MR-guidance in clinical reality: current treatment challenges and future perspectives.

Magnetic Resonance-guided radiotherapy (MRgRT) marks the beginning of a new era. MR is a versatile and suitable imaging modality for radiotherapy, as it enables direct visualization of the tumor and the surrounding organs at risk. Moreover, MRgRT provides real-time imaging to characterize and eventually track anatomical motion. Nevertheless, the successful translation of new technologies into clinical practice remains challenging. To date, the initial availability of next-generation hybrid MR-linac (MRL) systems is still limited and therefore, the focus of the present preview was on the initial applicability in current clinical practice and on future perspectives of this new technology for different treatment sites.MRgRT can be considered a groundbreaking new technology that is capable of creating new perspectives towards an individualized, patient-oriented planning and treatment approach, especially due to the ability to use daily online adaptation strategies. Furthermore, MRL systems overcome the limitations of conventional image-guided radiotherapy, especially in soft tissue, where target and organs at risk need accurate definition. Nevertheless, some concerns remain regarding the additional time needed to re-optimize dose distributions online, the reliability of the gating and tracking procedures and the interpretation of functional MR imaging markers and their potential changes during the course of treatment. Due to its continuous technological improvement and rapid clinical large-scale application in several anatomical settings, further studies may confirm the potential disruptive role of MRgRT in the evolving oncological environment.

Comparison of DCE-CT models for quantitative evaluation of K(trans) in larynx tumors.

Dynamic contrast enhanced CT (DCE-CT) can be used to estimate blood perfusion and vessel permeability in tumors. Tumor induced angiogenesis is generally associated with disorganized microvasculature with increased permeability or leakage. Estimated vascular leakage (K(trans)) values and their reliability greatly depend on the perfusion model used. To identify the preferred model for larynx tumor analysis, several perfusion models frequently used for estimating permeability were compared in this study. DCE-CT scans were acquired for 16 larynx cancer patients. Larynx tumors were delineated based on whole-mount histopathology after laryngectomy. DCE-CT data within these delineated volumes were analyzed using the Patlak and Logan plots, the Extended Tofts Model (ETM), the Adiabatic Approximation to the Tissue Homogeneity model (AATH) and a variant of AATH with fixed transit time (AATHFT). Akaike's Information Criterion (AIC) was used to identify the best fitting model. K(trans) values from all models were compared with this best fitting model. Correlation strength was tested with two-tailed Spearman's rank correlation and further examined using Bland-Altman plots. AATHFT was found to be the best fitting model. The overall median of individual patient medians K(trans) estimates were 14.3, 15.1, 16.1, 2.6 and 22.5 mL/100 g min( - 1) for AATH, AATHFT, ETM, Patlak and Logan, respectively. K(trans) estimates for all models except Patlak were strongly correlated (P < 0.001). Bland-Altman plots show large biases but no significant deviating trend for any model other than Patlak. AATHFT was found to be the preferred model among those tested for estimation of K(trans) in larynx tumors.

[Saliva and intensity modulated radiotherapy]. / Speeksel en intensiteitsgemoduleerde radiotherapie.

A dry mouth (xerostomia) is a serious side effect for head and neck cancer patients treated with radiotherapy. The degree of xerostomia is dependent on the dosage in the parotid glands. New, advanced radiation techniques, such as intensity-modulated radiotherapy, can reduce the dosage in the parotid glands, resulting in a significant improvement in the functioning of these glands by comparison with conventional radiation techniques.

Dose optimization for the MRI-accelerator: IMRT in the presence of a magnetic field.

A combined system of a 6 MV linear accelerator and a 1.5 T MRI scanner is currently being developed. In this system, the patient will be irradiated in the presence of a 1.5 T magnetic field. This causes a strong dose increase at tissue-air interfaces. Around air cavities in the patient, these effects may become problematic. Homogeneous dose distributions can be obtained around regularly shaped symmetrical cavities using opposing beams. However, for more irregularly shaped cavities this approach may not be sufficient. This study will investigate whether IMRT can be used to cope with magnetic field dose effects, in particular for target volumes adjacent to irregularly shaped air cavities. Therefore, an inverse treatment planning approach has been designed based on pre-calculated beamlet dose distribution kernels. Using this approach, optimized dose distributions were calculated for B = 1.5 T and for B = 0 T. Investigated target sites include a prostate cancer, a laryngeal cancer and an oropharyngeal cancer. Differences in the dose distribution between B = 0 and 1.5 T were minimal; only the skin dose increased for B = 1.5 T. Homogeneous dose distributions were obtained for target structures adjacent to air cavities without the use of opposing beams. These results show that a 1.5 T magnetic field does not compromise the ability to achieve desired dose distributions with IMRT.

Influence of the linac design on intensity-modulated radiotherapy of head-and-neck plans.

In this study, we quantify the impact of linac/MLC design parameters on IMRT treatment plans. The investigated parameters were leaf width in the MLC, leaf transmission, related to the thickness of the leaves, and penumbra related primarily to the source size. Seven head-and-neck patients with stage T1-T3N0-N2cM0 oropharyngeal cancer were studied. For each patient nine plans were made with a different set of linac/MLC parameters. The plans were optimized in Pinnacle(3) v7.6c and PLATO RTS v2.6.4, ITP v1.1.8. A hypothetical ideal linac/MLC was introduced to investigate the influence of one parameter at a time without interaction of other parameters. When any of the three parameters was increased from the ideal set-up values (leaf width 2.5 mm, transmission 0%, penumbra 3 mm), the mean dose to the parotid glands increased, given the same tumour coverage. The largest increase was found for increasing leaf transmission. The investigation showed that by changing more than one parameter of the ideal linac/MLC set-up, the increase in the mean dose was smaller than the sum of dose increments for each parameter separately. As a reference to clinical practice, we also optimized the plans of the seven patients with the clinically used Elekta SLi 15, equipped with a standard MLC with a leaf width of 10 mm. As compared to the ideal linac, this resulted in an increase of the average dose to the parotid glands of 5.8 Gy.

Assessment of induction of secondary tumours due to various radiotherapy modalities.

One of the objectives of the European Sixth Framework integrated project MAESTRO is to perform an assessment of risk due to various radiotherapy modalities, regarding secondary tumour induction. Initially, the study will focus on cancer of the prostate and the present work represents the first step towards that goal. One of the intended tools, to be used in the assessment, is the Monte Carlo radiation transport code ORANGE. A validation of the ORANGE code's capability to tally dose on a grid superimposed on an existing MCNP geometry is given. Preliminary results on the dose distribution due to conventional radiotherapy treatment of prostate cancer are discussed. Two mathematical models of the patient are proposed and the clinical relevance of the ADAM phantom is investigated. A problem in comparing average doses provided by commercial treatment planning systems and those calculated with Monte Carlo is noticed. The two proposed models are shown to receive a lower dose and average energy deposition than a 'real' patient.

An improved breast irradiation technique using three-dimensional geometrical information and intensity modulation.

BACKGROUND AND PURPOSE: In spite of the complex geometry of the breast, treatment planning for tangential breast irradiation is conventionally performed using two-dimensional patient anatomy information. The purpose of this work was to develop a new technique which takes the three-dimensional (3D) patient geometry into account. MATERIALS AND METHODS: An intensity-modulated radiotherapy (IMRT) technique was developed based on the division of the tangential fields in four multi-leaf collimator (MLC) shaped segments. The shape of these segments was obtained from an equivalent path length map of the irradiated volume. Approximately 88% of the dose was delivered by two open fields covering the whole treated volume. Dose calculations for the IMRT technique and the conventional technique were performed for five patients, using computer tomography (CT) data and a 3D calculation algorithm. A planning target volume (PTV) and ipsilateral lung volume were delineated in these CT data. RESULTS: All patients showed similar equivalent path length patterns. Analysis of the dose distribution showed an improved dose distribution using the IMRT technique. The dose inhomogeneity in the PTV was 9.0% (range 6.4-11.4%) for the conventional and 7.6% (range 6.5-10.3%) for the IMRT technique. The mean lung dose was reduced for the IMRT technique by approximately 10% compared with the conventional technique. CONCLUSION: A new breast irradiation technique has been developed which improves the dose homogeneity within the planning target volume and reduces the dose to the lung. Furthermore, the IMRT technique creates the possibility to improve the field matching in case of multiple field irradiations of the breast and lymph nodes.

Phantom materials for boron neutron capture therapy.

The aim of this work was to establish which reference phantom material is most suited for dosimetry under reference conditions of neutron beams for boron neutron capture therapy (BNCT). For this purpose, phantoms of dimensions 15 x 15 x 15 cm3 and 30 x 30 x 30 cm3, composed of water, tissue-equivalent (TE) liquid, polyethylene (PE), polymethyl methacrylate (PMMA) and water containing 10 microg g(-1) and 30 microg g(-1) 10B were irradiated using the Petten BNCT beam. Activation foils and a diode detector were used for the determination of the thermal neutron fluence rate. The gamma-ray dose rate and the fast neutron dose rate were determined using paired ionization chambers. In water, PMMA and TE liquid the absolute dose and fluence values agreed within 3% at a reference depth of 2 cm, with the exception of the gamma-ray dose rate in PMMA, which was 12% lower than in water. Due to a higher hydrogen concentration in PE compared with water, the dose and fluence values in PE differed more than 30% from those in water. Only minor differences were observed between the percentage depth dose curves for the various dose components in water, PMMA and TE liquid. The addition of 10 microg g(-1) and 30 microg g(-1) 10B to water resulted in a decrease in the absolute thermal neutron fluence at 2 cm depth of about 2% and 8%, respectively, and a decreased penetration of thermal neutrons at depth for the 30 microg g(-1) 10B concentration. For reference dosimetry of an epithermal neutron beam for BNCT, both water and TE liquid are suitable phantom materials. For practical reasons, water is therefore proposed as reference phantom material. For measurements requiring a solid phantom, PMMA is proposed. The lower gamma-ray dose in PMMA compared to water, however, needs to be taken into account.

A fast and accurate treatment planning method for boron neutron capture therapy.

BACKGROUND AND PURPOSE: The aim of this study was to test the applicability of conventional semi-empirical algorithms for the treatment planning of boron neutron capture therapy (BNCT). MATERIALS AND METHODS: Beam data of a clinical epithermal BNCT beam obtained in a large cuboid water phantom were introduced into a commercial treatment planning system (TPS). For the calculation of thermal neutron fluence distributions, the Gaussian pencil beam model of the electron beam treatment planning algorithm was used. A simple photon beam algorithm was used for the calculation of the gamma-ray and fast neutron dose distribution. The calculated dose and fluence distributions in the central plane of an anthropomorphic head phantom were compared with measurements for various field sizes. The calculation time was less than 1 min. RESULTS: At the normalization point in the head phantom, the absolute dose and fluence values agreed within the measurement uncertainty of approximately 2-3% (1 SD) with those at the same depth in a cuboid phantom of approximately the same size. Excellent agreement of within 2-3% (1 SD) was obtained between measured and calculated relative fluence and dose values on the central beam axis and at most off-axis positions in the head phantom. At positions near the phantom boundaries, generally in low dose regions, local differences of approximately 30% were observed. CONCLUSIONS: A fast and accurate treatment planning method has been developed for BNCT. This is the first treatment planning method that may allow the same interactive optimization procedures for BNCT as applied clinically for conventional radiotherapy.

Clinical dosimetry of an epithermal neutron beam for neutron capture therapy: dose distributions under reference conditions.

PURPOSE: The aim of this study was to asses the dose distribution under reference conditions for the various dose components of the Petten clinical epithermal neutron beam for boron neutron capture therapy (BNCT). METHODS AND MATERIALS: Activation foils and a silicon alpha-particle detector with a 6Li converter plate have been used for the determination of the thermal neutron fluence rate. The gamma-ray dose rate and the fast neutron dose rate have been determined using paired ionization chambers. Circular beam apertures of 8, 12 and 15 cm diameters have been investigated using a 15 x 15 x 15 cm3 solid polymethyl-methacrylate phantom, a water phantom of the same dimensions and a 30 x 30 x 30 cm3 water phantom at various phantom to beam-exit distances. RESULTS: The effect of phantom to beam-exit distance could be modeled using an inverse square law with a virtual source to beam-exit distance of 3.0 m. At a reference phantom to beam-exit distance of 30 cm, three-dimensional dose and fluence distributions of the various dose components have been determined in the phantoms. The absolute thermal neutron fluence rate at a reference depth of 2 cm in the 15 cm water phantom increased by 43% when the field size was increased from 8 to 15 cm. Simultaneously the gamma-ray dose rate increased by 46% while the fast neutron dose rate increased by only 5%. CONCLUSION: A reference treatment position at 30 cm from the beam exit allows convenient patient positioning with a relatively small increase in irradiation time compared to positions very close to the beam-exit. A more homogeneous distribution of thermal neutrons over a target volume, a higher absolute thermal neutron fluence rate and a lower contribution of the fast neutron dose to the total dose will result in improved treatment plans when using a 12 cm or 15 cm field compared to a 8 cm field. The dose distributions will be used as benchmark data for treatment planning systems for BNCT.

Dose monitoring for boron neutron capture therapy using a reactor-based epithermal neutron beam.

The aims of this study were (i) to determine the variation with time of the relevant beam parameters of a clinical reactor-based epithermal neutron beam for boron neutron capture therapy (BNCT) and (ii) to test a monitoring system for its applicability to monitor the dose delivered to the dose specification point in a patient treated with BNCT. For this purpose two fission chambers covered with Cd and two GM counters were positioned in the beam-shaping collimator assembly of the epithermal neutron beam. The monitor count rates were compared with in-phanton reference measurements of the thermal neutron fluence rate, the gamma-ray dose rate and the fast neutron dose rate, at a constant reactor power, over a period of 2 years. Differences in beam output, defined as the thermal neutron fluence rate at 2 cm depth in a phantom, of up to 15% were observed between various reactor cycles. A decrease in beam output of about 5% was observed in each reactor cycle. An unacceptable decrease of 50% in beam output due to malfunctioning of the beam filter assembly was detected. For safe and accurate treatment of patients, on-line monitoring of the beam is essential. Using the calibrated monitor system, the standard uncertainty in the total dose at depth due to variations with time of the beam output parameters has been reduced to a clinically acceptable value of 1% (one standard deviation).

The neutron sensitivity of dosimeters applied to boron neutron capture therapy.

To obtain a high accuracy in the dosimetry of an epithermal neutron beam used for boron neutron capture therapy (BNCT), the neutron sensitivity of dosimeters applied to determine the various dose components in-phantom has been investigated. The thermal neutron sensitivity of Mg(Ar) ionization chambers, TE(TE) ionization chambers, and thermoluminescent dosimeters (TLD) has been experimentally determined in a "pure" thermal neutron beam. Values much higher than theoretically expected were obtained and a variation up to a factor of 2.5 was found between values for the thermal neutron sensitivity of different Mg(Ar) ionization chambers of the same type. The sensitivity of the TE(TE) ionization chamber to intermediate and fast neutrons (kt) has been calculated for the neutron energy spectrum in a phantom irradiated by a clinical epithermal BNCT beam, obtained using Monte Carlo simulations. The kt value for muscle tissue ranged from 0.87 at small depths to 0.93 at larger depths in the phantom. The application of the thermal neutron sensitivities to measurements in a phantom irradiated by the epithermal BNCT beam yielded up to 17% higher gamma-ray dose rate values compared with measurements using 6Li containing caps to shield the detectors from thermal neutrons, due to a substantial perturbation of the in-phantom radiation field by the 6Li cap. The application of the new kt values resulted in a dose from intermediate and fast neutrons about 10% higher than the dose based on currently applied relative neutron sensitivities of TE(TE) chambers in BNCT beams. The resulting improvement in the accuracy of the determination of the dose from gamma rays and intermediate and fast neutrons is important in view of the required accuracy for dosimetry in radiotherapy.

Dose homogeneity in boron neutron capture therapy using an epithermal neutron beam.

Simulation models based on the neutron and photon Monte Carlo code MCNP were used to study the therapeutic possibilities of the HB11 epithermal neutron beam at the High Flux Reactor in Petten. Irradiations were simulated in two types of phantoms filled with water or tissue-equivalent material for benchmark treatment planning calculations. In a cuboid phantom the influence of different field sizes on the thermal-neutron-induced dose distribution was investigated. Various shapes of collimators were studied to test their efficacy in optimizing the thermal-neutron distribution over a planning target volume and healthy tissues. Using circular collimators of 8, 12 and 15 cm diameter it was shown that with the 15-cm field a relatively larger volume within 85% of the maximum neutron-induced dose was obtained than with the 8- or 12-cm-diameter field. However, even for this large field the maximum diameter of this volume was 7.5 cm. In an ellipsoid head phantom the neutron-induced dose was calculated assuming the skull to contain 10 ppm 10B, the brain 5 ppm 10B and the tumor 30 ppm 10B. It was found that with a single 15-cm-diameter circular beam a very inhomogenous dose distribution in a typical target volume was obtained. Applying two equally weighted opposing 15-cm-diameter fields, however, a dose homogeneity within +/- 10% in this planning target volume was obtained. The dose in the surrounding healthy brain tissue is 30% at maximum of the dose in the center of the target volume. Contrary to the situation for the 8-cm field, combining four fields of 15 cm diameter gave no large improvement of the dose homogeneity over the target volume or a lower maximum dose in the healthy brain. Dose-volume histograms were evaluated for the planning target volume as well as for the healthy brain to compare different irradiation techniques, yielding a graphical confirmation of the above conclusions. Therapy with BNCT on brain tumors must be performed either with an 8-cm four-field irradiation or with two opposing 15- or 12-cm fields to obtain an optimal dose distribution.

Determination of dose components in phantoms irradiated with an epithermal neutron beam for boron neutron capture therapy.

The application of activation foils, thermoluminescent detectors, and ionization chambers has been investigated for the determination of the different dose components in phantoms irradiated with a mixed gamma-ray and epithermal neutron beam for boron neutron capture therapy. The thermal neutron fluence has been determined using a set of AuAl and MnNi activation foils. TLD-700 and a Mg(Ar) ionization chamber have been used for the determination of the gamma-ray dose. The dose from epithermal neutrons has been determined using a TE(TE) ionization chamber. The detector characteristics and the relative sensitivities of the various detectors to the different dose components in the phantom have been determined. The following accuracies (1 standard deviation) in the determination of the different components have been obtained: thermal neutron fluence rate: 5%; gamma-ray dose rate: 7%; epithermal neutron dose rate: 15%. These values make these detectors suitable for obtaining the complete set of clinical dosimetry data required for patient dose assessment.

Monitoring of blood-10B concentration for boron neutron capture therapy using prompt gamma-ray analysis.

The aim of the present study was to monitor the blood-10B concentration of laboratory dogs receiving boron neutron capture therapy, in order to obtain optimal agreement between prescribed and actual dose. A prompt gamma-ray analysis system was developed for this purpose at the High Flux Reactor in Petten. The technique was compared with inductively coupled plasma-atomic emission spectrometry and showed good agreement. A substantial variation in 10B clearance pattern after administration of borocaptate sodium was found between the different dogs. Consequently, the irradiation commencement was adjusted to the individually determined boron elimination curve. Mean blood-10B concentrations during irradiation of 25.8 +/- 2.2 micrograms/g (1 SD, n = 18) and 49.3 +/- 5.3 micrograms/g (1 SD, n = 17) were obtained for intended concentrations of 25 micrograms/g and 50 micrograms/g, respectively. These variations are a factor of two smaller than irradiations performed at a uniform post-infusion irradiation starting time. Such a careful blood-10B monitoring procedure is a prerequisite for accurately obtaining such steep dose-response curves as observed during the dog study.

Determination of the gamma-ray dose in an epithermal neutron beam.

Neutron beams used for Boron Neutron Capture Therapy (BNCT) are always accompanied by photons. These two irradiation components have different relative biological effectiveness. Therefore it is necessary to determine the neutron and photon absorbed dose in the mixed field separately. All gamma-ray detectors however are also sensitive for neutrons. In this work preliminary results are presented using TLD-700 chips, a Mg(Ar) ionisation chamber and a GM-counter to determine the gamma-ray component in a mixed beam of gamma-rays and neutrons. The results show a good agreement between the GM-counter and the ionisation chamber, indicating a small relative neutron sensitivity (ku) for these detectors. The sensitivity of TLD-700 for thermal neutrons however gives rise to a detector response for which a correction is necessary. The uncertainty however in the relative gamma-ray sensitivity (hu) of the detectors is at this moment too large to determine accurate values of the relative neutron sensitivities.

An investigation of the possibilities of BNCT treatment planning with the Monte Carlo method.

The neutron fluence distribution inside two types of water phantom have been calculated with the Monte Carlo programme MCNP for the epithermal neutron beam at the Petten Low Flux Reactor. Comparison between the calculated and the measured neutron fluence distributions showed a reasonable agreement. The influence of beam and phantom geometry on the neutron fluence distribution has been calculated. An increase of the field size leads to a somewhat deeper position of the maximum of the thermal neutron fluence distribution in the cylindrical phantom. The possible use of beam modifying devices like wedges and blocks has been tested with this model. Blocks have been modelled that can locally reduce the fast neutron skin dose by 70%.