Jong H. Kung

An experimental investigation on intra-fractional organ motion effects in lung IMRT treatments

Respiration-induced tumour motion can potentially compromise the use of intensity-modulated radiotherapy (IMRT) as a dose escalation tool for lung tumour treatment. We have experimentally investigated the intra-fractional organ motion effects in lung IMRT treatments delivered by multi-leaf collimator (MLC). An in-house made motor-driven platform, which moves sinusoidally with an amplitude of 1 cm and a period of 4 s, was used to mimic tumour motion. Tumour motion was simulated along cranial-caudal direction while MLC leaves moved across the patient from left to right, as in most clinical cases. The dose to a point near the centre of the tumour mass was measured according to geometric and dosimetric parameters from two five-field lung IMRT plans. For each field, measurement was done for two dose rates (300 and 500 MU min(-1)), three MLC delivery modes (sliding window, step-and-shoot with 10 and 20 intensity levels) and eight equally spaced starting phases of tumour motion. The dose to the measurement point delivered from all five fields was derived for both a single fraction and 30 fractions by randomly sampling from measured dose values of each field at different initial phases. It was found that the mean dose to a moving tumour differs slightly (<2-3%) from that to a static tumour. The variation in breathing phase at the start of dose delivery results in a maximum variation around the mean dose of greater than 30% for one field. The full width at half maximum for the probability distribution of the point dose is up to 8% for all five fields in a single fraction, but less than 1-2% after 30 fractions. In general, lower dose rate can reduce the motion-caused dose variation and therefore might be preferable for lung IMRT when no motion mitigation techniques are used. From the two IMRT cases we studied where tumour motion is perpendicular to MLC leaf motion, the dose variation was found to be insensitive to the MLC delivery mode.

A monitor unit verification calculation in intensity modulated radiotherapy as a dosimetry quality assurance.

In standard teletherapy, a treatment plan is generated with the aid of a treatment planning system, but it is common to perform an independent monitor unit verification calculation (MUVC). In exact analogy, we propose and demonstrate that a simple and accurate MUVC in intensity modulated radiotherapy (IMRT) is possible. We introduce the concept of modified Clarkson integration (MCI). In MCI, we exploit the rotational symmetry of scattering to simplify the dose calculation. For dose calculation along a central axis (CAX), we first replace the incident IMRT fluence by an azimuthally averaged fluence. Second, the Clarkson integration is carried over annular sectors instead of over pie sectors. We wrote a computer code, implementing the MCI technique, in order to perform a MUVC for IMRT purposes. We applied the code to IMRT plans generated by CORVUS. The input to the code consists of CORVUS plan data (e.g., DMLC files, jaw settings, MU for each IMRT field, depth to isocenter for each IMRT field), and the output is dose contribution by individual IMRTs field to the isocenter. The code uses measured beam data for Sc, Sp, TPR, (D/MU)ref and includes effects from multileaf collimator transmission, and radiation field offset. On a 266 MHz desktop computer, the code takes less than 15 to calculate a dose. The doses calculated with the MCI algorithm agreed within +/-3% with the doses calculated by CORVUS, which uses a 1 cm x 1 cm pencil beam in dose calculation. In the present version of MCI, skin contour variations and inhomogeneities were neglected.

Dependence of fluence errors in dynamic IMRT on leaf-positional errors varying with time and leaf number

In d-MLC based IMRT, leaves move along a trajectory that lies within a user-defined tolerance (TOL) about the ideal trajectory specified in a d-MLC sequence file. The MLC controller measures leaf positions multiple times per second and corrects them if they deviate from ideal positions by a value greater than TOL. The magnitude of leaf-positional errors resulting from finite mechanical precision depends on the performance of the MLC motors executing leaf motions and is generally larger if leaves are forced to move at higher speeds. The maximum value of leaf-positional errors can be limited by decreasing TOL. However, due to the inherent time delay in the MLC controller, this may not happen at all times. Furthermore, decreasing the leaf tolerance results in a larger number of beam hold-offs, which, in turn leads, to a longer delivery time and, paradoxically, to higher chances of leaf-positional errors (< or = TOL). On the other end, the magnitude of leaf-positional errors depends on the complexity of the fluence map to be delivered. Recently, it has been shown that it is possible to determine the actual distribution of leaf-positional errors either by the imaging of moving MLC apertures with a digital imager or by analysis of a MLC log file saved by a MLC controller. This leads next to an important question: What is the relation between the distribution of leaf-positional errors and fluence errors. In this work, we introduce an analytical method to determine this relation in dynamic IMRT delivery. We model MLC errors as Random-Leaf Positional (RLP) errors described by a truncated normal distribution defined by two characteristic parameters: a standard deviation sigma and a cut-off value deltax0 (deltaxo approximately TOL). We quantify fluence errors for two cases: (i) deltax0 >> sigma (unrestricted normal distribution) and (ii) deltax0 << sigma (deltax0--limited normal distribution). We show that an average fluence error of an IMRT field is proportional to (i) sigma/ALPO and (ii) deltax0/ALPO, respectively, where ALPO is an Average Leaf Pair Opening (the concept of ALPO was previously introduced by us in Med. Phys. 28, 2220-2226 (2001). Therefore, dose errors associated with RLP errors are larger for fields requiring small leaf gaps. For an N-field IMRT plan, we demonstrate that the total fluence error (if we neglect inhomogeneities and scatter) is proportional to 1/square root of N, where N is the number of fields, which slightly reduces the impact of RLP errors of individual fields on the total fluence error. We tested and applied the analytical apparatus in the context of commercial inverse treatment planning systems used in our clinics (Helios and BrainScan). We determined the actual distribution of leaf-positional errors by studying MLC controller (Varian Mark II and Brainlab Novalis MLCs) log files created by the controller after each field delivery. The analytically derived relationship between fluence error and RLP errors was confirmed by numerical simulations. The equivalence of relative fluence error to relative dose error was verified by a direct dose calculation. We also experimentally verified the truthfulness of fluences derived from the log file data by comparing them to film data.

Intensity modulated radiotherapy dose delivery error from radiation field offset inaccuracy.

In Intensity Modulated Radiotherapy (IMRT), irradiation is delivered in a number of small aperture subfields. The fluences shaped by these small apertures are highly sensitive to inaccuracies in multileaf collimator (MLC) calibration. The Radiation Field Offset (RFO) is the difference between a radiation and a light field at the Source to Axis Distance (SAD) for a MLC. An Intensity Modulated Radiotherapy (IMRT) system must incorporate a RFO by closing in all leaf openings. In IMRT, RFO inaccuracy will result in a dose error to the interior of a target volume. We analyze dosimetric consequences of incorporating a wrong RFO into the CORVUS, 1 cm x 1 cm, step and shoot, IMRT system. The following method was employed. First an IMRT plan is generated for a target volume in a phantom, which produces a set of dynamic MLC (DMLC) files with the correct RFO value. To simulate delivery with a wrong RFO value, we wrote a computer code that reads in the DMLC file with the correct RFO value and produces another DMLC with an incorrect RFO specified by a user. Finally the phantom was irradiated with the correct and the incorrect RFO valued DMLC files, and the doses were measured with an ionization chamber. The method was applied to 9 fields, 6 MV, IMRT plans. We measured Dose Error Sensitivity Factor (DESF) for each plan, which ranged from (0-8)% mm(-1). The DESF(x) is defined as a fractional dose error to a point (x) in a target volume per mm of the RFO error, i.e., DESF(x) is equivalent to ¿deltaD(x)/D(x)deltaRFO¿. Therefore, we concluded that for CORVUS, 6 MV, 1 cm x 1 cm, step and shoot IMRT, RFO must be determined within an accuracy of 0.5 mm if a fractional dose error to a target volume is to be less than 4%. We propose an analytic framework to understand the measured DESFs. From the analysis we conclude that a large DESF was associated with an DMLC file with small average leaf openings. For 1 cm x 1 cm, step and shoot IMRT, the largest possible DESF is predicted to be 20% mm(-1). In addition, we wrote computer code that can calculate a DESF of a DMLC file. The code was written in Mathematica 3.0. The code can be used to screen patient IMRT plans that are highly sensitive to a RFO error.

A method of calculating a lung clinical target volume DVH for IMRT with intrafractional motion

The motion of lung tumors from respiration has been reported in the literature to be as large as 1-2 cm. This motion requires an additional margin between the Clinical Target Volume (CTV) and the Planning Target Volume (PTV). In Intensity Modulated Radiotherapy (IMRT), while such a margin is necessary, the margin may not be sufficient to avoid unintended high and low dose regions to the interior on moving CTV. Gated treatment has been proposed to improve normal tissues sparing as well as to ensure accurate dose coverage of the tumor volume. The following questions have not been addressed in the literature: (a) what is the dose error to a target volume without a gated IMRT treatment? (b) What is an acceptable gating window for such a treatment. In this study, we address these questions by proposing a novel technique for calculating the three-dimensional (3-D) dose error that would result if a lung IMRT plan were delivered without a gated linac beam. The method is also generalized for gated treatment with an arbitrary triggering window. IMRT plans for three patients with lung tumors were studied. The treatment plans were generated with HELIOS for delivery with 6 MV on a CL2100 Varian linear accelerator with a 26 pair MLC. A CTV to PTV margin of 1 cm was used. An IMRT planning system searches for an optimized fluence map phi(x,y) for each port, which is then converted into a dynamic MLC file (DMLC). The DMLC file contains information about MLC subfield shapes and the fractional Monitor Units (MUs) to be delivered for each subfield. With a lung tumor, a CTV that executes a quasiperiodic motion z(t) does not receive phi(x,y), but rather an Effective Incident Fluence EIF(x,y). We numerically evaluate the EIF(x,y) from a given DMLC file by a coordinate transformation to the Targets Eye View (TEV). In the TEV coordinate system, the CTV itself is stationary, and the MLC is seen to execute a motion -z(t) that is superimposed on the DMLC motion. The resulting EIF(x,y) is input back into the dose calculation engine to estimate the 3-D dose to a moving CTV. In this study, we model respiratory motion as a sinusoidal function with an amplitude of 10 mm in the superior-inferior direction, a period of 5 s, and an initial phase of zero.

Method of identifying dynamic multileaf collimator irradiation that is highly sensitive to a systematic MLC calibration error.

In intensity modulated radiotherapy (IMRT), radiation is delivered in a multiple of multileaf collimator (MLC) subfields. A subfield with a small leaf-to-leaf opening is highly sensitive to a leaf-positional error. We introduce a method of identifying and rejecting IMRT plans that are highly sensitive to a systematic MLC gap error (sensitivity to possible random leaf-positional errors is not addressed here). There are two sources of a systematic MLC gap error: centerline mechanical offset (CMO) and, in the case of a rounded end MLC, radiation field offset (RFO). In IMRT planning system, using an incorrect value of RFO introduces a systematic error ARFO that results in all leaf-to-leaf gaps that are either too large or too small by (2*DeltaRFO), whereas assuming that CMO is zero introduces systematic error DeltaCMO that results in all gaps that are too large by DeltaCMO=CMO. We introduce a concept of the average leaf pair Opening (ALPO) that can be calculated from a dynamic MLC delivery file. We derive an analytic formula for a fractional average fluence error resulting from a systematic gap error of Deltax and show that it is inversely proportional to ALPO; explicitly it is equal to Deltax/(ALPO+ 2 * RFO+ epsilon), in which epsilon is generally of the order of 1 mm and Deltax =2 * Delta RFO + CMO. This analytic relationship is verified with independent numerical calculations.

Four-Dimensional Imaging and Treatment Planning of Moving Targets

Four-dimensional CT acquisition is commercially available, and provides important information on the shape and trajectory of the tumor and normal tissues. The primary advantage of four-dimensional imaging over light breathing helical scans is the reduction of motion artifacts during scanning that can significantly alter tumor appearance. Segmentation, image registration, visualization are new challenges associated with four-dimensional data sets because of the overwhelming increase in the number of images. Four-dimensional dose calculations, while currently laborious, provide insights into dose perturbations due to organ motion. Imaging before treatment (image guidance) improves accuracy of radiation delivery, and recording transmission images can provide a means of verifying gated delivery.

Intensity-modulated radiotherapy for a prostate patient with a metal prosthesis.

When treating prostate patients having a metallic prosthesis with radiation, a 3D conformal radiotherapy (3DCRT) treatment plan is commonly created using only those fields that avoid the prosthesis in the beams-eye view (BEV). With a limited number of portals, the resulting plan may compromise the dose sparing of the rectum and bladder. In this work, we investigate the feasibility of using intensity-modulated radiotherapy (IMRT) to treat prostate patients having a metallic prosthesis. Three patients, each with a single metallic prosthesis, who were previously treated at the University of Chicago Medical Center for prostate cancer, were selected for this study. Clinical target volumes (CTV = prostate + seminal vesicles), bladder, and rectum volumes were identified on CT slices. Planning target volumes (PTV) were generated in 3D by a 1-cm expansion of the CTVs. For these comparative studies, treatment plans were generated from CT data using 3DCRT and IMRT treatment planning systems. The IMRT plans used 9 equally-spaced 6-MV coplanar fields, with each field avoiding the prosthesis. The 3DCRT plans used 5 coplanar 18-MV fields, with each field avoiding the prosthesis. A 1-cm margin around the PTV was used for the blocks. Each of the 9-field IMRT plans spared the bladder and rectum better than the corresponding 3DCRT plan. In the IMRT, plans, a bladder volume receiving 80% or greater dose decreased by 20-77 cc, and a volume rectal volume receiving 80% or greater dose decreased by 24-40 cc. One negative feature of the IMRT plans was the homogeneity across the target, which ranged from 95% to 115%.

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.

Disruption of SLX4-MUS81 Function Increases the Relative Biological Effectiveness of Proton Radiation

PURPOSE Clinical proton beam therapy has been based on the use of a generic relative biological effectiveness (RBE) of ∼1.1. However, emerging data have suggested that Fanconi anemia (FA) and homologous recombination pathway defects can lead to a variable RBE, at least in vitro. We investigated the role of SLX4 (FANCP), which acts as a docking platform for the assembly of multiple structure-specific endonucleases, in the response to proton irradiation. METHODS AND MATERIALS Isogenic cell pairs for the study of SLX4, XPF/ERCC1, MUS81, and SLX1 were irradiated at the mid-spread-out Bragg peak of a clinical proton beam (linear energy transfer 2.5 keV/μm) or with 250 kVp x-rays, and the clonogenic survival fractions were determined. To estimate the RBE of the protons relative to cobalt-60 photons (Co60Eq), we assigned a RBE(Co60Eq) of 1.1 to x-rays to correct the physical dose measured. Standard DNA repair foci assays were used to monitor the damage responses, and the cell cycle distributions were assessed by flow cytometry. The poly(ADP-ribose) polymerase inhibitor olaparib was used for comparison. RESULTS Loss of SLX4 function resulted in an enhanced proton RBE(Co60Eq) of 1.42 compared with 1.11 for wild-type cells (at a survival fraction of 0.1; P<.05), which correlated with increased persistent DNA double-strand breaks in cells in the S/G2 phase. Genetic analysis identified the SLX4-binding partner MUS81 as a mediator of resistance to proton radiation. Both proton irradiation and olaparib treatment resulted in a similar prolonged accumulation of RAD51 foci in SLX4/MUS81-deficient cells, suggesting a common defect in the repair of DNA replication fork-associated damage. CONCLUSIONS A defect in the FA pathway at the level of SLX4 results in hypersensitivity to proton radiation, which is, at least in part, due to impaired MUS81-mediated processing of replication forks that stall at clustered DNA damage. In vivo and clinical studies are needed to confirm these findings in human cancers.