End-to-end validation of the geometric dose delivery performance of MR linac adaptive radiotherapy.

The clinical introduction of hybrid magnetic resonance (MR) guided radiotherapy (RT) delivery systems has led to the need to validate the end-to-end dose delivery performance on such machines. In the current study, an MR visible phantom was developed and used to test the spatial deviation between planned and delivered dose at two 1.5 T MR linear accelerator (MR linac) systems, including pre-treatment imaging, dose planning, online imaging, image registration, plan adaptation, and dose delivery. The phantom consisted of 3D printed plastic and MR visible silicone rubber. It was designed to minimise air gaps close to the radiochromic film used as a dosimeter. Furthermore, the phantom was designed to allow submillimetre, reproducible positioning of the film in the phantom. At both MR linac systems, 54 complete adaptive, MR guided RT workflow sessions were performed. To test the dose delivery performance of the MR linac systems in various adaptive RT (ART) scenarios, the sessions comprised a range of systematic positional shifts of the phantom and imaging or plan adaptation conditions. In each workflow session, the positional translation between the film and the adaptive planned dose was determined. The results showed that the accuracy of the MR linac systems was between 0.1 and 0.9 mm depending on direction. The highest mean deviance observed was in the posterior-anterior direction, and the direction of the error was consistent between centres. The precision of the systems was related to whether the workflow utilized the internal image registration algorithm of the MR linac. Workflows using the internal registration algorithm led to a worse precision (0.2-0.7 mm) compared to workflows where the algorithm was decoupled (0.2 mm). In summary, the spatial deviation between planned and delivered dose of MR-guided ART at the two MR linac systems was well below 1 mm and thus acceptable for clinical use.

First clinical experiences with a high field 1.5 T MR linac.

Purpose: A 1.5 T MR Linac (MRL) has recently become available. MRL treatment workflows (WF) include online plan adaptation based on daily MR images (MRI). This study reports initial clinical experiences after five months of use in terms of patient compliance, cases, WF timings, and dosimetric accuracy. Method and materials: Two different WF were used dependent on the clinical situation of the day; Adapt To Position WF (ATP) where the reference plan position is adjusted rigidly to match the position of the targets and the OARs, and Adapt To Shape WF (ATS), where a new plan is created to match the anatomy of the day, using deformable image registration. Both WFs included three 3D MRI scans for plan adaptation, verification before beam on, and validation during IMRT delivery. Patient compliance and WF timings were recorded. Accuracy in dose delivery was assessed using a cylindrical diode phantom. Results: Nineteen patients have completed their treatment receiving a total of 176 fractions. Cases vary from prostate treatments (60Gy/20F) to SBRT treatments of lymph nodes (45 Gy/3F) and castration by ovarian irradiation (15 Gy/3F). The median session time (patient in to patient out) for 127 ATPs was 26 (21-78) min, four fractions lasted more than 45 min due to additional plan adaptation. For the 49 ATSs a median time of 12 (1-24) min was used for contouring resulting in a total median session time of 42 (29-91) min. Three SBRT fractions lasted more than an hour. The time on the MRL couch was well tolerated by the patients. The median gamma pass rate (2 mm,2% global max) for the adapted plans was 99.2 (93.4-100)%, showing good agreement between planned and delivered dose. Conclusion: MRL treatments, including daily MRIs, plan adaptation, and accurate dose delivery, are possible within a clinically acceptable timeframe and well tolerated by the patients.

Adapting automated treatment planning configurations across international centres for prostate radiotherapy.

BACKGROUND AND PURPOSE: Automated configurations are increasingly utilised for radiotherapy treatment planning. This study investigates whether automated treatment planning configurations are adaptable across clinics with different treatment planning protocols for prostate radiotherapy. MATERIAL AND METHODS: The study comprised three participating centres, each with pre-existing locally developed prostate AutoPlanning configurations using the Pinnacle3® treatment planning system. Using a three-patient training dataset circulated from each centre, centres modified local prostate configurations to generate protocol compliant treatment plans for the other two centres. Each centre applied modified configurations on validation datasets distributed from each centre (10 patients from 3 centres). Plan quality was assessed through DVH analysis and protocol compliance. RESULTS: All treatment plans were clinically acceptable, based off relevant treatment protocol. Automated planning configurations from Centre's A and B recorded 2 and 18 constraint and high priority deviations respectively. Centre C configurations recorded no high priority deviations. Centre A configurations produced treatment plans with superior dose conformity across all patient PTVs (mean = 1.14) compared with Centre's B and C (mean = 1.24 and 1.22). Dose homogeneity was consistent between all centre's configurations (mean = 0.083, 0.077, and 0.083 respectively). CONCLUSIONS: This study demonstrates that automated treatment planning configurations can be shared and implemented across multiple centres with simple adaptations to local protocols.

Magnetic resonance only workflow and validation of dose calculations for radiotherapy of prostate cancer.

BACKGROUND: Current state of the art radiotherapy planning of prostate cancer utilises magnetic resonance (MR) for soft tissue delineation and computed tomography (CT) to provide an electron density map for dose calculation. This dual scan workflow is prone to setup and registration error. This study evaluates the feasibility of an MR-only workflow and the validity of dose calculation from an MR derived pseudo CT. MATERIAL AND METHODS: Thirty prostate cancer patients were CT and MR scanned. Clinical treatment plans were generated on CT using a single 18 MV arc volumetric modulated arc therapy (VMAT) with a prescription of 78 Gy/39 fractions. Dose was recalculated on pseudo CT and assuming uniform water density. Pseudo CT and uniform density based dose calculations were compared to CT dose calculations by gamma analysis. One patient was treated with a plan based solely on MR and pseudo CT including daily image guided radiotherapy (IGRT) performed by manual match of implanted gold markers. RESULTS: A pseudo CT was generated for 29 of the 30 patients. Median gamma pass rates for 1%/1 mm passing criteria for dose calculated on pseudo CT when compared to CT were 100% for most evaluated structures. Dose calculated on uniform density also yielded high median pass rates, but with a higher occurrence of pass rates below 95%. Cases of pass rate below 95% on pseudo CT proved to originate from the presence of rectal air on CT, not represented by the pseudo CT. Treatment based on MR alone was successfully delivered to one patient, including manually performed daily IGRT. CONCLUSIONS: Median gamma pass rates were high for pseudo CT and proved superior to uniform density. Local differences in dose calculations were concluded not to have clinical relevance. Feasibility of the MR-only workflow was demonstrated through successful delivery of a treatment course planned based on MR alone.

Stereotactic body radiation therapy versus conventional radiation therapy in patients with early stage non-small cell lung cancer: an updated retrospective study on local failure and survival rates.

INTRODUCTION: Stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) is now an accepted and patient friendly treatment, but still controversy exists about its comparability to conventional radiation therapy (RT). The purpose of this single-institutional report is to describe survival outcome for medically inoperable patients with early stage NSCLC treated with SBRT compared with high dose conventional RT. MATERIAL AND METHODS: From August 2005 to June 2012, 100 medically inoperable patients were treated with SBRT at Odense University Hospital. The thoracic RT consisted of 3 fractions (F) of 15-22 Gy delivered in nine days. For comparison a group of 32 medically inoperable patients treated with conventional RT with 80 Gy/35-40 F (5 F/week) in the period of July 1998 to August 2011 were analyzed. All tumors had histological or cytological proven NSCLC T1-2N0M0. RESULTS: The median overall survival was 36.1 months versus 24.4 months for SBRT and conventional RT, respectively (p = 0.015). Local failure-free survival rates at one year were in SBRT group 93% versus 89% in the conventional RT group and at five years 69% versus 66%, SBRT and conventional RT respectively (p = 0.99). On multivariate analysis, female gender and performance status of 0-1 and SBRT predicted improved prognosis. CONCLUSION: In a cohort of patients with NSCLC there was a significant difference in overall survival favoring SBRT. Performance status of 0-1, female gender and SBRT predicted improved prognosis. However, staging procedure, confirmation procedure of recurrence and technical improvements of radiation treatment is likely to influence outcomes. However, SBRT seems to be as efficient as conventional RT and is a more convenient treatment for the patients.

Effect of the vitamin B12-binding protein haptocorrin present in human milk on a panel of commensal and pathogenic bacteria.

BACKGROUND: Haptocorrin is a vitamin B12-binding protein present in high amounts in different body fluids including human milk. Haptocorrin has previously been shown to inhibit the growth of specific E. coli strains, and the aim of the present study was to elucidate whether the antibacterial properties of this protein may exert a general defense against pathogens and/or affect the composition of the developing microbiota in the gastrointestinal tracts of breastfed infants. FINDINGS: The present work was the first systematic study of the effect of haptocorrin on bacterial growth, and included 34 commensal and pathogenic bacteria to which infants are likely to be exposed. Well-diffusion assays addressing antibacterial effects were performed with human milk, haptocorrin-free human milk, porcine holo-haptocorrin (saturated with B-12) and human apo-haptocorrin (unsaturated). Human milk inhibited the growth of S. thermophilus and the pathogenic strains L. monocytogenes LO28, L. monocytogenes 4446 and L. monocytogenes 7291, but the inhibition could not be ascribed to haptocorrin. Human apo-haptocorrin inhibited the growth of only a single bacterial strain (Bifidobacterium breve), while porcine holo-haptocorrin did not show any inhibitory effect. CONCLUSIONS: Our results suggest that haptocorrin does not have a general antibacterial activity, and thereby contradict the existing hypothesis implicating such an effect. The study contributes to the knowledge on the potential impact of breastfeeding on the establishment of a healthy microbiota in infants.

Reduction of Cone-Beam CT scan time without compromising the accuracy of the image registration in IGRT.

BACKGROUND: In modern radiotherapy accelerators are equipped with 3D cone-beam CT (CBCT) which is used to verify patient position before treatment. The verification is based on an image registration between the CBCT acquired just before treatment and the CT scan made for the treatment planning. The purpose of this study is to minimise the scan time of the CBCT without compromising the accuracy of the image registration in IGRT. MATERIAL AND METHODS: Fast scans were simulated by reducing the number of acquired projection images, i.e. new reconstructions based on a subset of the original projections were made. The deviation between the registrations of these new reconstructions and the original registration was measured as function of the amount of reduction. RESULTS AND DISCUSSION: Twenty nine head and neck (H&N) and 11 stereotactic lung patients were included in the study. The mean of the registration deviation did not differ significantly from zero independently of the number of projections included in the reconstruction. Except for the smallest subset of reconstructions (10% and 25% of the original projection for the lung and H&N patients, respectively) the standard deviation of the registration differences was constant. The standard deviations were approximately 0.1 mm and 0.2 mm for the H&N and lung group, respectively. Based on these results an in-house developed solution, able to reduce the Cone-Beam CT scan time, has been implemented clinically.

Cone beam CT evaluation of patient set-up accuracy as a QA tool.

PURPOSE: To quantify by means of cone beam CT the random and systematic uncertainty involved in radiotherapy, and to determine if this information can be used for e.g. technical quality assurance, evaluation of patient immobilization and determination of margins for the treatment planning. PATIENTS AND METHODS: Eighty four cancer patients have been cone beam CT scanned at treatment sessions 1, 2, 3, 10 and 20. Translational and rotational errors are analyzed. RESULTS AND CONCLUSIONS: For the first three treatment sessions the mean translational error in the AP direction is 1 mm; this indicates a small error in the calibration of coronal isocentric laser. The observed SD of the systematic error in each direction is 1 mm if a correction is made after the third fraction with an action limit of 4 mm. The SD of the random errors of the patient group is approximately 1 mm in each direction. The rotational errors have a vanishing mean and a systematic error of 0.5-1.2 degrees and a random error of 0.4-0.7 degrees. The uncertainties from the first three treatment sessions (disregarding rotations) lead to a margin of 4 mm from ITV to PTV for Head-and-Neck patients (all directions) and Thorax patients (AP and lateral directions). In the CC direction, the margin has to be 5 mm for the Thorax patients. The total uncertainty on the patient position grows during the treatment course, especially in the CC direction for patients receiving thoracical irradiation. This may stem from problems in the immobilization of these patients. Consequently, it may be necessary to increase the margins in the CC direction. Once the CBCT scans have been made, the information is available for off-line analysis without any extra workload. Thus, the CBCT data can supplement scheduled QA checks.

The representitativeness of patient position during the first treatment fractions.

BACKGROUND: During external radiotherapy daily or even weekly image verification of the patient position might be problematic due to the resulting workload. Therefore it has been customary to perform image verification only at the first treatment fraction. In this study it is investigated whether the patient position uncertainty at the initial three treatment fractions is representative for the uncertainty throughout the treatment course. METHODS: Seventy seven patients were treated using Elekta Synergy accelerators. The patients were immobilized during treatment by use of a customized VacFix bag and a mask of AquaPlast. Cone beam CT (CBCT) scans were performed at fractions 1, 2, and 3 and at the 10th and 20th treatment fractions. Displacements in patient position, translational and rotational, have been measured by an image registration of the CBCT and the planning CT scan. The displacements data are evaluated retrospectively and the effect of Action Level (AL) image verification protocols based on sessions 1, 2, 3 are simulated. The resulting overall patient position uncertainties of the different protocols are evaluated at the 10th and 20th fractions. RESULTS AND CONCLUSIONS: The differences between the addressed protocols are shown to be very small compared to the overall increase in patient position uncertainty during the treatment course. Thus the main problem in achieving the smallest possible uncertainty for the overall treatment is not the selection of 'the best' image verification protocol for the initial three fractions. The main challenge is that the overall patient position uncertainty increases during the treatment course. Information about the patient position during the first three fractions is therefore not representative for the overall patient position. For these types of patients and immobilization equipment it would consequently be an advantage to reduce the number of image verification sessions during the initial fractions and then compensate with additional imaging sessions during the remaining treatment course.

Inter- and intrafractional movement of the tumour in extracranial stereotactic radiotherapy of NSCLC.

PURPOSE: The purpose of this study is to determine the inter- and intra-fractional respiration induced tumour movements as well as setup accuracy in a stereotactic body frame for stereotactic treatments of NSCLC patients. PATIENTS AND METHODS: From August 2005 to March 2008, 26 patients with NSCLC where given a stereotactic treatment. The patients were scanned with normal and uncoached respiration without use of abdominal compression. Each patient had CT-scans performed at four occasions throughout the treatment: As part of the CT-simulation and before the three radiotherapy treatments. At every occasion five individual CT-scans covering the tumour volume were obtained. In this way 20 scans where obtained from each patient. In each CT-scan the maximum positions of the tumour where located in all six directions, represented by the top, bottom, anterior, posterior, left and right part of the tumour. These coordinate constitute the data of this study. RESULTS: The standard deviations of the respiration induced intra-fractional movements were: LR: 0.9 mm, AP: 1.6 mm and CC: 2.0 mm (1 SD). The inter-fractional movements were: LR: 1.1 mm, AP: 1.3 mm and CC: 1.7 mm (1 SD). Finally the set up accuracies in the body frame were LR: 1.5 mm, AP: 1.1 mm and CC: 1.7 mm (1 SD). DISCUSSION AND CONCLUSIONS: Consecutive CT scans can be used to evaluate the respiration induced tumour movement. For patients immobilized in a stereotactic body frame, large movements of the tumour are rarely seen within the lung. With consecutive scans, using a conventional CT-scanner, it is possible to select those patients in whom the tumour movement is large. Application of 4D CT and Cone beam verification is strongly encouraged to minimize the requested treatment margin.