体定向放疗(SRT)计划进行剂量验证,并比较它们的验证结果。方法:首先比较两种系统在不同方野(2 cm×2 cm、4 cm×4 cm、6 cm×6 cm、10 cm×10 cm)的γ通过率(3%/3 mm),然后选择29例SRT计划,分析两种系统在不同γ标准下的绝对剂量通过率,最后分析EDOSE建立的4种不同物理模型对SRT计划剂量验证的影响。结果:SRS MapCHECK在所有方野和29例SRT计划的绝对剂量γ通过率均高于EDOSE,两者的验证结果有统计学差异(P<0.05);SRS MapCHECK及EDOSE在29例SRT计划的γ通过率(2%/2 mm)分别是为98.60%±2.14%和96.53%±2.41%。基于EDOSE的不同物理模型验证结果有统计学差异,平均γ通过率(2%/2 mm)偏差为1.8%～5.1%。结论:SRS MapCHECK和EDOSE系统均满足SRT计划剂量验证的要求,且SRS MapCHECK的剂量验证通过率优于EDOSE;不同的EDOSE物理模型对SRT计划剂量验证有影响。     

立体定向放射治疗照射野剂量分布特点及应用

目的：测量目前广泛应用的立体定向放射治疗系统（SRT－X 刀）准直器射野的临床剂量学参数，探索正确的临床使用方法。材料与方法：用组织等效固体水模、仿真人体头模和胶片剂量测量系统测量BrainLAB X刀系统在静态、单靶（中心）旋转、两靶旋转照射时的离轴比、半影、锐度、平坦度等剂量学参数。结论：了解和掌握不同照射技术时，X刀准直器射野剂量学参数的变化是正确使用立体定向放射治疗技术的一个关键因素，特别是在鼻咽癌的多靶点补量治疗时尤为重要。本文提出了临床使用时的一些具体建议。