Investigation of secondary neutron dose for 18 MV dynamic MLC IMRT delivery

Secondary neutron doses from the delivery of 18 MV conventional and intensity modulated radiation therapy (IMRT) treatment plans were compared. IMRT was delivered using dynamic multileaf collimation (MLC). Additional measurements were made with static MLC using a primary collimated field size of 10 x 10 cm2 and MLC field sizes of 0 x 0, 5 x 5, and 10 x 10 cm2. Neutron spectra were measured and effective doses calculated. The IMRT treatment resulted in a higher neutron fluence and higher dose equivalent. These increases were approximately the ratio of the monitor units. The static MLC measurements were compared to Monte Carlo calculations. The actual component dimensions and materials for the Varian Clinac 2100/2300C including the MLC were modeled with MCNPX to compute the neutron fluence due to neutron production in and around the treatment head. There is excellent agreement between the calculated and measured neutron fluence for the collimated field size of 10 x 10 cm2 with the 0 x 0 cm2 MLC field. Most of the neutrons at the detector location for this geometry are directly from the accelerator head with a small contribution from room scatter. Future studies are needed to investigate the effect of different beam energies used in IMRT incorporating the effects of scattered photon dose as well as secondary neutron dose.     

The use of a realistic VMAT delivery emulator to optimize dynamic machine parameters for improved treatment efficiency

The delivery of volumetric modulated arc therapy (VMAT) requires the simultaneous movement of the linear accelerator gantry, multi-leaf collimators and jaws while the dose rate is varied. In this study, a VMAT delivery emulator was developed to accurately predict the characteristics of a given treatment plan, incorporating realistic parameters for gantry inertia and the variation in leaf speed with respect to gravity. The emulator was used to assess the impact of dynamic machine parameters on the delivery efficiency, using a set of prostate and head and neck VMAT plans. Initially, assuming a VMAT system with fixed dose rate bins, the allowable leaf and jaw speeds were increased and a significant improvement in treatment time and average dose rate was observed. The software was then adapted to simulate a VMAT system with continuously varying dose rate, and the increase in delivery efficiency was quantified, along with the impact of an increased leaf and jaw speed. Finally, a set of optimal dynamic machine parameters was derived assuming an idealized scenario in which the treatment is delivered in a single arc at constant maximum gantry speed.     

Optimization of intensity modulated radiotherapy under constraints for static and dynamic MLC delivery.

Multi-leaf collimators (MLCs) are emerging as the prevalent modality to apply intensity modulated radiotherapy (IMRT). Both the principle and the particular design of MLCs stipulate complex constraints on the practically applicable intensity modulated radiation fields. Most consequentially, the distribution of exposure times across the maximum field outline is either a piecewise constant function in the static mode or a piecewise linear function in the dynamic mode of driving an MLC. In view of clinical utility, the total leaf movement should be minimized, which requires that MLC-related constraints be considered in the dose optimization process. A method is proposed to achieve this for both static MLC fields and dynamic leaf close-in application. The method is an amendment to a generic gradient-based IMRT dose optimization algorithm and solves numerical problems related to the non-convexity of the MLC constraints, which can cause erratic behaviour of a gradient-based algorithm. It employs bistable penalty functions to select preferrable leaf configurations from the configuration space of the MLC, which is limited by specific design features. Together with an 'annealing' escape mechanism from local minima, the algorithm is capable of finding the optimum of an IMRT problem as leaf sequences with minimized leaf travel. In particular, the efficiency of static IMRT can be raised to the levels of unmodulated fields with very few field segments, thereby increasing the utility of IMRT in clinical practice.     

In vitro study of cell survival following dynamic MLC intensity-modulated radiation therapy dose delivery

The possibility of reduced cell kill following intensity-modulated radiation therapy (IMRT) compared to conventional radiation therapy has been debated in the literature. This potential reduction in cell kill relates to prolonged treatment times typical of IMRT dose delivery and consequently increased repair of sublethal lesions. While there is some theoretical support to this reduction in cell kill published in the literature, direct experimental evidence specific to IMRT dose delivery patterns is lacking. In this study we present cell survival data for three cell lines: Chinese hamster V79 fibroblasts, human cervical carcinoma, SiHa and colon adenocarcinoma, WiDr. Cell survival was obtained for 2.1 Gy delivered as acute dose with parallel-opposed pair (POP), irradiation time 75 s, which served as a reference; regular seven-field IMRT, irradiation time 5 min; and IMRT with a break for multiple leaf collimator (MLC) re-initialization after three fields were delivered, irradiation time 10 min. An actual seven-field dynamic MLC IMRT plan for a head and neck patient was used. The IMRT plan was generated for a Varian EX or iX linear accelerator with 120 leaf Millenium MLC. Survival data were also collected for doses 1X, 2X, 3X, 4X, and 5x 2.1 Gy to establish parameters of the linear-quadratic equation describing survival following acute dose delivery. Cells were irradiated inside an acrylic cylindrical phantom specifically designed for this study. Doses from both IMRT and POP were validated using ion chamber measurements. A reproducible increase in cell survival was observed following IMRT dose delivery. This increase varied from small for V79, with a surviving fraction of 0.8326 following POP vs 0.8420 following uninterrupted IMRT, to very pronounced for SiHa, with a surviving fraction of 0.3903 following POP vs 0.5330 for uninterrupted IMRT. When compared to IMRT or IMRT with a break for MLC initialization, cell survival following acute dose delivery was significantly different, p < 0.05, in three out of six cases. In contrast, when cell survival following IMRT was compared to that following IMRT with a break for MLC initialization the difference was always statistically insignificant. When projected to a 30 fraction treatment, dose deficit to bring cell survival to the same value as in POP was calculated as 4.1, 24.9, and 31.1 Gy for V79, WiDr, and SiHa cell lines, respectively. The dose deficit did not relate to the alpha/beta ratio obtained in this study for the three cell lines. Clinical data do not show reduction in local control following IMRT. Possible reasons for this are discussed. The obtained data set can serve as a test data set for models designed to explore the effect of dose delivery prolongation/fractionation in IMRT on radiation therapy outcome.     

Enhancement of IMRT delivery through MLC rotation

Multileaf collimator (MLC) based intensity modulated radiation therapy (IMRT) techniques are well established but suffer several physical limitations. Dosimetric spatial resolution is limited by the MLC leaf width; interleaf leakage and tongue-and-groove effects degrade dosimetric accuracy and the range of leaf motion limits the maximum deliverable field size. Collimator rotation is used in standard radiation therapy to improve the conformity of the MLC shape to the target volume. Except for opposed orthogonal fields, collimator rotation has not been exploited in IMRT due to the complexity of deriving the MLC leaf configurations for rotated sub-fields. Here we report on a new way that MLC-based IMRT is delivered which incorporates collimator rotation, providing an extra degree of freedom in deriving leaf sequences for a desired fluence map. Specifically, we have developed a series of unique algorithms that are capable of determining rotated MLC segments. These IMRT fields may be delivered statically (with the collimator rotating to a new position in between sub-fields) or dynamically (with the collimator rotating and leaves moving simultaneously during irradiation). This introductory study provides an analysis of the rotating leaf motion calculation algorithms with focus on radiation efficiency, the range of collimator rotation and number of segments. We then evaluate the technique by characterizing the ability of the algorithms to generate rotating leaf sequences for desired fluence maps. Comparisons are also made between our method and conventional sliding window and step-and-shoot techniques. Results show improvements in spatial resolution, reduced interleaf effects and maximum deliverable field size over conventional techniques. Clinical application of these enhancements can be realized immediately with static rotational delivery although improved dosimetric modelling of the MLC will be required for dynamic delivery.     

Simulations for inverse radiation therapy treatment planning using a dynamic MLC algorithm

The inverse radiation treatment planning model for a dynamic multileaf collimator (MLC) is used to find the optimal solution of planning problem. The model for dynamic MLC is explained in Tervo et al (2003 Appl. Math. Comput. 135 227-50). The advantage of this model is that it optimizes leaf velocity parameters directly. Our algorithm uses a gradient-based local optimization method. Two patient cases, prostate carcinoma and tonsilla carcinoma, are studied. Field arrangements are pre-selected and velocity parameters for MLC leaves are optimized to obtain the prescribed dose in the patient space. In both simulated cases, high dose distribution conforms the planning target volume well and organs-at-risk are saved in most parts. Simulations show that the model has its functionality in patient treatments, although it is still formal and needs further development.     

The impact of MLC transmitted radiation on EPID dosimetry for dynamic MLC beams

The purpose of this study was to experimentally quantify the change in response of an amorphous silicon (a-Si) electronic portal imaging device (EPID) to dynamic multileaf collimator (dMLC) beams with varying MLC-transmitted dose components and incorporate the response into a commercial treatment planning system (TPS) EPID prediction model. A combination of uniform intensity dMLC beams and static beams were designed to quantify the effect of MLC transmission on EPID response at the central axis of 10 x 10 cm2 beams, at off-axis positions using wide dMLC beam profiles, and at different field sizes. The EPID response to MLC transmitted radiation was 0.79 +/- 0.02 of the response to open beam radiation at the central axis of a 10 x 10 cm2 field. The EPID response to MLC transmitted radiation was further reduced relative to the open beam response with off-axis distance. The EPID response was more sensitive to field size changes for MLC transmitted radiation compared to open beam radiation by a factor of up to 1.17 at large field sizes. The results were used to create EPID response correction factors as a function of the fraction of MLC transmitted radiation, off-axis distance, and field size. Software was developed to apply the correction factors to each pixel in the TPS predicted EPID image. The corrected images agreed more closely with the measured EPID images in areas of intensity modulated fields with a large fraction of MLC transmission and, as a result the accuracy of portal dosimetry with a-Si EPIDs can be improved. Further investigation into the detector response function and the radiation source model are required to achieve improvements in accuracy for the general case.     

Spatial dependence of MLC transmission in IMRT delivery

In complex intensity-modulated radiation therapy cases, a considerable amount of the total dose may be delivered through closed leaves. In such cases an accurate knowledge of spatial characteristics of multileaf collimator (MLC) transmission is crucial, especially for the treatment of large targets with split fields. Measurements with an ionization chamber, radiographic films (EDR2, EBT) and EPID are taken to characterize all relevant effects related to MLC transmission for various field sizes and depths. Here we present a phenomenological model to describe MLC transmission, whereby the main focus is the off-axis decrease of transmission for symmetric and asymmetric fields as well as on effects due to the tongue and groove design of the leaves, such as interleaf transmission and the tongue and groove effect. Data obtained with the four different methods are presented, and the utility of each measurement method to determine the necessary model parameters is discussed. With the developed model, it is possible to predict the relevant MLC effects at any point in the phantom for arbitrary jaw settings and depths.     

Communication and sampling rate limitations in IMRT delivery with a dynamic multileaf collimator system

The delivery of an intensity modulated radiation field with a dynamic multileaf collimator (MLC) requires precise correlation between MLC positions and cumulative monitor units (MUs). The purpose of this study is to investigate the precision of this correlation as a function of delivered MUs and dose rate. A semi-Gaussian shaped intensity profile and a simple geometric intensity pattern consisting of four square segments were designed to deliver a total of 1, 4, 16, 64, and 100 MUs at three different dose rates of 100, 400, and 600 MU/min. The semi-Gaussian intensity pattern was delivered using both sliding window and step and shoot techniques. The dose profiles of this intensity pattern were measured with films. The four square intensity pattern was delivered using step and shoot and conventional delivery techniques for comparison. Because of geometrical symmetry, the dose to each segment in this intensity pattern is expected to be the same when the same MU is assigned to each segment. An ionization chamber was used to measure the dose in the center of each of the four square segments. For the semi-Gaussian shaped profile, significant artifacts were observed when the profile was delivered with small MUs and/or at a high dose rate. For the four square intensity pattern, the dose measured in each segment presented a large variation when delivered with small MUs and a high dose rate. The variation increases as the MU/segment decreases and as the dose rate increases. These MU and dose rate dependencies were not observed when the intensity pattern was delivered using a conventional delivery technique. The observed distortion of the semi-Gaussian profile and dose variations among the segments of the four square intensity pattern are explained by considering the sampling rate and the communication time lag between the control systems. Finally, clinical significance is discussed.     

IMRT delivery to a moving target by dynamic MLC tracking: delivery for targets moving in two dimensions in the beam's eye view

A new modification of the dynamic multileaf collimator (dMLC) delivery technique for intensity-modulated therapy (IMRT) is outlined. This technique enables the tracking of a target moving through rigid-body translations in a 2D trajectory in the beam's eye view. The accuracy of the delivery versus that of deliveries with no tracking and of 1D tracking techniques is quantified with clinically derived intensity-modulated beams (IMBs). Leaf trajectories calculated in the target-reference frame were iteratively synchronized assuming regular target motion. This allowed the leaves defined in the lab-reference frame to simultaneously follow the target motion and to deliver the required IMB without violation of the leaf maximum-velocity constraint. The leaves are synchronized until the gradient of the leaf position at every instant is less than a calculated maximum. The delivered fluence in the target-reference frame was calculated with a simple primary-fluence model. The new 2D tracking technique was compared with the delivered fluence produced by no-tracking deliveries and by 1D tracking deliveries for 33 clinical IMBs. For the clinical IMBs normalized to a maximum fluence of 200 MUs, the rms difference between the desired and the delivered IMB was 15.6 +/- 3.3 MU for the case of a no-tracking delivery, 7.9 +/- 1.6 MU for the case where only the primary component of motion was corrected and 5.1 +/- 1.1 MU for the 2D tracking delivery. The residual error is due to interpolation and sampling effects. The 2D tracking delivery technique requires an increase in the delivery time evaluated as between 0 and 50% of the unsynchronized delivery time for each beam with a mean increase of 13% for the IMBs tested. The 2D tracking dMLC delivery technique allows an optimized IMB to be delivered to moving targets with increased accuracy and with acceptable increases in delivery time. When combined with real-time knowledge of the target motion at delivery time, this technique facilitates improved target conformality relative to no-tracking deliveries and allows PTV margin reduction.     

Monte Carlo dose calculation of segmental IMRT delivery to a moving phantom using dynamic MLC and gating log files

Respiratory gating is emerging as a tool to limit the effect of motion for liver and lung tumors. In order to study the impact of target motion and gated intensity modulated radiation therapy (IMRT) delivery, a computer program was developed to simulate segmental IMRT delivery to a moving phantom. Two distinct plans were delivered to a rigid-motion phantom with a film insert in place under four conditions: static, sinusoidal motion, gated sinusoidal motion with a duty cycle of 25% and gated sinusoidal motion with duty cycle of 50% under motion conditions of a typical patient (A = 1 cm, T = 4 s). The MLC controller log files and gating log files were retained to perform a retrospective Monte Carlo dose calculation of the plans. Comparison of the 2D planar dose distributions between simulation and measurement demonstrated that our technique had at least 94% of the points passing gamma criteria of 3% for dose difference and 3 mm as the distance to agreement. This note demonstrates that the use of dynamic multi-leaf collimator and respiratory monitoring system log files together with a fast Monte Carlo dose calculation algorithm is an accurate and efficient way to study the dosimetric effect of motion for gated or non-gated IMRT delivery on a rigidly-moving body.     

Incorporation of heparin into biomaterials

This review provides an overview of the incorporation of heparin into biomaterials with a focus on drug delivery and the use of heparin-based biomaterials for self-assembly of polymer networks. Heparin conjugation to biomaterials was originally explored to reduce the thrombogenicity of materials in contact with blood. Many of the conjugation strategies that were developed for these applications are still popular today for other applications. More recently heparin has been conjugated to biomaterials for drug delivery applications. Many of the delivery approaches have taken advantage of the ability of heparin to bind to a wide variety of growth factors, protecting them from degradation and potentiating interactions with cell surface receptors. More recently, the use of heparin as a base polymer for scaffold fabrication has also been explored, often utilizing non-covalent binding of heparin with peptides or proteins to promote self-assembly of hydrogel networks. This review will highlight recent advances in each of these areas.     

Incorporation of proteinase inhibitors into silk-based delivery devices for enhanced control of degradation and drug release

Controlling the rate of silk degradation is critical to its potential use in biomedical applications, including drug delivery and tissue engineering. The effect of protease concentration on accelerating degradation, and the use of ethylenediamine tetraacetic acid (EDTA) on reducing rates of degradation and on drug release from silk-based drug carriers was studied. Increased rates of proteolysis resulted in increased dye release from silk carriers, while EDTA release from the silk carriers inhibited proteolysis. The sustained release of EDTA from silk carriers in combination with the release of the small molecule anti-convulsant adenosine was investigated in vitro. This combination of factors resulted in delayed release of adenosine by inhibiting proteolytic activity. These results introduce a promising strategy to control drug delivery through the regulation of silk degradation rate, achieved via manipulation of local proteolytic activity. This ability to modulate enzyme function could be applicable to a range of silk biomaterial formats as well as other biodegradable polymers where enzymatic functions control biomaterial degradation and drug release rates.     

Dosimetric discrepancies caused by differing MLC parameters for dynamic IMRT

Radiotherapy patients will from time to time be treated on another linac than originally planned due to service or logistical challenges. For patients treated with dynamic intensity modulated radiotherapy (IMRT), extra care should be taken to make sure the delivered dose remains as planned. Four linacs with the same type of dynamic multileaf collimator (MLC) were compared to find a general prediction of the potential dosimetric error caused by treating IMRT patients on another linac without recalculating the treatment plan. The MLC parameters, transmission and dosimetric leaf separation (DLS) were measured for all four linacs. The dynamic fields that were measured to find the DLS value were imported into the treatment planning system to compare the calculated and measured doses. Measured values of transmission and DLS were used directly in the calculations to obtain dose differences of less than 1% between the calculated and measured doses at the reference setup. The dosimetric discrepancy between the linacs was acceptable for all but one linac. Recalculation of the treatment plan therefore remains as standard procedure for this linac when a planned patient must switch linac during the course of treatment. The depth and field size dependences of the MLC parameters were also tested, finding dose differences of up to 4%.     

Leaf transmission reduction using moving jaws for dynamic MLC IMRT

The aim of this work is to investigate to what extent it is possible to use the secondary collimator jaws to reduce the transmitted radiation through the multileaf collimator (MLC) during an intensity modulated radiation therapy (IMRT). A method is developed and introduced where the jaws follow the open window of the MLC dynamically (dJAW method). With the aid of three academic cases (Closed MLC, Sliding-gap, and Chair) and two clinical cases (prostate and head and neck) the feasibility of the dJAW method and the influence of this method on the applied dose distributions are investigated. For this purpose the treatment planning system Eclipse and the Research-Toolbox were used as well as measurements within a solid water phantom were performed. The transmitted radiation through the closed MLC leads to an inhomogeneous dose distribution. In this case, the measured dose within a plane perpendicular to the central axis differs up to 40% (referring to the maximum dose within this plane) for 6 and 15 MV. The calculated dose with Eclipse is clearly more homogeneous. For the Sliding-gap case this difference is still up to 9%. Among other things, these differences depend on the depth of the measurement within the solid water phantom and on the application method. In the Chair case, the dose in regions where no dose is desired is locally reduced by up to 50% using the dJAW method instead of the conventional method. The dose inside the chair-shaped region decreased up to 4% if the same number of monitor units (MU) as for the conventional method was applied. The undesired dose in the volume body minus the planning target volume in the clinical cases prostate and head and neck decreased up to 1.8% and 1.5%, while the number of the applied MU increased up to 3.1% and 2.8%, respectively. The new dJAW method has the potential to enhance the optimization of the conventional IMRT to a further step.