Temporal Distribution Of Dose Research Articles

A design of a DICOM-RT-based tool box for nonrigid 4D dose calculation.

The study was aimed to introduce a design of a DICOM‐RT‐based tool box to facilitate 4D dose calculation based on deformable voxel‐dose registration. The computational structure and the calculation algorithm of the tool box were explicitly discussed in the study. The tool box was written in MATLAB in conjunction with CERR. It consists of five main functions which allow a) importation of DICOM‐RT‐based 3D dose plan, b) deformable image registration, c) tracking voxel doses along breathing cycle, d) presentation of temporal dose distribution at different time phase, and e) derivation of 4D dose. The efficacy of using the tool box for clinical application had been verified with nine clinical cases on retrospective‐study basis. The logistic and the robustness of the tool box were tested with 27 applications and the results were shown successful with no computational errors encountered. In the study, the accumulated dose coverage as a function of planning CT taken at end‐inhale, end‐exhale, and mean tumor position were assessed. The results indicated that the majority of the cases (67%) achieved maximum target coverage, while the planning CT was taken at the temporal mean tumor position and 56% at the end‐exhale position. The comparable results to the literature imply that the studied tool box can be reliable for 4D dose calculation. The authors suggest that, with proper application, 4D dose calculation using deformable registration can provide better dose evaluation for treatment with moving target.PACS number(s): 87.55.kh

MO‐B‐211A‐01: Biological/Clinical Outcomes Models in Radiation Therapy Planning

Radiation therapy must strike a balance between clinically acceptable tumor control probability (TCP) and normal tissue complication probability (NTCP). Typical treatments expose several normal organs to incidental dose with an associated risk of a variety of radiation‐induced complications, each of which may depend differently on the spatial and temporal dose distribution. Dose/volume effects, wherein the ‘iso‐complication dose’ increases if the irradiated volume fraction decreases, are particularly important in designing and evaluating treatment plans. These effects are pronounced for some complications and weak for others. The classic “Emami” paper of 1991 summarized guidelines based on decades of clinical experience derived from the simple beam arrangements of the 2‐dimensional planning era when discrete parts of normal tissues typically received uniform doses at conventional fractionation schedules (partial organ irradiation). More recently, 3‐dimensional planning (including IMRT) has led to more conformal distributions with superior patient‐specific dosimetric information. Three‐dimensionl techniques have also encouraged treatment to higher doses and exposed normal tissues to a more variable and inhomogeneous range of dose distributions and fraction sizes. These complex relationships are often summarized in dose‐volume histograms (DVH).Depending on the suspected volume effect, treatment planners use various DVH‐based metrics to estimate complication risks. These include single DVH points (e.g. maximum dose or percent or absolute volume above a dose cut‐point), combinations of such points, generalized equivalent uniform dose (including mean dose) and models (e.g. Lyman model). Co‐morbidities, chemotherapies and other medical factors may also need to be considered. We will describe commonly used evaluation metrics, some of which date back to the early 1990's and others from more recent publications or in‐house experience.The current metrics used to evaluate normal tissue DVHs are sub‐optimal. Under the QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) initiative, a project that is jointly funded by AAPM and ASTRO, approximately 60 physicists and physicians have critically surveyed the NTCP literature. Their updated consensus guidelines will be published in the near future. Some of their preliminary findings will be discussed here (check the proffered sessions for other presentations).Learning Objectives:1. Understand the general features of the volume effect as applied to NTCP.2. Be familiar with the dose/volume metrics commonly used for complications risk estimation in treatment planning.3. Understand some of the difficulties in determining reliable dosimetric predictors of normal tissue complications.

Dosimetric guidance on using brachytherapy (low-dose-rate or high-dose-rate) to offset a flawed permanent prostate implant

Purpose To provide practical dosimetric advice on mending suboptimal permanent implants using low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The problem is to make the combination of the two radiation treatments (the initial, flawed one and the compensatory boost) clinically isoeffective with the planned dose. Methods and Materials The device of isoeffective dose is the appropriate tool for this purpose as it accounts for the physical (temporal distribution of dose) and biologic (radiosensitivity, repair kinetics, proliferation rate) treatment settings. Results I give, as a function of separation time from the initial, flawed treatment, and stratified by risk group representative values for the additional dose (low-dose-rate or high-dose-rate) needed to make the combined treatment isoeffective with a prescription of 144 Gy of permanently implanted 125I seeds. Conclusions Although the isoeffective dose concept, within the constraints stated in the text, is rigorously valid, its practical implementation depends importantly on the relevant radiobiologic parameters, and in this respect the reader is urged to use his own critical judgment.

SU‐FF‐T‐180: Dosimetric Guidance On Using Brachytherapy (LDR Or HDR) to Offset a Flawed Permanent Prostate Implant

Purpose: To provide practical dosimetric advice on mending suboptimal permanent implants using low dose‐rate (LDR) or high dose‐rate (HDR) brachytherapy (BRT). The problem is to make the combination of the two radiation treatments (the initial, flawed one and the compensatory boost) clinically isoeffective with the planned dose. Methods: The device of isoeffective dose (IED) is the appropriate tool for this purpose as it accounts for the physical (temporal distribution of dose) and biological (radiosensitivity, repair kinetics, proliferation rate) treatment setting. Results: I give, as a function of separation time from the initial, flawed treatment, and stratified by risk group representative values for the additional dose (LDR or HDR) needed to make the combined treatment isoeffective with a prescription of 144 Gy of permanently‐implanted seeds. Conclusions: While the IED concept, within the constraints stated in the presentation, is rigorously valid, its practical implementation depends importantly on the relevant radiobiological parameters, and in this respect the reader is urged to use his own critical judgment.

Physical mechanism of the Schwarzschild effect in film dosimetry—theoretical model and comparison with experiments

In consideration of the importance of film dosimetry for the dosimetric verification of IMRT treatment plans, the Schwarzschild effect or failure of the reciprocity law, i.e. the reduction of the net optical density under ‘protraction’ or ‘fractionation’ conditions at constant dose, has been experimentally studied for Kodak XOMAT-V (Martens et al 2002 Phys. Med. Biol. 47 2221–34) and EDR 2 dosimetry films (Djouguela et al 2005 Phys. Med. Biol. 50 N317–N321). It is known that this effect results from the competition between two solid-state physics reactions involved in the latent-image formation of the AgBr crystals, the aggregation of two Ag atoms freshly formed from Ag+ ions near radiation-induced occupied electron traps and the spontaneous decomposition of the Ag atoms. In this paper, we are developing a mathematical model of this mechanism which shows that the interplay of the mean lifetime τ of the Ag atoms with the time pattern of the irradiation determines the magnitude of the observed effects of the temporal dose distribution on the net optical density. By comparing this theory with our previous protraction experiments and recent fractionation experiments in which the duration of the pause between fractions was varied, a value of the time constant τ of roughly 10 s at room temperature has been determined for EDR 2. The numerical magnitude of the Schwarzschild effect in dosimetry films under the conditions generally met in radiotherapy amounts to only a few per cent of the net optical density (net OD), so that it can frequently be neglected from the viewpoint of clinical applications. But knowledge of the solid-state physical mechanism and a description in terms of a mathematical model involving a typical time constant of about 10 s are now available to estimate the magnitude of the effect should the necessity arise, i.e. in cases of large fluctuations of the temporal pattern of film exposure.

International Survey of 4D Dose-Prescriptions in IMRT for Head and Neck Squamous Cell Carcinoma: A Modeled Comparison of Expected Outcome

Purpose/Objective: Prescribing a course of IMRT requires explicit definition of spatial (3D) and temporal distribution of dose judged to produce a favorable balance between tumor control and early and late toxicities. 4D prescription involves the definition of a number of clinical target volumes and the choice of total dose, fraction size and overall treatment time for each volume. This is especially challenging in head and neck squamous cell carcinoma (HNSCC) due to the prospect for long-term survival if tumor control is achieved but also due to the risk of treatment related morbidity if the tolerance of a number of critical normal structures is exceeded.

Radiation tolerance of rat spinal cord to pulsed dose rate (PDR-) brachytherapy: the impact of differences in temporal dose distribution

Purpose: To investigate the impact of a time-variable dose rate during a high dose rate (HDR-) or pulsed dose rate (PDR-) brachytherapy fraction with the HDR-microSelectron and to compare this with the biological effect of a constant dose rate treatment with the same average dose rate (as in the case of 192Ir-wires). Moreover, the kinetics of repair in rat spinal cord are investigated using a wide spectrum of temporal dose distributions. Materials and methods: Two parallel catheters are inserted on each side of the vertebral bodies of the rat spinal column (Th 10–L 4) and connected to the HDR-microSelectron. Interstitial irradiation (IRT) is performed with a stepping 192Ir-point source, varying the activity of the point source between 0.3 and 6.5 Ci. Three different groups of experiments are defined, varying the overall treatment time and average dose rates in the range of 3–8, 28–53 and 82–182 min and 312–489 Gy/h, 32–56 Gy/h and 13–15 Gy/h, respectively. Difference in temporal dose distribution (dose rate variation) during almost the same overall treatment time is obtained by varying the number of pulses per dwell position in either one or ten runs through the implant. For reasons of comparison, previously reported results of continuous irradiation at a constant dose rate obtained with two 192Ir-wires in a fixed position are reanalyzed. Paralysis of the hindlegs after 5–6 months and histopathological examination of the spinal cord of each animal are used as experimental endpoints. Results: During one run of the 192Ir-point source, the peak dose rate is at least 25 times higher as compared with the minimum local dose rate and almost four times higher as compared with the average dose rate. For the three different groups of varying overall treatment times and average dose rates there is a significant difference in biological effect, with an ED 50-value of 23.1–23.6 Gy (average dose rate 312–489 Gy/h), 25.4–27.9 Gy (average dose rate 312–489 Gy/h) and 29.3–33 Gy (average dose rate 13–15 Gy/h). For these range of single doses, difference in temporal dose distribution with either one or ten runs is only significant for treatment times less then 1 h. For the prolonged treatment times at lower average dose rates, the difference between one or ten run is no longer significant. However, the results with the 192Ir-point source at an average dose rate/run of 13–15 Gy/h are significantly different from the ED 50-value of 33 Gy using 192Ir-wires at the same but constant dose rate. Using different types of analysis to estimate the repair parameters, the best fit of the data is obtained assuming biphasic repair kinetics and a variable dose rate (geometrically dependent) for the 192Ir-point source. On the basis of the incomplete repair LQ model, two repair processes with an α/β ratio=2.47 Gy and repair halftimes of 0.19 and 2.16 h are detected. The partition coefficient for the longer repair process is 0.98. This results in the proportion of total damage associated with the longer repair halftime being 0.495 for short sharp fractions with complete repair in between. Conclusions: Even in the range of high dose rates of 15–500 Gy/h, spinal cord radiation tolerance is significantly increased by a reduction in dose rate. For larger doses per fraction in PDR-brachytherapy dose rate variation is important, especially for tissues with very short repair half times (components). In rat spinal cord the repair of sublethal damage (SLD) is governed by a biphasic repair process with repair halftimes of 0.19 and 2.16 h.

Tumour control probability: a formulation applicable to any temporal protocol of dose delivery

An analytic expression for the tumour control probability (TCP), valid for any temporal distribution of dose, is discussed. The TCP model, derived using the theory of birth-and-death stochastic processes, generalizes several results previously obtained. The TCP equation is where S(t) is the survival probability at time t of the n clonogenic tumour cells initially present (at t = 0), and b and d are, respectively, the birth and death rates of these cells. Equivalently, b = 0.693/Tpot and d/b is the cell loss factor of the tumour. In this expression t refers to any time during or after the treatment; typically, one would take for t the end of the treatment period or the expected remaining life span of the patient. This model, which provides a comprehensive framework for predicting TCP, can be used predictively, or - when clinical data are available for one particular treatment modality (e.g. fractionated radiotherapy) - to obtain TCP-equivalent regimens for other modalities (e.g. low dose-rate treatments).

100 years of radiobiology: implications for biomedicine and future perspectives.

The development of radiobiology from the very early detection of the biological action of X-rays to the knowledge of today is described in sections on radiation chemistry and biochemistry, mutation and cancer induction, and embryonic damage, as well as the dependence of radiation response on radiation quality and temporal dose distribution (repair) and the interaction with other factors. For medicine radiobiology serves as a basis for radiotherapy and radiological protection. The effect of very low doses, and their possible biopositive effect (hormesis and adaptive response), is also discussed, as are the health hazard of radon, health risks after the Chernobyl accident, and space radiobiology. The radiobiology of the future will be concerned with biomolecular and genetic implications, problems of damage and repair, and connected problems like hormesis.

Neoplastic Transformation of C3H 10T1/2 Cells: A Study with Fractionated Doses of Monoenergetic Neutrons

As most occupational and environmental exposures to ionizing radiation are at low dose rates or in small dose fractions, risk estimation requires that the effects of the temporal distribution of dose are taken into account. Previous in vitro studies of oncogenic transformation, as well as in vivo studies of carcinogenesis induced by high-LET radiation, yielded controversial results concerning the presence of an inverse dose-rate effect. The present study tested the influence of one scheme of dose fractionation of monoenergetic neutrons on neoplastic transformation of C3H 10T1/2 cells. Neutrons of 0.5, 1.0 and 6.0 MeV were used. Cells were exposed to doses of 0.25 and 0.5 Gy, given acutely or in five fractions at 2-h intervals. The acute and fractionated irradiations with each energy were done on the same day. No significant difference between the two irradiation modes was found for both cell inactivation and neoplastic transformation at all energies. These results are in agreement with our data for fractionated fission-spectrum neutrons from the RSV-TAPIRO reactor.

Unconventional fractionation with or without mitomycin C in advanced head and neck cancer

The effectiveness of accelerated fractionation and hyperfractionation in cancer of the head and neck has been confirmed by randomized studies. These new fractionation strategies are almost invariably accompanied by an increase of early normal tissue reactions, in particular mucosal reactions. This paper presents a survey of the available experimental and clinical mucositis data and aims to assess to what extent the upper aerodigestive tract mucosa is limiting to treatment intensification by altered fractionation.The rate of dose delivery is the most important determinant for early radiation reactions. With accelerated radiotherapy, relative to a conventional treatment of 7 weeks, the achievable gain in treatment time is 2 weeks at most with the mucosa being the limiting tissue. Any further acceleration requires a reduction of dose. Manipulations with the temporal distribution of dose, fraction dose, and optimization of interfraction intervals can improve tolerance but probably do not allow significant further intensification of the existing accelerated schedules. Dose escalation by hyperfractionation does not seem to be directly limited by early mucosal reactions. Late reacting tissues are more likely to limit intensification of these schedules.Suggestions for further improvement of treatment outcome include: the generation of a potent agent which can ameliorate radiation mucositis and so permit further intensification of radiotherapy schedules; combination of altered fractionation schedules with hypoxic modifiers; and tailoring of the treatment strategy based on patient and tumour characteristics.

Oncogenic Transformation of C3H 10T1/2 Cells by Acute and Protracted Exposures to Monoenergetic Neutrons

An in vitro assay was used to assess cell killing and induction of neoplastic transformation in C3H 10T1/2 cells exposed to X rays and a range of monoenergetic neutrons administered at various dose rates. Curves for cell survival and induction of neoplastic transformation showed nonlinearity for cells exposed to acute graded doses of X rays, while irradiation of cells with 0.05 to 1.5 Gy of 0.23-, 0.35-, 0.45-, 0.70-, 0.96-, 5.90-, and 13.7-MeV neutrons resulted in a linear response as a function of dose for both neoplastic transformation and killing. When compared to results obtained with 250-kVp X rays, all neutron energies were more effective at both cell killing and induction of neoplastic transformation. When expressed as maximum biological effectiveness (RBEM), both cell survival and induction of neoplastic transformation showed an initial increase with neutron energy (maximal at 0.35 MeV), followed by a decrease in effectiveness with further increases in energy. These responses are consistent with microdosimetric predictions in that recoil protons from neutron interaction are shifted to lower lineal energies as neutron energies increase. To examine the effects of temporal distribution of dose on neutron-induced neoplastic transformation, cells were exposed to either a single dose or five equal dose fractions spread over 8 h. As a function of dose for single or fractionated exposures to 0.5 Gy or 0.23-, 0.35-, 0.45-, 5.9-, or 13.7-MeV neutrons, neither a sparing nor an enhancing effect was seen with survival. Similarly, the frequency of induction of neoplastic transformation was independent of dose fractionation for all but 5.9-MeV neutrons. The enhancing effects of exposure to fractionated doses of 5.9-MeV neutrons were further studied by comparing exposures for a range of doses given singly, in five fractions over 8 h, or continuously for 8 h. Results reaffirm the enhancing effects of dose fractionation on the induction of oncogenic transformation for 5.9-MeV neutrons. Within the limits of the data, there is modest enhancement of neutron-induced neoplastic transformation when the exposure dose is extended from a few minutes to several hours, with the enhancement being dependent on neutron energy.

The Effects of the Temporal Distribution of Dose on Oncogenic Transformation by Neutrons and Charged Particles of Intermediate LET

The effects of dose rate and dose fractionation on high-LET radiation-induced oncogenic transformation of C3H 10T1/2 cells were examined. Cells were irradiated with graded doses of 5.9-MeV monoenergetic neutrons administered either in single acute exposures (30 mGy/min) or extended over an 8-h period at low dose rates (from 0.21 to 1 mGy/min). Although cell survival studies showed no difference in effect with a change in radiation delivery rate, enhancement of oncogenic transformation occurred when the dose rate was reduced. When the neutron dose was divided into three fractions over 8 h, the biological effect was intermediate between that for the acute and that for the low-dose-rate exposures. Further irradiations were made using deuterons with an LET of 40 keV/microns. The dose-mean lineal energy was comparable to that measured for the 5.9-MeV monoenergetic neutrons. An inverse dose-rate/fractionation effect for the induction of transformation by high-LET deuterons was observed when the time between each of three fractions for a 0.3-Gy total dose was at least 45 min. No further enhancement was seen for longer dose fractionations, suggesting that very long protracted exposures of high-LET radiation would produce no additional enhancement.