Isodoses-a set theory-based patient-specific QA measure to compare planned and delivered isodose distributions in photon radiotherapy.

BACKGROUND: The gamma index and dose-volume histogram (DVH)-based patient-specific quality assurance (QA) measures commonly applied in radiotherapy planning are unable to simultaneously deliver detailed locations and magnitudes of discrepancy between isodoses of planned and delivered dose distributions. By exploiting statistical classification performance measures such as sensitivity or specificity, compliance between a planned and delivered isodose may be evaluated locally, both for organs-at-risk (OAR) and the planning target volume (PTV), at any specified isodose level. Thus, a patient-specific QA tool may be developed to supplement those presently available in clinical radiotherapy. MATERIALS AND METHODS: A method was developed to locally establish and report dose delivery errors in three-dimensional (3D) isodoses of planned (reference) and delivered (evaluated) dose distributions simultaneously as a function the dose level and of spatial location. At any given isodose level, the total volume of delivered dose containing the reference and the evaluated isodoses is locally decomposed into four subregions: true positive-subregions within both reference and evaluated isodoses, true negative-outside of both of these isodoses, false positive-inside the evaluated isodose but not the reference isodose, and false negatives-inside the reference isodose but not the evaluated isodose. Such subregions may be established over the whole volume of delivered dose. This decomposition allows the construction of a confusion matrix and calculation of various indices to quantify the discrepancies between the selected planned and delivered isodose distributions, over the complete range of values of dose delivered. The 3D projection and visualization of the spatial distribution of these discrepancies facilitates the application of the developed method in clinical practice. RESULTS: Several clinical photon radiotherapy plans were analyzed using the developed method. In some plans at certain isodose levels, dose delivery errors were found at anatomically significant locations. These errors were not otherwise highlighted-neither by gamma analysis nor by DVH-based QA measures. A specially developed 3D projection tool to visualize the spatial distribution of such errors against anatomical features of the patient aids in the proposed analysis of therapy plans. CONCLUSIONS: The proposed method is able to spatially locate delivery errors at selected isodose levels and may supplement the presently applied gamma analysis and DVH-based QA measures in patient-specific radiotherapy planning.

Are gamma passing rate and dose-volume histogram QA metrics correlated?

PURPOSE: The quality of a measured distribution of dose delivered against its corresponding radiotherapy plan is routinely assessed by gamma index (GI) and dose-volume histogram (DVH) metrics. Any correlation between error detection rates, as based on either of these approaches, while argued, has never been convincingly demonstrated. The dependence of the strength of correlation between the GI passing rate ( γ P ) and DVH quality assurance (QA) metrics on various elements of the therapy plan has not been systematically investigated. METHODS: A formal analysis of the relation between γ P and DVH metrics has been undertaken, leading to a relationship which may partly approximate γ P with respect to the DVH. This relationship was further validated by studying examples of simulated clinical radiotherapy plans and by studying the correlation between γ P and the derived relationship using a simple two-dimensional representations of the planning target volume (PTV) and organs at risk (OAR), where penumbra regions, distance-to-agreement tolerances and dose delivery errors were systematically varied. RESULTS: It is shown formally that there cannot be any correlation between γ P and other commonly applied DVH-derived QA measures. However, γ P may be partly approximated given the planned and measured DVH. The derived γ P approximation (the " γ -slope indicator") may be clinically useful in some practical cases of radiotherapy plan QA. CONCLUSIONS: In formal terms, there cannot be any correlation between γ P and any common DVH-calculated patient-specific measures, with respect to PTV or OAR. However, as demonstrated analytically and further confirmed in our simulation studies, the γ P approximation derived in this study (the " γ -slope indicator") may in some cases offer a degree of correlation between γ P and the PTV and OAR DVH QA metrics in measured and planned patient-specific dose distributions-which may be potentially useful in clinical practice.

DeepBeam: a machine learning framework for tuning the primary electron beam of the PRIMO Monte Carlo software.

BACKGROUND: Any Monte Carlo simulation of dose delivery using medical accelerator-generated megavolt photon beams begins by simulating electrons of the primary electron beam interacting with a target. Because the electron beam characteristics of any single accelerator are unique and generally unknown, an appropriate model of an electron beam must be assumed before MC simulations can be run. The purpose of the present study is to develop a flexible framework with suitable regression models for estimating parameters of the model of primary electron beam in simulators of medical linear accelerators using real reference dose profiles measured in a water phantom. METHODS: All simulations were run using PRIMO MC simulator. Two regression models for estimating the parameters of the simulated primary electron beam, both based on machine learning, were developed. The first model applies Principal Component Analysis to measured dose profiles in order to extract principal features of the shapes of the these profiles. The PCA-obtained features are then used by Support Vector Regressors to estimate the parameters of the model of the electron beam. The second model, based on deep learning, consists of a set of encoders processing measured dose profiles, followed by a sequence of fully connected layers acting together, which solve the regression problem of estimating values of the electron beam parameters directly from the measured dose profiles. Results of the regression are then used to reconstruct the dose profiles based on the PCA model. Agreement between the measured and reconstructed profiles can be further improved by an optimization procedure resulting in the final estimates of the parameters of the model of the primary electron beam. These final estimates are then used to determine dose profiles in MC simulations. RESULTS: Analysed were a set of actually measured (real) dose profiles of 6 MV beams from a real Varian 2300 C/D accelerator, a set of simulated training profiles, and a separate set of simulated testing profiles, both generated for a range of parameters of the primary electron beam of the Varian 2300 C/D PRIMO simulator. Application of the two-stage procedure based on regression followed by reconstruction-based minimization of the difference between measured (real) and reconstructed profiles resulted in achieving consistent estimates of electron beam parameters and in a very good agreement between the measured and simulated photon beam profiles. CONCLUSIONS: The proposed framework is a readily applicable and customizable tool which may be applied in tuning virtual primary electron beams of Monte Carlo simulators of linear accelerators. The codes, training and test data, together with readout procedures, are freely available at the site: https://github.com/taborzbislaw/DeepBeam .

Chemopotentiating effects of low-dose fractionated radiation on cisplatin and paclitaxel in cervix cancer cell lines and normal fibroblasts from patients with cervix cancer.

The aim of the present study was to compare the effects (assessed by clonogenic survival and γH2AX foci assays) of low-dose fractionated radiation LDFR (4 × 0.125 Gy, 4 × 0.25 Gy and 4 × 0.5 Gy) versus single radiation doses (0.5 Gy, 1 Gy and 2 Gy) on cisplatin and paclitaxel in HRS-negative cervix cancer cell lines SiHa and CaSki to see if the effects of LDFR can emerge in cells that not present low-dose hyper-radiosensitivity (HRS) phenomenon. Additionally, we report the effects in normal fibroblasts (HRS-negative and HRS-positive) from two patients with cervix cancer to see if the chemopotentiating effects of LDFR also apply to normal cells. LDFR (4 × 0.125 Gy, 4 × 0.25 Gy and 4 × 0.5 Gy) as well as single doses (0.5 Gy, 1 Gy and 2 Gy) enhanced cytotoxicity of cisplatin and paclitaxel in all the cell lines. Cisplatin-potentiating effects were maximum with LDFR 4 × 0.5 Gy, and were two-fold greater than those with a single dose of 2 Gy in SiHa, CaSki and HFIB2 cells. Paclitaxel-enhancing effects were also maximum with LDFR 4 × 0.5 Gy, however only in HRS-positive HFIB2 fibroblasts were significantly greater than those with a single dose of 2 Gy. The results demonstrate that LDFR may enhance the effects of cisplatin and paclitaxel in SiHa and CaSki cells, although they lack HRS phenomenon, and show that the magnitude of the potentiating effects of LDFR depends on cytostatic type and the size of low doses. In normal fibroblasts the chemopotentiating effects of LDFR seem to depend on HRS status. In conclusion, the unique enhancing effects of LDFR on cisplatin in cervical cancer cell lines, even when HRS negative, suggest that all patients with cervical cancer may benefit from the addition of LDFR to adjuvant cisplatin-based chemotherapy.

Statistical approach to the selection of the tolerances for distance to agreement improves the quality control of the dose delivery in radiotherapy.

In the study, a local approach to setting reference tolerance values for the distance-to-agreement (DTA) component of the gamma index is proposed. The reference tolerance values are calculated in simulations, following a dose delivery model presented in a previous work. An analytical model for determining the quantiles of DTA distribution is also proposed and verified. It is shown that the distributions of DTA values normalized with either quantiles or standard deviation of DTA distributions are universal over analyzed plans and points within a single plan. This enables statistically sound inference about the quality of dose delivery. In particular, based on the normalized distributions the comparison of planned and delivered doses can be formulated within the framework of statistical inference as a problem of multiple statistical testing. For every evaluated point P of a plan, one may formulate and test a null hypothesis that there is no delivery error against an alternative hypothesis that there is a delivery error in P. It is also shown that the proposed approach is more sensitive than the current standard approach to shift errors in high dose gradient regions.

A simulation-based method for evaluating geometric tests of a linac c-arm in quality control in radiotherapy.

PURPOSE: Assessment of the accuracy of geometric tests of a linac used in external beam therapy is crucial for ensuring precise dose delivery. In this paper, a new simulation-based method for assessing accuracy of such geometric tests is proposed and evaluated on a set of testing procedures. METHODS: Linac geometry testing methods used in this study are based on an established design of a two-module phantom. Electronic portal imaging device (EPID) images of fiducial balls contained in these modules can be used to automatically reconstruct linac geometry. The projection of the phantom modules fiducial balls onto the EPID detector plane is simulated for assumed nominal geometry of a linac. Then, random errors are added to the coordinates of the projections of the centers of the fiducial balls and the linac geometry is reconstructed from these data. RESULTS: Reconstruction is performed for a set of geometric test designs and it is shown how the dispersion of the reconstructed values of geometric parameters depends on the design of a geometric test. Assuming realistic accuracy of EPID image analysis, it is shown that for selected testing plans the reconstruction accuracy of geometric parameters can be significantly better than commonly used action thresholds for these parameters. CONCLUSIONS: Proposed solution has the potential to improve geometric testing design and practice. It is an important part of a fully automated geometric testing solution.

Use of statistical approaches to improve the quality control of the dose delivery in radiotherapy.

The gamma index is a measure used routinely for the quality control of dose delivery in radiotherapy, implemented in commercial systems for the verification of treatment plans. It involves comparison of the difference between planned and delivered doses to a single reference. The same reference value is selected for all points in the plan that can potentially hide dose delivery errors, especially in medium and low dose areas. In this study, a receiver operating characteristic analysis is used to demonstrate the limits of the performance of the global gamma index as a method for detecting dose delivery errors. The performance of a global gamma index is compared with two approaches based on statistical tests for outlier detection. Two statistical approaches are considered: according to the first, the distribution of the delivered doses is estimated based on an appropriate calibration procedure. According to the second, the distribution of the delivered doses is estimated based on the detection of relatively homogeneous regions of a plan and analyzing the distributions of planned doses within these regions. The performance of the three approaches is compared based on analytical considerations and in simulations in which errors are intentionally introduced to the plan delivery and noise related to dose delivery is modeled. We have shown that a statistics-based approach to gamma analysis generally leads to better detection of true delivery errors. The results of analytical consideration coincide with the simulations. In simulations, we observe that both statistical approaches are better detectors of true delivery errors than the global method for the gamma-index passing rate in the range from 0.9-1.0. It is shown that the global gamma index is a weak detector of dose delivery errors, which in some circumstances behaves only slightly better than a purely random classifier.

INVESTIGATION OF SECONDARY MIXED RADIATION FIELD AROUND A MEDICAL LINEAR ACCELERATOR.

The aim of this study is to investigate secondary mixed radiation field around linac, as the first part of an overall assessment of out-of-field contribution of neutron dose for new advanced radiation dose delivery techniques. All measurements were performed around Varian Clinic 2300 C/D accelerator at Maria Sklodowska-Curie Memorial, Cancer Center and Institute of Oncology, Krakow Branch. Recombination chambers REM-2 and GW2 were used for recombination index of radiation quality Q4 determination (as an estimate of quality factor Q), measurement of total tissue dose Dt and calculation of gamma and neutron components to Dt. Estimation of Dt and Q4 allowed for the ambient dose equivalent H*(10) per monitor unit (MU) calculations. Measurements around linac were performed on the height of the middle of the linac's head (three positions) and on the height of the linac's isocentre (five positions). Estimation of secondary radiation level was carried out for seven different configurations of upper and lower jaws position and multileaf collimator set open or closed in each position. Study includes the use of two photon beam modes: 6 and 18 MV. Spatial distribution of ambient dose equivalent H*(10) per MU on the height of the linac's head and on the standard couch height for patients during the routine treatment, as well as relative contribution of gamma and neutron secondary radiation inside treatment room were evaluated.

Low-Dose Hypersensitive Response for Residual pATM and γH2AX Foci in Normal Fibroblasts of Cancer Patients.

PURPOSE: To define the dose-response relationship for initial and residual pATM and γH2AX foci and temporal response of pATM foci in fibroblasts of 4 hyper-radiosensitivity (HRS)-positive cancer patients and 8 HRS-negative cancer patients and answer the question regarding the role of DNA double-strand break (DSB) recognition and repair in the mechanism of HRS. METHODS AND MATERIALS: The cells were irradiated with single doses (0.1-4 Gy) of 6-MV X rays. The number of initial and residual pATM and γH2AX foci was assessed 1 hour and 24 hours after irradiation, respectively. Kinetics of DSB recognition and repair was estimated by pATM foci assay after irradiation with 0.2 and 2 Gy. RESULTS: Hyper-radiosensitivity response (confirmed by the induced-repair model) was clearly evident for residual pATM and γH2AX foci in fibroblasts of HRS-positive patients but not in fibroblasts of HRS-negative patients. Significantly less DSB was recognized by pATM early (10-30 minutes) after irradiation with 0.2 Gy in HRS-positive compared with HRS-negative fibroblasts. CONCLUSIONS: The present results provide evidence for the role of DSB recognition by pATM and repair in the mechanism of HRS and seem to support the idea of nucleo-shuttling of the pATM protein to be involved in HRS response.

A generic multimodule phantom for testing geometry of a linac c-arm as a part of quality control in radiotherapy.

PURPOSE: To develop an assumption-free methodology for testing geometry of linacs. METHODS: The problem of projecting a fiducial positioned in a predefined point in a 3D space and attached rigidly to a treatment table of a radiotherapeutic device onto an imaging plane with unknown characteristics from a source with unknown coordinates is formulated. The problem of determining these unknowns is formulated as an optimization problem. The problem of determining the gantry/the collimator rotation axis and angle from projection of additional fiducials is also formulated and solved. Analytical methodology is developed for determining isocenter position and an error of estimating isocenter position. The developed methodology is tested in simulations. RESULTS: Very good agreement between preset and calculated values of quantities of interest was found in the simulations. In all cases, the proposed schemes enabled determination of the geometric characteristics of a radiotherapeutic device with accuracy better than one hundredth of a millimeter and one hundredth of a degree. CONCLUSIONS: A concept of a multimodule multifiducial phantom has been introduced. Analytical framework has been developed to extract geometric characteristics of radiotherapy devices from projection images of a phantom. The phantom design and the methodology developed have been tested in simulations.

OUT-OF-FIELD DOSE MEASUREMENTS FOR 3D CONFORMAL AND INTENSITY MODULATED RADIOTHERAPY OF A PAEDIATRIC BRAIN TUMOUR.

The purpose of this study was to measure out-of-field organ doses in clinical conditions in anthropomorphic paediatric phantoms which received a simulated treatment of a brain tumour with intensity modulated radiotherapy (IMRT) and 3D conformal radiotherapy (3D CRT). Organ doses measured with radiophotoluminescent and thermoluminescent dosemeters were on average 1.6 and 3.0 times higher for the 5 y-old than for the 10 y-old phantom for IMRT and 3D CRT, respectively. A larger 5-y to 10-y organ dose ratio for 3D CRT can be explained because the use of a mechanical wedge for the 5-y-old 3D CRT phantom treatment increased out-of-field doses. Due to different configurations of the radiation fields, for both phantoms, the IMRT technique resulted in a higher non-target brain dose and higher eye doses but lower thyroid doses compared to 3D CRT. For 3D CRT (which used a non-coplanar field configuration), eye doses were 3-6% and for IMRT (which used a coplanar field configuration) 27-30% of the treatment dose, respectively. For thyroid and more distant organs, doses were less than 1% of the treatment dose. Comparison of measured doses and doses calculated by the treatment planning system (TPS) showed that the TPS underestimated out-of-field doses both for IMRT and 3D CRT.

An association between low-dose hyper-radiosensitivity and the early G2-phase checkpoint in normal fibroblasts of cancer patients.

In our previous study, low-dose hyper-radiosensitivity (HRS) effect was demonstrated for normal fibroblasts (asynchronous and G2-phase enriched) of 4 of the 25 cancer patients investigated. For the rest of patients, HRS was not defined in either of the 2 fibroblast populations. Thus, the study indicated that G2-phase enrichment had no influence on HRS identification. The conclusion contradicts that reported for human tumor cells, and suggests different mechanism of HRS in normal human cells. In the present paper we report, for the first time, the activity of early G2-phase checkpoint after low-dose irradiation in normal fibroblasts of these 4 HRS-positive patients and 4 HRS-negative patients and answer the question regarding the role of this checkpoint in normal human cells. The response of the early G2-phase checkpoint was determined by assessment of the progression of irradiated cells into mitosis using the mitotic marker, phosphorylated histone H3. We found evident differences in the activity of the early G2-phase checkpoint between HRS-positive and HRS-negative fibroblasts. In HRS-positive fibroblasts the checkpoint was not triggered and DNA damage was not recognized after doses lower than 0.2Gy resulting in HRS response. On the contrary, in HRS-negative fibroblasts the early G2-phase checkpoint was activated regardless of the dose in the range 0.1-2Gy. In conclusion, although cell cycle phase has no effect on the presence of HRS effect in normal human fibroblasts, the data reported here indicate that HRS response in these cells is associated with the functioning of early G2-phase checkpoint in a threshold-dose dependent manner, similarly as it takes place in most of human tumor and other cells.

Relative biological effectiveness of the 60-MeV therapeutic proton beam at the Institute of Nuclear Physics (IFJ PAN) in Kraków, Poland.

The aim of the study was to determine the relative biological effectiveness (RBE) of a 60-MeV proton radiotherapy beam at the Institute of Nuclear Physics, Polish Academy of Sciences (IFJ PAN) in Kraków, the first one to operate in Poland. RBE was assessed at the surviving fractions (SFs) of 0.01, 0.1, and 0.37, for normal human fibroblasts from three cancer patients. The cells were irradiated near the Bragg peak of the pristine beam and at three depths within a 28.4-mm spread-out Bragg peak (SOBP). Reference radiation was provided by 6-MV X-rays. The mean RBE value at SF = 0.01 for fibroblasts irradiated near the Bragg peak of pristine beam ranged between 1.06 and 1.15. The mean RBE values at SF = 0.01 for these cells exposed at depths of 2, 15, and 27 mm of the SOBP ranged between 0.95-1.00, 0.97-1.02, and 1.05-1.11, respectively. A trend was observed for RBE values to increase with survival level and with depth in the SOBP: at SF = 0.37 and at the depth of 27 mm, RBE values attained their maximum (1.19-1.24). The RBE values estimated at SF = 0.01 using normal human fibroblasts for the 60-MeV proton radiotherapy beam at the IFJ PAN in Kraków are close to values of 1.0 and 1.1, used in clinical practice.

Low-dose hyper-radiosensitivity is not a common effect in normal asynchronous and G2-phase fibroblasts of cancer patients.

PURPOSE: In our previous study, using the micronucleus assay, a low-dose hyper-radiosensitivity (HRS)-like phenomenon was observed for normal fibroblasts of 2 of the 40 cancer patients investigated. In this article we report, for the first time, the survival response of primary fibroblasts from 25 of these patients to low-dose irradiation and answer the question regarding the effect of G2-phase enrichment on HRS elicitation. METHODS AND MATERIALS: The clonogenic survival of asynchronous as well as G2-phase enriched fibroblast populations was measured. Separation of G2-phase cells and precise cell counting was performed using a fluorescence-activated cell sorter. Sorted and plated cells were irradiated with single doses (0.1-4 Gy) of 6-MV x-rays. For each patient, at least 4 independent experiments were performed, and the induced-repair model was fitted over the whole data set to confirm the presence of HRS effect. RESULTS: The HRS response was demonstrated for the asynchronous and G2-phase enriched cell populations of 4 patients. For the rest of patients, HRS was not defined in either of the 2 fibroblast populations. Thus, G2-phase enrichment had no effect on HRS elicitation. CONCLUSIONS: The fact that low-dose hyper-radiosensitivity is not a common effect in normal human fibroblasts implies that HRS may be of little consequence in late-responding connective tissues with regard to radiation fibrosis.

Application of IMRT in adjuvant treatment of soft tissue sarcomas of the thigh-Preliminary results.

BACKGROUND: Fracture of the femur is the most frequent late complication in patients with soft tissue sarcomas (STS) who receive external beam radiotherapy after limb-sparing surgery. AIM: To reduce the risk of bone fracture following radiotherapy of STS of the thigh, we minimized the dose to the femur and to surrounding normal tissues by applying intensity modulated radiation therapy (IMRT). We report preliminary results of post-surgery IMRT of the thigh in patients with STS in this extremity. MATERIALS AND METHODS: 10 adult patients undergoing post-operative radiotherapy of STS of the thigh were treated using IMRT. Clinical IMRT plans with simultaneous integrated boost (SIB) and 3-phase three-dimensional conformal radiotherapy (3D-CRT) were designed to adequately treat the planning target volume and to spare the femur to the largest extent possible. Dose distributions and dose-volume histograms were compared. RESULTS: For either technique, a comparable target coverage was achieved; however, target volume was better covered and critical structures were better spared in IMRT plans. Mean and maximum doses to OAR structures were also significantly reduced in the IMRT plans. On average, the mean dose to the femur in 3D-CRT plans was about two times higher than that in IMRT plans. CONCLUSION: Compared with 3D-CRT, the application of IMRT improves the dose distribution within the concave target volumes and reduces dose to the OAR structures without compromising target coverage.