Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

The HILUS-Trial-a Prospective Nordic Multicenter Phase 2 Study of Ultracentral Lung Tumors Treated With Stereotactic Body Radiotherapy.

INTRODUCTION: Stereotactic body radiation therapy of thoracic tumors close to the central airways implies risk of severe toxicity. We report a prospective multicenter phase 2 trial for tumors located less than or equal to 1 cm from the proximal bronchial tree with primary end point of local control and secondary end point of toxicity. METHODS: Stereotactic body radiation therapy with 7 Gy × 8 was prescribed to the 67% isodose encompassing the planning target volume. The patients were stratified to group A (tumors ≤ 1 cm from the main bronchi and trachea) or group B (all other tumors). Risk factors for treatment-related death were tested in univariate analysis, and a logistic regression model was developed for fatal bronchopulmonary bleeding versus dose to the main bronchi and trachea. RESULTS: A total of 65 patients (group A/group B, n = 39/26) were evaluated. The median distance between the tumor and the proximal bronchial tree was 0 mm (0-10 mm). The 2-year local control was 83%. Grade 3 to 5 toxicity was noted in 22 patients, including 10 cases of treatment-related death (bronchopulmonary hemorrhage, n = 8; pneumonitis, n = 1; fistula, n = 1). Dose to the combined structure main bronchi and trachea and tumor distance to the main bronchi were important risk factors. Dose modeling revealed minimum dose to the "hottest" 0.2 cc to the structure main bronchi and trachea as the strongest predictor for lethal bronchopulmonary hemorrhage. CONCLUSIONS: On the basis of the presented data, 7 Gy × 8, prescribed to the planning target volume-encompassing isodose, should not be used for tumors located within 1 cm from the main bronchi and trachea. Group B-type tumors may be considered for the treatment on the basis of an individual risk-benefit assessment and a maximum dose to the main bronchi and trachea in the order of 70 to 80 Gy (equivalent dose in 2 Gy fractions).

Effect of gradient field nonlinearity distortions in MRI-based attenuation maps for PET reconstruction.

PURPOSE: Attenuation correction is a requirement for quantification of the activity distribution in PET. The need to base attenuation correction on MRI instead of CT has arisen with the introduction of integrated PET/MRI systems. The aim was to describe the effect of residual gradient field nonlinearity distortions on PET attenuation correction. METHODS: MRI distortions caused by gradient field nonlinearity were simulated in CT images used for attenuation correction in PET reconstructions. The simulations yielded radial distortion of up to ±2.3mm at 15cm from the scanner isocentre for distortion corrected images. The mean radial distortion of uncorrected images were 6.3mm at the same distance. Reconstructions of PET data were performed using the distortion corrected images as well as the images where no correction had been applied. RESULTS: The mean relative difference in reconstructed PET uptake intensity due to incomplete distortion correction was less than ±5%. The magnitude of this difference varied between patients and the size of the distortions remaining after distortion correction. CONCLUSIONS: Radial distortions of 2mm at 15cm radius from the scanner isocentre lead to PET attenuation correction errors smaller than 5%. Keeping the gradient field nonlinearity distortions below this limit can be a reasonable goal for MRI systems used for attenuation correction in PET for quantification purposes. A higher geometrical accuracy may, however, be warranted for quantification of peripheral lesions. These distortions can, e.g., be controlled at acceptance testing and subsequent quality assurance intervals.

A practical approach to diode based in vivo dosimetry for intensity modulated radiotherapy.

A method for in vivo entrance dosimetry, using point detectors, in intensity modulated radiotherapy has been clinically evaluated. Diode dosimetry was performed for treatments of the head and neck and prostate regions. The results were good; 92.2% of the measurements showed deviations within ±5% of the expected values.

No difference in migration or wear between cemented low-profile cups and standard cups : a randomized radiostereographic study of 53 patients over 3 years.

BACKGROUND: Minor design changes may cause major changes in implant performance. Thus, as part of a stepwise introduction of a new low-profile cup, we performed a randomized trial comparing it to a well-documented standard cup. PATIENTS AND METHODS: 60 patients, stratified according to sex, weight, and age, underwent cemented total hip arthroplasty using a Lubinus SP2 stem with ceramic head and were randomized to either the new low-profile Lubinus Flanged Anti-Luxation cup (FAL) or the Lubinus Standard Eccentric cup (Standard). 7 patients were excluded and 53 (28 FAL) were evaluated at 3, 6, 12, and 36 months postoperatively. Primary outcome variables, cup migration (MTPM), and wear (total 3-dimensional femoral head penetration) were measured with radiostereometry (RSA). Clinical outcome was evaluated with the western Ontario and McMaster osteoarthritis index (Womac) and the visual analog pain score (VAS). RESULTS: We found no difference in migration between the FAL and Standard cups. There was no difference in wear between the two cups and there was no correlation between wear and migration. 3 cups (2 FAL and 1 Standard) showed continuous migration of a magnitude that indicated an increased risk of early loosening. Clinical outcome was excellent, without any difference between the 2 groups.

Clinical evaluation of monitor unit software and the application of action levels.

PURPOSE: The aim of this study was the clinical evaluation of an independent dose and monitor unit verification (MUV) software which is based on sophisticated semi-analytical modelling. The software was developed within the framework of an ESTRO project. Finally, consistent handling of dose calculation deviations applying individual action levels is discussed. MATERIALS AND METHODS: A Matlab-based software ("MUV") was distributed to five well-established treatment centres in Europe (Vienna, Graz, Basel, Copenhagen, and Umeå) and evaluated as a quality assurance (QA) tool in clinical routine. Results were acquired for 226 individual treatment plans including a total of 815 radiation fields. About 150 beam verification measurements were performed for a portion of the individual treatment plans, mainly with time variable fluence patterns. The deviations between dose calculations performed with a treatment planning system (TPS) and the MUV software were scored with respect to treatment area, treatment technique, geometrical depth, radiological depth, etc. RESULTS: In general good agreement was found between calculations performed with the different TPSs and MUV, with a mean deviation per field of 0.2+/-3.5% (1 SD) and mean deviations of 0.2+/-2.2% for composite treatment plans. For pelvic treatments less than 10% of all fields showed deviations larger than 3%. In general, when using the radiological depth for verification calculations the results and the spread in the results improved significantly, especially for head-and-neck and for thorax treatments. For IMRT head-and-neck beams, mean deviations between MUV and the local TPS were -1.0+/-7.3% for dynamic, and -1.3+/-3.2% for step-and-shoot IMRT delivery. For dynamic IMRT beams in the pelvis good agreement was obtained between MUV and the local TPS (mean: -1.6+/-1.5%). Treatment site and treatment technique dependent action levels between +/-3% and +/-5% seem to be clinically realistic if a radiological depth correction is performed, even for dynamic wedges and IMRT. CONCLUSION: The software MUV is well suited for patient specific treatment plan QA applications and can handle all currently available treatment techniques that can be applied with standard linear accelerators. The highly sophisticated dose calculation model implemented in MUV allows investigation of systematic TPS deviations by performing calculations in homogeneous conditions.

Patient-specific IMRT verification using independent fluence-based dose calculation software: experimental benchmarking and initial clinical experience.

Experimental methods are commonly used for patient-specific intensity-modulated radiotherapy (IMRT) verification. The purpose of this study was to investigate the accuracy and performance of independent dose calculation software (denoted as 'MUV' (monitor unit verification)) for patient-specific quality assurance (QA). 52 patients receiving step-and-shoot IMRT were considered. IMRT plans were recalculated by the treatment planning systems (TPS) in a dedicated QA phantom, in which an experimental 1D and 2D verification (0.3 cm(3) ionization chamber; films) was performed. Additionally, an independent dose calculation was performed. The fluence-based algorithm of MUV accounts for collimator transmission, rounded leaf ends, tongue-and-groove effect, backscatter to the monitor chamber and scatter from the flattening filter. The dose calculation utilizes a pencil beam model based on a beam quality index. DICOM RT files from patient plans, exported from the TPS, were directly used as patient-specific input data in MUV. For composite IMRT plans, average deviations in the high dose region between ionization chamber measurements and point dose calculations performed with the TPS and MUV were 1.6 +/- 1.2% and 0.5 +/- 1.1% (1 S.D.). The dose deviations between MUV and TPS slightly depended on the distance from the isocentre position. For individual intensity-modulated beams (total 367), an average deviation of 1.1 +/- 2.9% was determined between calculations performed with the TPS and with MUV, with maximum deviations up to 14%. However, absolute dose deviations were mostly less than 3 cGy. Based on the current results, we aim to apply a confidence limit of 3% (with respect to the prescribed dose) or 6 cGy for routine IMRT verification. For off-axis points at distances larger than 5 cm and for low dose regions, we consider 5% dose deviation or 10 cGy acceptable. The time needed for an independent calculation compares very favourably with the net time for an experimental approach. The physical effects modelled in the dose calculation software MUV allow accurate dose calculations in individual verification points. Independent calculations may be used to replace experimental dose verification once the IMRT programme is mature.

Optimization of photon beam flatness for radiation therapy.

In this work, we investigate the relation between lateral fluence/dose distributions and photon beam uniformity, possibly identifying ways to improve these characteristics. The calculations included treatment head scatter properties associated with three common types of linear accelerators in order to study their impact on the results. For 6 and 18 MV photon beams the lateral fluence distributions were optimized with respect to the resulting calculated flatness, as defined by the International Electrotechnical Commission (IEC), at 10 cm depth in six different field sizes. The limits proposed by IEC for maximum dose ratios ('horns') at the depth of dose maximum have also been accounted for in the optimization procedure. The conclusion was that typical head scatter variations among different types of linear accelerators have a very limited effect on the optimized results, which implies that the existing differences in measured off-axis dose distributions are related to non-equivalent optimization objectives. Finally, a comparison between the theoretically optimized lateral dose distributions and corresponding dose measurements for the three investigated accelerator types was performed. Although the measured data generally fall within the IEC requirements the optimized distributions show better results overall for the evaluated uniformity parameters, indicating that there is room for improved flatness performance in clinical photon beams.

Pencil kernel correction and residual error estimation for quality-index-based dose calculations.

Experimental data from 593 photon beams were used to quantify the errors in dose calculations using a previously published pencil kernel model. A correction of the kernel was derived in order to remove the observed systematic errors. The remaining residual error for individual beams was modelled through uncertainty associated with the kernel model. The methods were tested against an independent set of measurements. No significant systematic error was observed in the calculations using the derived correction of the kernel and the remaining random errors were found to be adequately predicted by the proposed method.

Dose uncertainties in photon pencil kernel calculations at off-axis positions.

The purpose of this study was to investigate the specific problems associated with photon dose calculations in points located at a distance from the central beam axis. These problems are related to laterally inhomogeneous energy fluence distributions and spectral variations causing a lateral shift in the beam quality, commonly referred to as off-axis softening (OAS). We have examined how the dose calculation accuracy is affected when enabling and disabling explicit modeling of these two effects. The calculations were performed using a pencil kernel dose calculation algorithm that facilitates modeling of OAS through laterally varying kernel properties. Together with a multi-source model that provides the lateral energy fluence distribution this generates the total dose output, i.e., the dose per monitor unit, at an arbitrary point of interest. The dose calculation accuracy was evaluated through comparisons with 264 measured output factors acquired at 5, 10, and 20 cm depth in four different megavoltage photon beams. The measurements were performed up to 18 cm from the central beam axis, inside square fields of varying size and position. The results show that calculations including explicit modeling of OAS were considerably more accurate, up to 4%, than those ignoring the lateral beam quality shift. The deviations caused by simplified head scatter modeling were smaller, but near the field edges additional errors close to 1% occurred. When enabling full physics modeling in the dose calculations the deviations display a mean value of -0.1%, a standard deviation of 0.7%, and a maximum deviation of -2.2%. Finally, the results were analyzed in order to quantify and model the inherent uncertainties that are present when leaving the central beam axis. The off-axis uncertainty component showed to increase with both off-axis distance and depth, reaching 1% (1 standard deviation) at 20 cm depth.

Evaluation of uncertainty predictions and dose output for model-based dose calculations for megavoltage photon beams.

In many radiotherapy clinics an independent verification of the number of monitor units (MU) used to deliver the prescribed dose to the target volume is performed prior to the treatment start. Traditionally this has been done by using methods mainly based on empirical factors which, at least to some extent, try to separate the influence from input parameters such as field size, depth, distance, etc. The growing complexity of modern treatment techniques does however make this approach increasingly difficult, both in terms of practical application and in terms of the reliability of the results. In the present work the performance of a model-based approach, describing the influence from different input parameters through actual modeling of the physical effects, has been investigated in detail. The investigated model is based on two components related to megavoltage photon beams; one describing the exiting energy fluence per delivered MU, and a second component describing the dose deposition through a pencil kernel algorithm solely based on a measured beam quality index. Together with the output calculations, the basis of a method aiming to predict the inherent calculation uncertainties in individual treatment setups has been developed. This has all emerged from the intention of creating a clinical dose/MU verification tool that requires an absolute minimum of commissioned input data. This evaluation was focused on irregular field shapes and performed through comparison with output factors measured at 5, 10, and 20 cm depth in ten multileaf collimated fields on four different linear accelerators with varying multileaf collimator designs. The measurements were performed both in air and in water and the results of the two components of the model were evaluated separately and combined. When compared with the corresponding measurements the resulting deviations in the calculated output factors were in most cases smaller than 1% and in all cases smaller than 1.7%. The distribution describing the calculation errors in the total dose output has a mean value of -0.04% and a standard deviation of 0.47%. In the dose calculations a previously developed correction of the pencil kernel was applied that managed to contract the error distribution considerably. A detailed analysis of the predicted uncertainties versus the observed deviations suggests that the predictions indeed can be used as a basis for creating action levels and tracking dose calculation errors in homogeneous media.

Photon pencil kernel parameterisation based on beam quality index.

BACKGROUND AND PURPOSE: New treatment techniques in radiotherapy employ increasing dose calculation complexity in treatment planning. For an adequate check of the results coming from a modern treatment planning system, clinical tools with almost the same degree of generality and accuracy as the planning system itself are needed. To fulfil this need we propose a photon pencil kernel parameterization based on a minimum of input data that can be used for phantom scatter calculations. Through scatter integration the pencil kernel model can calculate common parameters, such as TPR or phantom scatter factors, used in various dosimetric QA (quality assurance) procedures. MATERIAL AND METHODS: The proposed model originates from an already published radially parameterized pencil kernel. A depth parameterization of the pencil kernel parameters has been introduced, based on a large database containing commissioned beam data for a commercial treatment planning system. The entire pencil kernel model demands only one photon beam quality index, TPR20,10, as input. RESULTS: By comparing the dose calculation results to the extensive experimental data set in the database, it has been possible to make a thorough analysis of the resulting accuracy. The errors in calculated doses, normalized to the reference geometry, are in most cases smaller than 2%. CONCLUSIONS: The investigation shows that a pencil kernel model based only on TPR20,10 can be used for dosimetric verification purposes in megavoltage photon beams at depths below the range of contaminating electrons.

The use of risk estimation models for the induction of secondary cancers following radiotherapy.

Theoretical predictions of cancer risk from radiotherapy may be used as a complementary criterion for the selection of successful treatment plans together with the classical approach of estimating the possible deterministic effects. However, any such attempts must take into consideration the specific features of radiation treatment. This paper explores several possible methods for estimating the risk of cancer following radiotherapy in order to investigate the influences of the fractionation and the non-uniformity of the dose to the irradiated organ. The results indicate that dose inhomogeneity plays an important role in predicting the risk for secondary cancer and therefore for predictive purposes it must be taken into account through the use of the dose volume histograms. They also suggest that the competition between cell killing and the induction of carcinogenic mutations has to be taken into consideration for more realistic risk estimations. Furthermore, more realistic parameters could be obtained if this competition is also included in analyses of epidemiological data from radiotherapy applications.

A practical method to calculate head scatter factors in wedged rectangular and irregular MLC shaped beams for external and internal wedges.

Factor based methods for absorbed dose or monitor unit calculations are often based on separate data sets for open and wedged beams. The determination of basic beam parameters can be rather time consuming, unless equivalent square methods are applied. When considering irregular wedged beams shaped with a multileaf collimator, parametrization methods for dosimetric quantities, e.g. output ratios or wedge factors as a function of field size and shape, become even more important. A practical method is presented to derive wedged output ratios in air (S(c,w)) for any rectangular field and for any irregular MLC shaped beam. This method was based on open field output ratios in air (S(c)) for a field with the same collimator setting, and a relation f(w) between S(c,w) and S(c). The relation f(w) can be determined from measured output ratios in air for a few open and wedged fields including the maximum wedged field size. The function f(w) and its parametrization were dependent on wedge angle and treatment head design, i.e. they were different for internal and external wedges. The proposed method was tested for rectangular wedged fields on three accelerators with internal wedges (GE, Elekta, BBC) and two accelerators with external wedges (Varian). For symmetric regular beams the average deviation between calculated and measured S(c,w) / S(c) ratios was 0.3% for external wedges and about 0.6% for internal wedges. Maximum deviations of 1.8% were obtained for elongated rectangular fields on the GE and ELEKTA linacs with an internal wedge. The same accuracy was achieved for irregular MLC shaped wedged beams on the accelerators with MLC and internal wedges (GE and Elekta), with an average deviation < 1% for the fields tested. The proposed method to determine output ratios in air for wedged beams from output ratios of open beams, combined with equivalent square approaches, can be easily integrated in empirical or semi-empirical methods for monitor unit calculations.

On empirical methods to determine scatter factors for irregular MLC shaped beams.

Multileaf collimators (MLCs) are in clinical use for more than a decade and are a well accepted tool in radiotherapy. For almost each MLC design different empirical or semianalytical methods have been presented for calculating output ratios in air for irregularly shaped beams. However, until now no clear recommendations have been given on how to handle irregular fields shaped by multileaf collimators for independent monitor unit (MU) verification. The present article compares different empirical methods, which have been proposed for independent MU verification, to determine (1) output ratios in air (Sc) and (2) phantom scatter factors (Sp) for irregular MLC shaped fields. Ten dedicated field shapes were applied to five different types of MLCs (Elekta, Siemens, Varian, Scanditronix, General Electric). All calculations based on empirical relations were compared with measurements and with calculations performed by a treatment planning system with a fluence based algorithm. For most irregular MLC shaped beams output ratios in air could be adequately modeled with an accuracy of about 1%-1.5% applying a method based on the open field aperture defined by the leaf and jaw setting combined with the equivalent square formula suggested by Vadash and Bjärngard [P. Vadash and B. E. Bjärngard, Med. Phys. 20, 733-734 (1993)]. The accuracy of this approach strongly depends on the inherent head scatter characteristics of the accelerator in use and on the irregular field under consideration. Deviations of up to 3% were obtained for fields where leaves obscure central parts of the flattening filter. Simple equivalent square methods for Sp calculations in irregular fields did not provide acceptable results (deviations mostly >3%). Sp values derived from Clarkson integration, based on published tables of phantom scatter correction factors, showed the same accuracy level as calculations performed using a pencil beam algorithm of a treatment planning system (in a homogeneous media). The separation of head scatter and phantom scatter contributions is strongly recommended for irregular MLC shaped beams as both contributions have different factors of influence. With rather simple methods Sc and Sp can be determined for independent MU calculation with an accuracy better than 1.5% for most clinical situations encountered in conformal radiotherapy.

A widely tested model for head scatter influence on photon beam output.

PURPOSE: To construct and test a semi-analytical model describing the effects on Monitor Unit (MU) verification caused by scattering in the treatment head. The implementation of the model should be accomplished using a small set of experimental data. Furthermore, the model should include a geometry dependent estimation of the resulting uncertainty. MATERIAL AND METHODS: The input required by the created model consists of basic treatment head geometry and 10 measured output factors in air (OFair) for square fields. It considers primary energy fluence, scattered radiation from an extra-focal source and from secondary collimators, as well as backscatter to the monitor chamber. Measurements and calculations were performed in open symmetric and asymmetric fields at points located both on and off the collimator axis, as well as at arbitrary treatment distances. The model has been verified for 19 photon beams in the range from 4 up to 50 MV, provided by nine different treatment units from six manufacturers. RESULTS: The presented model provided results with errors smaller than 1% (2 S.D.) in typical clinical situations for all beams tested. In more exceptional situations, i.e. combinations of unconventional treatment head designs, very elongated fields, and dosimetry points far away from the isocenter, the total uncertainty increased to approximately 2%. The spread in the results was further analysed in order to create a method for predicting the uncertainties under different treatment conditions. CONCLUSIONS: A general head scatter model that is easy to implement has been developed and can be used as the basis for computerised MU verification. The model handles all commercially available treatment units adequately and also includes an estimation of the resulting uncertainty.