Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience.

BACKGROUND AND PURPOSE: Daily online adaptation of the clinical target volume (CTV) using MR-guided radiotherapy enables margin reduction of the planning target volume (PTV). This study describes the implementation and initial experience of MR-guided radiotherapy on the 1.5T MR-linac and evaluates treatment time, patient compliance, and target coverage, including an initial assessment of margin reduction. MATERIALS AND METHODS: Patients were treated on a 1.5T MR-linac (7MV, FFF). At each fraction a 3D T2 weighted (T2w) MR-sequence was acquired on which the CTV was adapted after a deformable registration of the contours from the pre-planning CT scan. Based on the new contours a full online replanning was done after which a new 3D T2w MR-sequence was acquired for position verification. A 5 field Intensity Modulated Radiotherapy (IMRT) plan was delivered. RESULTS: Forty-three patients with rectal cancer were treated with 25 Gy in 5 fractions of which 18 with reduced margins. In total, 204 of 215 fractions were delivered on the MR-linac all of which obtained a clinically acceptable treatment plan. Median in-room time per fraction was 48 min (interquartile range 8). No fractions were canceled or interrupted because of patient intolerance. CTV coverage after margin reduction was good on all post-treatment scans but one due to passing gas. CONCLUSION: MR-guided radiotherapy using daily full online recontouring and replanning on a 1.5T MR-linac for rectal cancer is feasible and currently takes about 48 min per fraction.

Beam characterisation of the 1.5 T MRI-linac.

As a prerequisite for clinical treatments it was necessary to characterize the Elekta 1.5 T MRI-linac 7 MV FFF radiation beam. Following acceptance testing, beam characterization data were acquired with Semiflex 3D (PTW 31021), microDiamond (PTW 60019), and Farmer-type (PTW 30013 and IBA FC65-G) detectors in an Elekta 3D scanning water phantom and a PTW 1D water phantom. EBT3 Gafchromic film and ion chamber measurements in a buildup cap were also used. Special consideration was given to scan offsets, detector effective points of measurement and avoiding air gaps. Machine performance has been verified and the system satisfied the relevant beam requirements of IEC60976. Beam data were acquired for field sizes between 1 × 1 and 57 × 22 cm2. New techniques were developed to measure percentage depth dose (PDD) curves including the electron return effect at beam exit, which exhibits an electron-type practical range of 1.2 ± 0.1 cm. The Lorentz force acting on the secondary charged particles creates an asymmetry in the crossline profiles with an average shift of +0.24 cm. For a 10 × 10 cm2 beam, scatter from the cryostat contributes 1% of the dose at isocentre. This affects the relative output factors, scatter factors and beam profiles, both in-field and out-of-field. The average 20%-80% penumbral width measured for small fields with a microDiamond detector at 10 cm depth is 0.50 cm. MRI-linac penumbral widths are very similar to that of the Elekta Agility linac MLC, as is the near-surface dose PDD(0.2 cm) = 57%. The entrance surface dose is ∼36% of Dmax. Cryostat transmission is quantified for inclusion within the treatment planning system. As a result, the 1.5 T MRI-linac 7 MV FFF beam has been characterised for the first time and is suitable for clinical use. This was a key step towards the first clinical treatments with the MRI-linac, which were delivered at University Medical Center Utrecht in May 2017 (Raaymakers et al 2017 Phys. Med. Biol. 62 L41-50).

First patients treated with a 1.5 T MRI-Linac: clinical proof of concept of a high-precision, high-field MRI guided radiotherapy treatment.

The integration of 1.5 T MRI functionality with a radiotherapy linear accelerator (linac) has been pursued since 1999 by the UMC Utrecht in close collaboration with Elekta and Philips. The idea behind this integrated device is to offer unrivalled, online and real-time, soft-tissue visualization of the tumour and the surroundings for more precise radiation delivery. The proof of concept of this device was given in 2009 by demonstrating simultaneous irradiation and MR imaging on phantoms, since then the device has been further developed and commercialized by Elekta. The aim of this work is to demonstrate the clinical feasibility of online, high-precision, high-field MRI guidance of radiotherapy using the first clinical prototype MRI-Linac. Four patients with lumbar spine bone metastases were treated with a 3 or 5 beam step-and-shoot IMRT plan. The IMRT plan was created while the patient was on the treatment table and based on the online 1.5 T MR images; pre-treatment CT was deformably registered to the online MRI to obtain Hounsfield values. Bone metastases were chosen as the first site as these tumors can be clearly visualized on MRI and the surrounding spine bone can be detected on the integrated portal imager. This way the portal images served as an independent verification of the MRI based guidance to quantify the geometric precision of radiation delivery. Dosimetric accuracy was assessed post-treatment from phantom measurements with an ionization chamber and film. Absolute doses were found to be highly accurate, with deviations ranging from 0.0% to 1.7% in the isocenter. The geometrical, MRI based targeting as confirmed using portal images was better than 0.5 mm, ranging from 0.2 mm to 0.4 mm. In conclusion, high precision, high-field, 1.5 T MRI guided radiotherapy is clinically feasible.

Minimizing the magnetic field effect in MR-linac specific QA-tests: the use of electron dense materials.

To address the quality assurance (QA) of a MR-linac which is an MRI combined with a linear accelerator (linac), the traditional linac QA-tests need to be redesigned, since the presence of the static magnetic field in the MR-linac alters the electron trajectory. The latter causes the asymmetry in the dose kernel which is introduced by the magnetic field and hinders accurate geometrical QA-tests for the MR-linac. We introduced the use of electron dense materials (e.g. copper) to reduce the size of the dose kernel and thereby the magnetic field effect on the dose deposition. Two examples of QA-tests are presented in which the geometrical accuracy of the MR-linac was addressed; beam profile and star-shot measurements. The introduced setup was compared with a reference setup and both were tested on a conventional and the MR-linac. The results showed that the symmetry of the recorded beam profile was restored in presence of the copper material and that the isocenter size of the MR-linac can be determined accurately with the introduced star-shot setup. The use of electron dense materials is not limited to the presented QA-tests but has a broad application for beam-specific QA-tests in presence of a magnetic field.

Quantification of platelet-surface interactions in real-time using intracellular calcium signaling.

Platelets get easily activated when in contact with a surface. Therefore in the design of microfluidic blood analysis devices surface activation effects have to be taken into account. So far, platelet-surface interactions have been quantified by morphology changes, membrane marker expression or secretion marker release. In this paper we present a simple and effective method that allows quantification of platelet-surface interactions in real-time. A calcium indicator was used to visualize intracellular calcium variations during platelet adhesion. We designated cells that showed a significant increase in cytosolic calcium as responding cells. The fraction of responding cells upon binding was analyzed for different types of surfaces. Thereafter, the immobilized platelets were chemically stimulated and the fraction of responding cells was analyzed. Furthermore, the time between the binding or chemical stimulation and the increased cytosolic calcium level (i.e. the response delay time) was measured. We used surface coatings relevant for platelet-function testing including Poly-L-lysine (PLL), anti-GPIb and collagen as well as control coatings such as Bovine Serum Albumin (BSA) and mouse immunoglobulin (IgG). We found that a lower percentage of responding cells upon binding, results in a higher percentage of responding cells upon chemical stimulation after binding. The measured delay time between platelet binding under sedimentation and calcium response was the lowest on a PLL-coated surface, followed by an anti-GPIb and collagen-coated surface and IgG-coated surface. The presented method provides real-time information of platelet-surface interactions on a single cell as well as on a cell ensemble level. For future in-vitro diagnostic tests, this real-time single-cell function analysis can reveal heterogeneities in the biological processes of a cell population.