Linear Energy Transfer Measurements and Estimation of Relative Biological Effectiveness in Proton and Helium Ion Beams Using Fluorescent Nuclear Track Detectors.

PURPOSE: Our objective was to develop a methodology for assessing the linear energy transfer (LET) and relative biological effectiveness (RBE) in clinical proton and helium ion beams using fluorescent nuclear track detectors (FNTDs). METHODS AND MATERIALS: FNTDs were exposed behind solid water to proton and helium (4He) ion spread-out Bragg peaks. Detectors were imaged with a confocal microscope, and the LET spectra were derived from the fluorescence intensity. The track- and dose-averaged LET (LETF and LETD, respectively) were calculated from the LET spectra. LET measurements were used as input on RBE models to estimate the RBE. Human alveolar adenocarcinoma cells (A549) were exposed at the same positions as the FNTDs. The RBE was calculated from the resulting survival curves. All measurements were compared with Monte Carlo simulations. RESULTS: For protons, average relative differences between measurements and simulations were 6% and 19% for LETF and LETD, respectively. For helium ions, the same differences were 11% for both quantities. The position of the experimental LET spectra primary peaks agreed with the simulations within 9% and 14% for protons and helium ions, respectively. For the RBE models using LETD as input, FNTD-based RBE values ranged from 1.02 ± 0.01 to 1.25 ± 0.04 and from 1.08 ± 0.09 to 2.68 ± 1.26 for protons and helium ions, respectively. The average relative differences between these values and simulations were 2% and 4%. For A549 cells, the RBE ranged from 1.05 ± 0.07 to 1.47 ± 0.09 and from 0.89 ± 0.06 to 3.28 ± 0.20 for protons and helium ions, respectively. Regarding the RBE-weighted dose (2.0 Gy at the spread-out Bragg peak), the differences between simulations and measurements were below 0.10 Gy. CONCLUSIONS: This study demonstrates for the first time that FNTDs can be used to perform direct LET measurements and to estimate the RBE in clinical proton and helium ion beams.

Clinical Workflow of Cone Beam Computer Tomography-Based Daily Online Adaptive Radiotherapy with Offline Magnetic Resonance Guidance: The Modular Adaptive Radiotherapy System (MARS).

PURPOSE: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. METHODS: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. RESULTS: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5-63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7-39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6-32.2), 0.4 min (IQR 0.3-1,0) and 5.3 min (IQR 4.5-6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. CONCLUSION: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

The Treatment of Capsular Contracture Around Breast Implants Induced by Fractionated Irradiation: The Collagenase of the Bacterium Clostridium Histolyticum as a Novel Therapeutic Approach.

BACKGROUND: Irradiation therapy limits the utilization of silicone implants for breast reconstruction due to a significant risk for capsular contracture. The injection of the collagenase of the bacterium Clostridium histolyticum (CCH) might trivialize this risk by providing a minimal-invasive treatment option by capsular contracture degradation. However, efficacy in degrading breast implant capsules induced by fractionated irradiation remains unclear. METHODS: Twenty-four rats in three groups received miniature silicone implants in a submuscular pocket. After 3D dose calculation and treatment field definition, rats of two groups underwent fractionated radiotherapy (6 × 8 Gy) using a linear accelerator. A third group served as control. On day 120, one irradiated group received injections of 0.3 mg/ml collagenase. Administration of plain solvent solution served as control in the two other groups. Outcome parameters included CT-imaging, histology, vessel wall analysis, immunohistochemistry, chemical collagen quantification and gene expression analysis. RESULTS: Fractioned irradiation leads to a significant increase in collagen deposition around silicone implants with higher capsule thickness and collagen density when comparing all groups. Additionally, significant alterations of collagen fiber deposition were evident. Vessel wall thickness was significantly increased after radiotherapy. The injection of collagenase led to a significant reduction of capsule thickness, collagen density and content. However, the collagenase application induced a significant overexpression of TGFß1. No side effects were monitored. CONCLUSIONS: The CCH proved to be a safe and effective approach to degrade capsule tissue induced by fractionated irradiation in an animal model. This may pave its way for clinical application in implant-based breast reconstruction patients. LEVEL OF EVIDENCE: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Cone-Beam-CT Guided Adaptive Radiotherapy for Locally Advanced Non-small Cell Lung Cancer Enables Quality Assurance and Superior Sparing of Healthy Lung.

PURPOSE: To evaluate the potential of cone-beam-CT (CB-CT) guided adaptive radiotherapy (ART) for locally advanced non-small cell lung cancer (NSCLC) for sparing of surrounding organs-at-risk (OAR). MATERIALS AND METHODS: In 10 patients with locally advanced NSCLC, daily CB-CT imaging was acquired during radio- (n = 4) or radiochemotherapy (n = 6) for simulation of ART. Patients were treated with conventionally fractionated intensity-modulated radiotherapy (IMRT) with total doses of 60-66 Gy (pPlan) (311 fraction CB-CTs). OAR were segmented on every daily CB-CT and the tumor volumes were modified weekly depending on tumor changes. Doses actually delivered were recalculated on daily images (dPlan), and voxel-wise dose accumulation was performed using a deformable registration algorithm. For simulation of ART, treatment plans were adapted using the new contours and re-optimized weekly (aPlan). RESULTS: CB-CT showed continuous tumor regression of 1.1 ± 0.4% per day, leading to a residual gross tumor volume (GTV) of 65.3 ± 13.4% after 6 weeks of radiotherapy (p = 0.005). Corresponding PTVs decreased to 83.7 ± 7.8% (p = 0.005). In the actually delivered plans (dPlan), both conformity (p = 0.005) and homogeneity (p = 0.059) indices were impaired compared to the initial plans (pPlan). This resulted in higher actual lung doses than planned: V20Gy was 34.6 ± 6.8% instead of 32.8 ± 4.9% (p = 0.066), mean lung dose was 19.0 ± 3.1 Gy instead of 17.9 ± 2.5 Gy (p = 0.013). The generalized equivalent uniform dose (gEUD) of the lung was 18.9 ± 3.1 Gy instead of 17.8 ± 2.5 Gy (p = 0.013), leading to an increased lung normal tissue complication probability (NTCP) of 15.2 ± 13.9% instead of 9.6 ± 7.3% (p = 0.017). Weekly plan adaptation enabled decreased lung V20Gy of 31.6 ± 6.2% (-3.0%, p = 0.007), decreased mean lung dose of 17.7 ± 2.9 Gy (-1.3 Gy, p = 0.005), and decreased lung gEUD of 17.6 ± 2.9 Gy (-1.3 Gy, p = 0.005). Thus, resulting lung NTCP was reduced to 10.0 ± 9.5% (-5.2%, p = 0.005). Target volume coverage represented by conformity and homogeneity indices could be improved by weekly plan adaptation (CI: p = 0.007, HI: p = 0.114) and reached levels of the initial plan (CI: p = 0.721, HI: p = 0.333). CONCLUSION: IGRT with CB-CT detects continuous GTV and PTV changes. CB-CT-guided ART for locally advanced NSCLC is feasible and enables superior sparing of healthy lung at high levels of plan conformity.

Overcoming hypoxia-induced tumor radioresistance in non-small cell lung cancer by targeting DNA-dependent protein kinase in combination with carbon ion irradiation.

BACKGROUND: Hypoxia-induced radioresistance constitutes a major obstacle for a curative treatment of cancer. The aim of this study was to investigate effects of photon and carbon ion irradiation in combination with inhibitors of DNA-Damage Response (DDR) on tumor cell radiosensitivity under hypoxic conditions. METHODS: Human non-small cell lung cancer (NSCLC) models, A549 and H1437, were irradiated with dose series of photon and carbon ions under hypoxia (1% O2) vs. normoxic conditions (21% O2). Clonogenic survival was studied after dual combinations of radiotherapy with inhibitors of DNA-dependent Protein Kinase (DNAPKi, M3814) and ATM serine/threonine kinase (ATMi). RESULTS: The OER at 30% survival for photon irradiation of A549 cells was 1.4. The maximal oxygen effect measured as survival ratio was 2.34 at 8 Gy photon irradiation of A549 cells. In contrast, no significant oxygen effect was found after carbon ion irradiation. Accordingly, the relative effect of 6 Gy carbon ions was determined as 3.8 under normoxia and. 4.11 under hypoxia. ATM and DNA-PK inhibitors dose dependently sensitized tumor cells for both radiation qualities. For 100 nM DNAPKi the survival ratio at 4 Gy more than doubled from 1.59 under normoxia to 3.3 under hypoxia revealing a strong radiosensitizing effect under hypoxic conditions. In contrast, this ratio only moderately increased after photon irradiation and ATMi under hypoxia. The most effective treatment was combined carbon ion irradiation and DNA damage repair inhibition. CONCLUSIONS: Carbon ions efficiently eradicate hypoxic tumor cells. Both, ATMi and DNAPKi elicit radiosensitizing effects. DNAPKi preferentially sensitizes hypoxic cells to radiotherapy.

Tweety-Homolog 1 Drives Brain Colonization of Gliomas.

Early and progressive colonization of the healthy brain is one hallmark of diffuse gliomas, including glioblastomas. We recently discovered ultralong (>10 to hundreds of microns) membrane protrusions [tumor microtubes (TMs)] extended by glioma cells. TMs have been associated with the capacity of glioma cells to effectively invade the brain and proliferate. Moreover, TMs are also used by some tumor cells to interconnect to one large, resistant multicellular network. Here, we performed a correlative gene-expression microarray and in vivo imaging analysis, and identified novel molecular candidates for TM formation and function. Interestingly, these genes were previously linked to normal CNS development. One of the genes scoring highest in tests related to the outgrowth of TMs was tweety-homolog 1 (TTYH1), which was highly expressed in a fraction of TMs in mice and patients. Ttyh1 was confirmed to be a potent regulator of normal TM morphology and of TM-mediated tumor-cell invasion and proliferation. Glioma cells with one or two TMs were mainly responsible for effective brain colonization, and Ttyh1 downregulation particularly affected this cellular subtype, resulting in reduced tumor progression and prolonged survival of mice. The remaining Ttyh1-deficient tumor cells, however, had more interconnecting TMs, which were associated with increased radioresistance in those small tumors. These findings imply a cellular and molecular heterogeneity in gliomas regarding formation and function of distinct TM subtypes, with multiple parallels to neuronal development, and suggest that Ttyh1 might be a promising target to specifically reduce TM-associated brain colonization by glioma cells in patients.SIGNIFICANCE STATEMENT In this report, we identify tweety-homolog 1 (Ttyh1), a membrane protein linked to neuronal development, as a potent driver of tumor microtube (TM)-mediated brain colonization by glioma cells. Targeting of Ttyh1 effectively inhibited the formation of invasive TMs and glioma growth, but increased network formation by intercellular TMs, suggesting a functional and molecular heterogeneity of the recently discovered TMs with potential implications for future TM-targeting strategies.

Experimental determination of the photon-energy dependent dose-to-water response of TLD600 and TLD700 (LiF:Mg,Ti) thermoluminescence detectors.

The aim of this study has been the experimental determination of the energy dependent dose-to-water response of TLD600 and TLD700 thermoluminescent detectors (Harshaw) in X-ray beams with mean photon energies from about 20 to 200keV in comparison with 60Co gamma rays and 6MV X-rays. Experiments were carried out in collaboration with the German secondary standard laboratory PTW Freiburg. The energy dependent relative responses of TLD600 and TLD700 thermoluminescence detectors were determined at radiation qualities between 30kVp and 280kVp. The overall uncertainty of the measured values was characterized by standard deviations varying from 1.2 to 3%. The present results agree with previous studies on the energy dependent dose-to-water response of TLD100. As an application example, the results were used to measure doses associated with X-ray imaging in image-guided radiotherapy.

Investigation of the mechanical performance of Siemens linacs components during arc: gantry, MLC, and electronic portal imaging device.

BACKGROUND: In radiotherapy treatments, it is crucial to monitor the performance of linac components including gantry, collimation system, and electronic portal imaging device (EPID) during arc deliveries. In this study, a simple EPID-based measurement method is suggested in conjunction with an algorithm to investigate the stability of these systems at various gantry angles with the aim of evaluating machine-related errors in treatments. METHODS: The EPID sag, gantry sag, changes in source-to-detector distance (SDD), EPID and collimator skewness, EPID tilt, and the sag in leaf bank assembly due to linac rotation were separately investigated by acquisition of 37 EPID images of a simple phantom with five ball bearings at various gantry angles. A fast and robust software package was developed for automated analysis of image data. Three Siemens linacs were investigated. RESULTS: The average EPID sag was within 1 mm for all tested linacs. Two machines showed >1 mm gantry sag. Changes in the SDD values were within 7.5 mm. EPID skewness and tilt values were <1° in all machines. The maximum sag in leaf bank assembly was <1 mm. CONCLUSION: The method and software developed in this study provide a simple tool for effective investigation of the behavior of Siemens linac components with gantry rotation. Such a comprehensive study has been performed for the first time on Siemens machines.

Brain tumour cells interconnect to a functional and resistant network.

Astrocytic brain tumours, including glioblastomas, are incurable neoplasms characterized by diffusely infiltrative growth. Here we show that many tumour cells in astrocytomas extend ultra-long membrane protrusions, and use these distinct tumour microtubes as routes for brain invasion, proliferation, and to interconnect over long distances. The resulting network allows multicellular communication through microtube-associated gap junctions. When damage to the network occurred, tumour microtubes were used for repair. Moreover, the microtube-connected astrocytoma cells, but not those remaining unconnected throughout tumour progression, were protected from cell death inflicted by radiotherapy. The neuronal growth-associated protein 43 was important for microtube formation and function, and drove microtube-dependent tumour cell invasion, proliferation, interconnection, and radioresistance. Oligodendroglial brain tumours were deficient in this mechanism. In summary, astrocytomas can develop functional multicellular network structures. Disconnection of astrocytoma cells by targeting their tumour microtubes emerges as a new principle to reduce the treatment resistance of this disease.

Development, physical properties and clinical applicability of a mechanical Multileaf Collimator for the use in Cobalt-60 radiotherapy.

According to the Directory of Radiotherapy Centres (DIRAC) there are 2348 Cobalt-60 (Co-60) teletherapy units worldwide, most of them in low and middle income countries, compared to 11046 clinical accelerators. To improve teletherapy with Co-60, a mechanical Multi-Leaf Collimator (MLC) was developed, working with pneumatic pressure and thus independent of electricity supply. Instead of tungsten, brass was used as leaf material to make the mechanical MLC more affordable. The physical properties and clinical applicability of this mechanical MLC are presented here. The leakage strongly depends on the fieldsize of the therapy unit due to scatter effects. The maximum transmission through the leaves measured 2.5 cm from the end-to-end gap, within a field size of 20 cm × 30 cm defined by jaws of the therapy unit at 80 cm SAD, amounts 4.2%, normalized to an open 10 cm × 10 cm field, created by the mechanical MLC. Within a precollimated field size of 12.5 cm × 12.5 cm, the end-to-end leakage is 6.5% normalized to an open 10 cm × 10 cm field as well. This characteristic is clinically acceptable considering the criteria for non-IMRT MLCs of the International Electrotechnical Commission (IEC 60601-2-1). The penumbra for a 10 cm × 10 cm field was measured to be 9.14 mm in plane and 8.38 mm cross plane. The clinical applicability of the designed mechanical MLC was affirmed by measurements relating to all relevant clinical properties such as penumbra, leakage, output factors and field widths. Hence this novel device presents an apt way forward to make radiotherapy with conformal fields possible in low-infrastructure environments, using gantry based Co-60 therapy units.

MR-guidance--a clinical study to evaluate a shuttle- based MR-linac connection to provide MR-guided radiotherapy.

BACKGROUND: The purpose of this clinical study is to investigate the clinical feasibility and safety of a shuttle-based MR-linac connection to provide MR-guided radiotherapy. METHODS/DESIGN: A total of 40 patients with an indication for a neoadjuvant, adjuvant or definitive radiation treatment will be recruited including tumors of the head and neck region, thorax, upper gastrointestinal tract and pelvic region. All study patients will receive standard therapy, i.e. highly conformal radiation techniques like CT-guided intensity-modulated radiotherapy (IMRT) with or without concomitant chemotherapy or other antitumor medication, and additionally daily short MR scans in treatment position with the same immobilisation equipment used for irradiation for position verification and imaging of the anatomical and functional changes during the course of radiotherapy. For daily position control, skin marks and a stereotactic frame will be used for both imaging modalities. Patient transfer between the MR device and the linear accelerator will be performed with a shuttle system which uses an air-bearing patient platform for both procedures. The daily acquired MR and CT data sets will be digitally registrated, correlated with the planning CT and compared with each other regarding translational and rotational errors. Aim of this clinical study is to establish a shuttle-based approach for realising MR-guided radiotherapy for certain clinical situations. Second objectives are to compare MR-guided radiotherapy with the gold standard of CT image guidance for quality assurance of radiotherapy, to establish an appropriate MR protocol therefore, and to assess the possibility of using MR-based image guidance not only for position verification but also for adaptive strategies in radiotherapy. DISCUSSION: Compared to CT, MRI might offer the advantage of providing IGRT without delivering an additional radiation dose to the patients and the possibility of optimisation of adaptive therapy strategies due to its superior soft tissue contrast. However, up to now, hybrid MR-linac devices are still under construction and not clinically applicable. For the near future, a shuttle-based approach would be a promising alternative for providing MR-guided radiotherapy, so that the present study was initiated to determine feasibility and safety of such an approach. Besides positioning information, daily MR data under treatment offer the possibility to assess tumor regression and functional parameters, with a potential impact not only on adaptive therapy strategies but also on early assessment of treatment response.

6 MV dosimetric characterization of the 160 MLC, the new Siemens multileaf collimator.

New technical developments constantly aim at improving the outcome of radiation therapy. With the use of a computer-controlled multileaf collimator (MLC), the quality of the treatment and the efficiency in patient throughput is significantly increased. New MLC designs aim to further enhance the advantages. In this article, we present the first detailed experimental investigation of the new 160 MLC, Siemens Medical Solutions. The assessment included the experimental investigation of typical MLC characteristics such as leakage, tongue-and-groove effect, penumbra, leaf speed, and leaf positioning accuracy with a 6 MV treatment beam. The leakage is remarkably low with an average of 0.37% due to a new design principle of slightly tilted leaves instead of the common tongue-and-groove design. But due to the tilt, the triangular tongue-and-groove effect occurs. Its magnitude of approximately 19% is similar to the dose defect measured for MLCs with the common tongue-and-groove design. The average longitudinal penumbra measured at depth d(max) = 15 mm with standard 100 x 100 mm2 fields is 4.1 +/- 0.5 mm for the central range and increases to 4.9 +/- 1.3 mm for the entire field range of 400 x 400 mm2. The increase is partly due to the single-focusing design and the large distance between the MLC and the isocenter enabling a large patient clearance. Regarding the leaf speed, different velocity tests were performed. The positions of the moving leaves were continuously recorded with the kilovoltage-imaging panel. The maximum leaf velocities measured were 42.9 +/- 0.6 mm/s. In addition, several typical intensity-modulated radiation therapy treatments were performed and the delivery times compared to the Siemens OPTIFOCUS MLC. An average decrease of 11% in delivery time was observed. The experimental results presented in this article indicate that the dosimetric characteristics of the 160 MLC are capable of improving the quality of dose delivery with respect to precision and dose conformity.

Correction of patient positioning errors based on in-line cone beam CTs: clinical implementation and first experiences.

BACKGROUND: The purpose of the study was the clinical implementation of a kV cone beam CT (CBCT) for setup correction in radiotherapy. PATIENTS AND METHODS: For evaluation of the setup correction workflow, six tumor patients (lung cancer, sacral chordoma, head-and-neck and paraspinal tumor, and two prostate cancer patients) were selected. All patients were treated with fractionated stereotactic radiotherapy, five of them with intensity modulated radiotherapy (IMRT). For patient fixation, a scotch cast body frame or a vacuum pillow, each in combination with a scotch cast head mask, were used. The imaging equipment, consisting of an x-ray tube and a flat panel imager (FPI), was attached to a Siemens linear accelerator according to the in-line approach, i.e. with the imaging beam mounted opposite to the treatment beam sharing the same isocenter. For dose delivery, the treatment beam has to traverse the FPI which is mounted in the accessory tray below the multi-leaf collimator. For each patient, a predefined number of imaging projections over a range of at least 200 degrees were acquired. The fast reconstruction of the 3D-CBCT dataset was done with an implementation of the Feldkamp-David-Kress (FDK) algorithm. For the registration of the treatment planning CT with the acquired CBCT, an automatic mutual information matcher and manual matching was used. RESULTS AND DISCUSSION: Bony landmarks were easily detected and the table shifts for correction of setup deviations could be automatically calculated in all cases. The image quality was sufficient for a visual comparison of the desired target point with the isocenter visible on the CBCT. Soft tissue contrast was problematic for the prostate of an obese patient, but good in the lung tumor case. The detected maximum setup deviation was 3 mm for patients fixated with the body frame, and 6 mm for patients positioned in the vacuum pillow. Using an action level of 2 mm translational error, a target point correction was carried out in 4 cases. The additional workload of the described workflow compared to a normal treatment fraction led to an extra time of about 10-12 minutes, which can be further reduced by streamlining the different steps. CONCLUSION: The cone beam CT attached to a LINAC allows the acquisition of a CT scan of the patient in treatment position directly before treatment. Its image quality is sufficient for determining target point correction vectors. With the presented workflow, a target point correction within a clinically reasonable time frame is possible. This increases the treatment precision, and potentially the complex patient fixation techniques will become dispensable.

The influence of breathing motion on intensity modulated radiotherapy in the step-and-shoot technique: phantom measurements for irradiation of superficial target volumes.

For intensity modulated radiotherapy (IMRT) of deep-seated tumours, dosimetric variations of the original static dose profiles due to breathing motion can be primarily considered as blurring effects known from conventional radiotherapy. The purpose of this dosimetric study was to clarify whether these results are transferable to superficial targets and to quantify the additional effect of fractionation. A solid polystyrene phantom and an anthropomorphic phantom were used for film and ion chamber dose measurements. The phantoms were installed on an electric driven device and moved with a frequency of 6 or 12 cycles per minute and an amplitude of 4 mm or 10 mm. A split beam geometry of two adjacent asymmetric fields and an IMRT treatment plan with 12 fields for irradiation of the breast were investigated. For the split beam geometry the dose modifications due to unintended superposition of partial fields were reduced by fractionation and completely smoothed out after 20 fractions. IMRT applied to the moving phantom led to a more homogeneous dose distribution compared to the static phantom. The standard deviation of the target dose which is a measure of the dose homogeneity was 10.3 cGy for the static phantom and 7.7 cGy for a 10 mm amplitude. The absolute dose values, measured with ionization chambers, remained unaffected. Irradiation of superficial targets by IMRT in the step-and-shoot technique did not result in unexpected dose perturbations due to breathing motion. We conclude that regular breathing motion does not jeopardize IMRT of superficial target volumes.

Measurements of characteristics of time pattern in dose delivery in step-and-shoot IMRT.

BACKGROUND AND PURPOSE: Although intensity-modulated radiotherapy (IMRT) has already shown its clinical benefit, there are some issues which are not yet fully understood. Among these is the question whether the protracted dose delivery due to the lowered dose rate has any radiobiological consequences. To investigate this question, an exact characterization of dose rate profiles in typical clinical plans is needed. Furthermore, such a characterization may lead to an increased knowledge how to improve IMRT technically. MATERIAL AND METHODS: A new IMRT phantom which allows precise measurement of up to nine points of interest simultaneously with pin-point ionization chambers was developed. To examine dose rates, a new software tool (GRAYHOUND) was developed which can measure doses in short time intervals of up to 0.5 s. 250 points in four clinical IMRT plans were examined. A set of parameters was defined to describe the dose rate profiles including the effective fraction time (eft, which is the percentage of the fraction time in which any dose is delivered to a specific point), and a quotient of the percentage of dose delivered in high dose pulses (> 0.01 Gy/s) divided by the percentage of fraction time needed to deliver this dose (d(HD)/t(HD)). RESULTS: These quotients are excellent markers for the inhomogeneity of dose rate delivery in IMRT. In both parameters a wide variance in points of the same plan and between different plans was found. For example, eft ranged between 11.6% and 37.3% in high dose points and the time in which high dose rates are delivered to a single high dose point ranged between 3.6% and 10.1% of total fraction time. CONCLUSIONS: These data show a great inhomogeneity of dose rates not only between different plans but also between different points in the same plan. Biological investigations are needed to quantify the relevance of these inhomogeneities. The parameters which are introduced in this work may be suitable to compare different optimization algorithms in IMRT.

Stereotactic intensity-modulated radiation therapy (IMRT) and inverse treatment planning for advanced pleural mesothelioma. Feasibility and initial results.

BACKGROUND AND PURPOSE: Complex-shaped malignant pleural mesotheliomas (MPMs) with challenging volumes are extremely difficult to treat by conventional radiotherapy due to tolerance doses of the surrounding normal tissue. In a feasibility study, we evaluated if inversely planned stereotactic intensity-modulated radiation therapy (IMRT) could be applied in the treatment of MPM. PATIENTS AND METHODS: Eight patients with unresectable lesions were treated after failure of chemotherapy. All patients were positioned using noninvasive patient fixation techniques which can be attached to the applied extracranial stereotactic system. Due to craniocaudal extension of the tumor, it was necessary to develop a special software attached to the inverse planning program KonRad, which can connect two inverse treatment plans and consider the applied dose of the first treatment plan in the area of the matchline of the second treatment plan. RESULTS: Except for one patient, in whom radiotherapy was canceled due to abdominal metastasis, treatment could be completed in all patients and was well tolerated. Median survival after diagnosis was 20 months and after IMRT 6.5 months. Therefore, both the 1-year actuarial overall survival from the start of radiotherapy and the 2-year actuarial overall survival since diagnosis were 28%. IMRT did not result in clinically significant acute side effects. By using the described inverse planning software, over or underdosage in the region of the field matchline could be prevented. Pure treatment time ranged between 10 and 21 min. CONCLUSION: This study showed that IMRT is feasible in advanced unresectable MPM. The presented possibilities of stereotactic IMRT in the treatment of MPM will justify the evaluation of IMRT in early-stage pleural mesothelioma combined with chemotherapy in a study protocol, in order to improve the outcome of these patients. Furthermore, dose escalation should be possible by using IMRT.

Inverse treatment planning and stereotactic intensity-modulated radiation therapy (IMRT) of the tumor and lymph node levels for nasopharyngeal carcinomas. Description of treatment technique, plan comparison, and case study.

PURPOSE: Inverse treatment planning and intensity-modulated radiation therapy (IMRT) promise advantages in the treatment of tumors of the head and neck region. Currently published studies use IMRT only in the treatment of the primary tumor. In these studies, the lymph nodes of the neck were treated using conventional techniques. The feasibility of an IMRT technique which allows treatment of the complete target volume, including the primary tumor and lymph nodes, without a beam split is described. PATIENT AND METHOD: For inverse treatment planning, the KonRad planning system was used. The primary as well as the secondary PTV (bilateral lymph node levels) were treated with one intensity-modulated primary plan. To increase the dose in the primary PTV and suspicious lymph nodes, an intensity-modulated boost plan was performed. The "step and shoot" IMRT technique was used. A plan comparison between the described IMRT approach and an IMRT approach using a split-beam technique was performed focusing on the treatment time. A patient with a carcinoma of the nasopharynx was treated with curative intent by a combined radiochemotherapy. RESULTS: The median total dose to the primary PTV was 70 Gy, to suspicious lymph nodes > or = 66.0 Gy, and to the secondary PTV 52 Gy. The defined maximum doses to the organs at risk were not exceeded, and the median dose to the protected parotid gland amounted to 21 Gy. Comparison of the treatment time between both IMRT approaches revealed only a slightly shorter treatment time (1-3 min) for the split-beam IMRT technique without considering the remaining conventional treatment parts of the split-beam IMRT technique. The patient achieved a complete response, and 18 months after treatment no signs of recurrent disease are visible. CONCLUSIONS: IMRT allows the treatment of the target volumes with high doses combined with an excellent sparing of the organs at risk. The IMRT approach presented here makes the treatment of the whole target volume with a single-beam arrangement feasible and does not increase the treatment time compared to a split-beam IMRT technique. Treatment time was comparable to a conventional three-field technique combined with electrons. This IMRT technique can prevent over- or underdosage at field matchlines in the head and neck region and, moreover, is able to spare parotid glands and therefore better avoid xerostomia compared to conventional techniques.

[Dosimetric verification of IMRT treatment plans at the German Cancer Research Center (DKFZ)]. / Dosimetrische Verifikation von IMRT-Gesamtplänen am Deutschen Krebsforschungszentrum Heidelberg.

The present paper describes a method for the individual dosimetric verification of IMRT treatment plans. The German Cancer Research Center (Deutsches Krebsforschungszentrum; DKFZ) has implemented the intensity modulated radiotherapy (IMRT) since 1997. So far, 246 patients with head and neck cancer, cancer of the prostate, breast, and vertebral column, as well as mesothelioma of the pleura have been treated. Every IMRT plan is transferred into a special IMRT verification phantom, recalculated, and dosimetrically verified. Absolute dose distributions are measured with Kodak EDR films and compared with the results of the dose calculation. After correction of the optical density in relationship to the dose, EDR films are able to measure the absolute dose with an accuracy of +/- 2% compared to an ionization chamber. A visual C++ software tool has been developed to correlate and evaluate the film dose distributions with the corresponding slices of the 3D dose cube. Beside the overlay of absolute or relative isodoses and dose profiles, the median dose within correlated regions of interest (ROIs) is also included in the quantitative dose evaluation. The deviation between EDR film dosimetry and dose calculation is delta D = -0.3% +/- 2.3%. After introduction of the verification software, the total verification time (including handling, correlation, evaluation, and documentation of the data), could be reduced to less than 2 hours.

Sensory and chemical changes in tomato sauces during storage.

The present work aimed to identify the key odorants of tomato sauces responsible for the flavor change during storage. Products made from paste or canned tomatoes were stored at 25 and 40 degrees C. Sensory properties and quantification of the key odorants were measured and correlated. Significant sensory changes appeared after 1 and 3 months at 25 degrees C in the respective dice and paste sauces (p < 0.01). The dice sauce was characterized by a steep loss of the sensory quality during the early storage and then by identical changes within the same time span at 25 and 40 degrees C. In the paste sauce the sensory deterioration was slower than for the dice sauce and occurred more extensively at 40 degrees C than at 25 degrees C. Correlation between sensory and instrumental data revealed that the source of sensory changes should be (E,E)-deca-2,4-dienal in the dice sauce. The sensory change in the paste sauce could be due to acetaldehyde, methylpropanal, 3-methylbutanal, oct-1-en-3-one, 3-methylbutanoic acid, deca-2,4-dienal, 2-methoxyphenol, and beta-damascenone.