Modeling and computer simulations of tumor growth and tumor response to radiotherapy

A model of tumor growth and tumor response to radiation is introduced in which each tumor cell is taken into account individually. Each cell is assigned a set of radiobiological parameters, and the status of each cell is checked in discrete intervals. Tumor proliferation is governed by the cell cycle times of tumor cells, the growth fraction, the apoptotic capacity of the tumor, and the degree of tumor angiogenesis. The response of tumor cells to radiation is determined by the radiosensitivities and the oxygenation status. Computer simulation is performed on a 3D rigid cubic lattice, starting out from a single tumor cell. Random processes are simulated by Monte Carlo methods. Short cell cycle time, high growth fraction, and tumor angiogenesis all increase tumor proliferation rates. Accelerated time-dose patterns result in lower total doses needed for tumor control, but the extent of dose reduction depends on the kinetics and the radiosensitivities of tumor cells. Tumor angiogenesis alters fully oxygenated and hypoxic fractions within the tumor and subsequently affects the radiation response. It is demonstrated for selected radiobiological parameters that the simulation tools are suitable to quantitatively assess the total doses needed for tumor control. Using the simulation tools, it is feasible to simulate time-dependent effects during fractionated radiotherapy and to compare different time-dose patterns in terms of their tumor control.     

Intensity-modulated radiation therapy

Intensity-modulated radiation therapy (IMRT) is an increasingly popular technical means of tightly focusing the radiation dose around a cancer. As with stereotactic radiotherapy, IMRT uses multiple fields and angles to converge on the target. The potential for total dose escalation and for escalation of daily fraction size to the gross cancer is exciting. The excitement, however, has greatly overshadowed a range of radiobiological and clinical concerns.     

Radiobiological models in prediction of radiation cardiotoxicity

Coronary disease induced by previous radiotherapy is the most common cause of death among patients treated with radiotherapy for cancer. Risk factors that may affect the frequency and intensity of radiotherapy’s cardiac toxicity are primarily the radiation dose and the volume of the heart exposed to radiation. The prolonged survival time of patients after radiotherapy, but also the intensive development of modern radiotherapy techniques results in the necessity of precise estimation of both tumor control probability, and the risk of normal tissue damage, thus the models describing the probability of complications in normal tissues have also been developed. The response from the cardiovascular system to high-dose radiation is known and associated with a pro-inflammatory response. However, the effect of low doses may be completely different because it induces an anti-inflammatory response. Also, there is no unambiguous answer to the question of whether RICD is a deterministic effect. Moreover, there is a lack of literature data on the use of known radiobiological models to assess the risk of cardiovascular complications. The models described are general and concerns any healthy tissue. Therefore, when planning treatment for patients, particular attention should be paid to the dose and area of ​​the heart to be irradiated.     

陀螺旋转式伽玛刀分次治疗颅内转移瘤的临床疗效观察

目的:评价大分割伽玛射线立体定向放射治疗对颅内转移瘤的临床疗效.方法:采用陀螺旋转式伽玛射线立体定向放射设备治疗颅内转移瘤患者91例.单纯伽玛射线立体定向放射治疗采取大分割分次方式,处方剂量3.2-5Gy,每周5次,计划靶区边缘(45％或65％等剂量线处)总剂量全程为35-50Gy.结果:近期有效率(CR+PR)颅内移瘤少于3个组为93.06％ (67/72),大于3个组为73.69％ (14/19);局部剂量与肿瘤复发的关系,照射剂量50GY者复发率为11.86％(7/59),照射剂量为40GY者复发率为31.25％(10/32);生存率陀螺刀治疗的中位生存期为11.9个月.6、12、24个月生存率分别为:76.92％ (70/91)、60.44％(55/91)、29.67％(27/91).结论:大分割伽玛射线立体定向放射治疗脑部和体部恶性肿瘤近期疗效满意.     

Imaging opportunities for treatment planning in intraoperative electron beam radiotherapy (IOERT): Developments in the context of RADIANCE system

AimThe purpose of this report is to store the information of the pre-planning and compare this data with the actual data of the procedure.BackgroundCurrently, intraoperative electron beam radiotherapy clinical practice lacks a treatment planning system.Materials and methodsThe RADIANCE concept approaches treatment planning by providing the user with a navigation platform based on a three-dimensional imaging system in which the radiation oncologist can target the tumor and risk areas in different sections (axial, coronal, sagittal), while a volume rendering engine displays a 3D image that is automatically updated as we make any changes of the space. Finally, the user may select the parameters of the applicator, energy and dose of treatment to optimize the procedure. Six cases are clinically described and illustrated.ResultsRADIANCE is a useful tool in planning IOERT. Tumor segmentation and risk areas with minimal guide in the selection of parameters for the applicator. Complex locations are challenging, where the experience and skill of the radiation oncologist is necessary to optimize the process. New developments include imaging innovated uses. Intraoperative imaging will approach reality and allow real time, dosimetry estimations, stereotactic recognition of patient and tumor bed position, will guide automatization of radiation beam recognition and pre-robotic arrangements with linear accelerator movements.ConclusionsRADIANCE offers a new imaging expansion for IOERT, in the context of a multidisciplinary approach to optimize and define the treatment parameters to approximate the actual treatment radiotherapy procedure.     

Dosimetric and radiobiological comparison of TG-43 and Monte Carlo calculations in 192Ir breast brachytherapy applications

PurposeTo investigate the clinical significance of introducing model based dose calculation algorithms (MBDCAs) as an alternative to TG-43 in ¹⁹²Ir interstitial breast brachytherapy.Materials and methodsA 57 patient cohort was used in a retrospective comparison between TG-43 based dosimetry data exported from a treatment planning system and Monte Carlo (MC) dosimetry performed using MCNP v. 6.1 with plan and anatomy information in DICOM-RT format. Comparison was performed for the target, ipsilateral lung, heart, skin, breast and ribs, using dose distributions, dose-volume histograms (DVH) and plan quality indices clinically used for plan evaluation, as well as radiobiological parameters.ResultsTG-43 overestimation of target DVH parameters is statistically significant but small (less than 2% for the target coverage indices and 4% for homogeneity indices, on average). Significant dose differences (>5%) were observed close to the skin and at relatively large distances from the implant leading to a TG-43 dose overestimation for the organs at risk. These differences correspond to low dose regions (<50% of the prescribed dose), being less than 2% of the prescribed dose. Detected dosimetric differences did not induce clinically significant differences in calculated tumor control probabilities (mean absolute difference <0.2%) and normal tissue complication probabilities.ConclusionWhile TG-43 shows a statistically significant overestimation of most indices used for plan evaluation, differences are small and therefore not clinically significant. Improved MBDCA dosimetry could be important for re-irradiation, technique inter-comparison and/or the assessment of secondary cancer induction risk, where accurate dosimetry in the whole patient anatomy is of the essence.     

Olminska and colleagues’ study, “Conversion of the helical tomotherapy plans to the step-and-shoot IMRT plans for patients with hip prosthesis during radiotherapy for prostate cancer” was interesting to read

Olmińska and colleagues’ study, Olmińska et al. (2016) was interesting to read [1]. While prasining the authors for their great work, I want to emphasize e few points.In the recent years, with the development of new device technology, Intensity Modulated Radiotherapy (IMRT) and complex treatment modalities such as stereotactic radiosurgery and helical tomotherapy were started to be implemented. Thus, due to increased local control of tumor growth and reduction of dose received by surrounding critical organs, serious complications were avoided. In this new treatment modality, while calculating appropriate dose, all the parameters such as patient anatomy and characteristics of radiation should be taken into account. Besides, during conformal radiotherapy, if hip prosthesis is located around or in the clinical target volume (CTV), type, thickness and density of biomaterial should be considered to avoid dose differences.     

A Bayesian mixture model relating dose to critical organs and functional complication in 3D conformal radiation therapy

A goal of cancer radiation therapy is to deliver maximum dose to the target tumor while minimizing complications due to irradiation of critical organs. Technological advances in 3D conformal radiation therapy has allowed great strides in realizing this goal; however, complications may still arise. Critical organs may be adjacent to tumors or in the path of the radiation beam. Several mathematical models have been proposed that describe the relationship between dose and observed functional complication; however, only a few published studies have successfully fit these models to data using modern statistical methods which make efficient use of the data. One complication following radiation therapy of head and neck cancers is the patient's inability to produce saliva. Xerostomia (dry mouth) leads to high susceptibility to oral infection and dental caries and is, in general, unpleasant and an annoyance. We present a dose-damage-injury model that subsumes any of the various mathematical models relating dose to damage. The model is a nonlinear, longitudinal mixed effects model where the outcome (saliva flow rate) is modeled as a mixture of a Dirac measure at zero and a gamma distribution whose mean is a function of time and dose. Bayesian methods are used to estimate the relationship between dose delivered to the parotid glands and the observational outcome-saliva flow rate. A summary measure of the dose-damage relationship is modeled and assessed by a Bayesian chi(2) test for goodness-of-fit.     

Modelling the correlation between EGFr expression and tumour cell radiosensitivity, and combined treatments of radiation and monoclonal antibody EGFr inhibitors

ABSTRACT: Purpose To estimate the effects of heterogeneity on tumour cell sensitivity to radiotherapy combined with radiosensitizing agents attributable to differences in expression levels of Epidermal Growth Factor Receptor (EGFr). Materials and methods Differences in radiosensitivity are not limited to cells of different cancer histotypes but also occur within the same cancer, or appear during radiotherapy if radiosensitizing drugs are combined with ionizing radiation. A modified biologically effective dose (MBED), has been introduced to account for changes in radiosensitivity parameters (alpha and alpha/beta) rather than changes in dose/fraction or total dose as normally done with standard biologically effective dose (BED). The MBED approach was applied to cases of EGFr over-expression and cases where EGFr inhibitors were combined with radiation. Representative examples in clinical practice were considered. RESULTS: Assuming membrane EGFr over-expression corresponds to reduced radiosensitivity (alphaH = 0.15 Gy-1 and alphaH/betaH = 7.5 Gy) relative to normal radiosensitivity (alpha = 0.2 Gy-1 and alpha/beta = 10 Gy), an increased dose per fraction of 2.42 Gy was obtained through the application of MBED, which is equivalent to the effect of a reference schedule with 30 fractions of 2 Gy. An equivalent hypo-fractionated regime with a dose per fraction of 2.80 Gy is obtained if 25 fractions are set. Dose fractionations modulated according to drug pharmacokinetics are estimated for combined treatments with biological drugs. Soft and strong modulated equivalent hypo-fractionations result from subtraction of 5 or 10 fractions, respectively. CONCLUSIONS: During this computational study, a new radiobiological tool has been introduced. The MBED allows the required dose per fraction to be estimated when tumour radiosensitivity is reduced because EGFr is over-expressed. If radiotherapy treatment is combined with EGFr inhibitors, MBED suggests new treatment strategies, with schedules modulated according to drug pharmacokinetics.     

Choice of radioisotope in stereotactic interstitial radiotherapy of small brain tumors

In stereotactic interstitial radiotherapy, small radioactive sources are placed within the brain tumor to deliver locally high radiation doses. The choice of the radioisotope depends upon the dose distribution around the isotope, energy of the emitted radiation, relative biological effectiveness, and finally, the cost and availability of the isotope. We have analyzed 198gold, 125iodine and 192iridium in terms of these four factors. Our results have shown that 125I is superior to the other two isotopes due to its soft X-rays and dosimetric as well as radiobiological properties. Unfortunately, it is the most expensive of these radioisotopes, and can be difficult to obtain in specific activities.     

Bone in the breast? Long term toxicity 21 years after interstitial brachytherapy as a boost

An 81-year-old patient developed an exulcerous tumor in her left breast 21 years after breast cancer treatment with lumpectomy and adjuvant radiotherapy. At the time of the initial treatment 21 years ago, whole breast irradiation was performed with a prescribed dose of 48?Gy and a maximal dose of 69?Gy. In addition, the patient received a 14.7?Gy boost with multicatheter brachytherapy as partial breast irradiation.In general, fat necrosis after radiotherapy, surgery or trauma is a minor problem for patients, but can lead to diagnostic difficulties. The incidence varies: the literature indicates that it occurs in up to 34% of cases. The direct pathogenesis is not clear; it can be due to high radiation dose to the breast, dosimetric inhomogeneities or surgical complications (seromas and inflammation).The tumor in the case described here, occurring more than two decades after the primary treatment, is a rarity in this extent and is an unusual clinical, radiological, and histological finding. It provides a good example of the need for an individualized approach to treatment.     

A radiobiological comparison of hypo-fractionation versus conventional fractionation for breast cancer 3D-conformal radiation therapy

BackgroundThe present research was aimed to compare the toxicity and effectiveness of conventional fractionated radiotherapy versus hypo-fractionated radiotherapy in breast cancer utilizing a radiobiological model.Materials and methodsThirty-five left-sided breast cancer patients without involvement of the supraclavicular and axillary lymph nodes (with the nodal stage of N0) that had been treated with conventional or hypo-fractionated were incorporated in this study. A radiobiological model was performed to foretell normal tissue complication probability (NTCP) and tumor control probability (TCP).ResultsThe data represented that TCP values for conventional and hypo-fractionated regimens were 99.16 ± 0.09 and 95.96 ± 0.48, respectively (p = 0.00). Moreover, the NTCP values of the lung for conventional and hypo-fractionated treatment were 0.024 versus 0.13 (p = 0.035), respectively. Also, NTCP values of the heart were equal to zero for both regimens.ConclusionIn summary, hypo-fractionated regimens had comparable efficacy to conventional fraction radiation therapy in the case of dosimetry parameters for patients who had left breast cancer. But, utilizing the radiobiological model, conventional fractionated regimens presented better results compared to hypo-fractionated regimens.     

Kybernetische Aspekte der Strahlenschädigung

Starting with experimentally established radiobiological facts concerning cellular effects of ionizing radiation, the differences between single cells and tissues are discussed. A new classification for “size”-controlled tissues is proposed, and the relevant mathematical formulations are outlined. It is suggested that the different sensitivities of tissues against ionizing radiation may be explained on the basis of differently operating control mechanisms. As examples, root meristems, intestinal epithelium and blood forming organs are described in more detail.     

Report on the third annual meeting of the Society for Biological Radiation Research, GBS ’99

During the past few decades radiation research has developed into specialized sub-disciplines, ranging from basic physics and chemistry to tumor biology and experimental radiotherapy. Scientific issues as well as the techniques and methodologies applied are subject to diverging discussion. The annual scientific meetings of the German ”Gesellschaft für Biologische Strahlenfor-schung (GBS)” were established with the primary aim of allowing up-to-date transfer of current knowledge in any of the topics in radiation research and of promoting interaction between different research groups. This report provides a summary of the presentations at the third annual meeting which took place in 1999 in Dresden, Germany. The meeting particularly focussed on frontline research in radiation chemistry, modeling of radiation effects, dosimetry of non-ionizing radiation and unconventional radiation qualities, e.g., heavy ions or soft x-rays, stochastic radiation effects, DNA repair, and various aspects of radiobiological research of cells, normal tissues and tumors. Received: 3 February 2000 / Accepted: 10 May 2000     

Stereology techniques in radiation biology

Clinicians involved in conventional radiation therapy are very concerned about the dose-response relationships of normal tissues. Before proceeding to new clinical protocols, radiation biologists involved with conformal proton therapy believe it is necessary to quantify the dose response and tolerance of the organs and tissues that will be irradiated. An important focus is on the vasculature. This presentation reviews the methodology and format of using confocal microscopy and stereological methods to quantify tissue parameters, cell number, tissue volume and surface area, and vessel length using the microvasculature as a model tissue. Stereological methods and their concepts are illustrated using an ongoing study of the dose response of the microvessels in proton-irradiated hemibrain. Methods for estimating the volume of the brain and the brain cortex, the total number of endothelial cells in cortical microvessels, the length of cortical microvessels, and the total surface area of cortical microvessel walls are presented step by step in a way understandable for readers with little mathematical background. It is shown that stereological techniques, based on a sound theoretical basis, are powerful and reliable and have been used successfully.     

Cardiac endothelial cells isolated from mouse heart - a novel model for radiobiology

Cardiovascular disease is recognized as an important clinical problem in radiotherapy and radiation protection. However, only few radiobiological models relevant for assessment of cardiotoxic effects of ionizing radiation are available. Here we describe the isolation of mouse primary cardiac endothelial cells, a possible target for cardiotoxic effects of radiation. Cells isolated from hearts of juvenile mice were cultured and irradiated in vitro. In addition, cells isolated from hearts of locally irradiated adult animals (up to 6 days after irradiation) were tested. A dose-dependent formation of histone γH2A.X foci was observed after in vitro irradiation of cultured cells. However, such cells were resistant to radiation-induced apoptosis. Increased levels of actin stress fibres were observed in the cytoplasm of cardiac endothelial cells irradiated in vitro or isolated from irradiated animals. A high dose of 16 Gy did not increase permeability to Dextran in monolayers formed by endothelial cells. Up-regulated expression of Vcam1, Sele and Hsp70i genes was detected after irradiation in vitro and in cells isolated few days after irradiation in vivo. The increased level of actin stress fibres and enhanced expression of stress-response genes in irradiated endothelial cells are potentially involved in cardiotoxic effects of ionizing radiation.     

Epigenetic modifications in radiation-induced non-targeted effects and their clinical significance

BackgroundIonizing radiation (IR) plays an important role in the diagnosis and treatment of cancer. Besides the targeted effects, the non-targeted effects, which cause damage to non-irradiated cells and genomic instability in normal tissues, also play a role in the side effects of radiotherapy and have been shown to involve both alterations in DNA sequence and regulation of epigenetic modifications.Scope of reviewWe summarize the recent findings regarding epigenetic modifications that are involved in radiation-induced non-targeted effects as well as their clinical significance in radiotherapy and radioprotection.Major conclusionsEpigenetic modifications play an important role in both the realization and modulation of radiobiological effects. However, the molecular mechanisms underlying non-targeted effects still need to be clarified.General significanceA better understanding of the epigenetic mechanisms related to radiation-induced non-targeted effects will guide both individualized clinical radiotherapy and individualized precise radioprotection.     

Dosimetric and radiobiological comparison in head-and-neck radiotherapy using JO-IMRT and 3D-CRT

IntroductionDosimetric and radiobiological evaluations for the Jaws-only Intensity-modulated radiotherapy (JO-IMRT) technique for head and neck jaws-only intensity-modulated radiation therapy (JO-IMRT) and 3D conformal radiation therapy (3D-CRT). To compare the head-and-neck therapeutic approaches utilizing JO-IMRT and 3D-CRT techniques, different radiation dose indices were calculated, including: conformity index (CI), homogeneity index (HI), and radiobiological variables like Niemierko's equivalent uniform dose based tumor control probability (TCP) of planning target volume (PTV), normal tissue complication probability (NTCP) of organs at risk (OAR) (brainstem, spinal cord, and parotid grand).Materials and methodsTwenty-five nasopharynx patients were studied using the Prowess Panther Treatment Planning System (Prowess Inc). The results were compared with the dose distribution obtained using 3D-CRT.ResultsRegarding tumor coverage and CI, JO-IMRT showed better results than 3D-CRT. The average doses received by the PTVs were quite similar: 72.1 ± 0.8 Gy by 3D-CRT and 72.5 ± 0.6 Gy by JO-IMRT plans (p > 0.05). The mean doses received by the parotid gland were 56.7 ± 0.7 Gy by 3D-CRT and 26.8 ± 0.3 Gy by JO-IMRT (p > 0.05). The HI and CI were 0.13 ± 0.01 and 0.14 ± 0.05 and (p > 0.05) by 3D-CRT and 0.83 ± 0.05 and 0.73 ± 0.10 by JO-IMRT (p < 0.05). The average TCP of PTV was 0.82 ± 0.08 by 3D-CRT and 0.92 ± 0.02 by JO-IMRT. Moreover, the NTCP of the parotid glands, brain stem, and spinal cord were lower using the JO-IMRT than 3D-CRT plans. In comparison to the 3D-CRT approach, the JO-IMRT technique was able to boost dose coverage to the PTV, improve the target's CI and HI, and spare the parotid glands. This suggests the power of the JO-IMRT over 3D-CRT in head-and-neck radiotherapy.