Clinically Delivered Treatment for Glioma Patients on a Hybrid Magnetic Resonance Imaging (MRI)-Linear Accelerator (MR-Linac) and a Cone Beam CT (CBCT)-Guided Linac: Dosimetric Comparisons with In Vivo Skin Dose Correlation

Magnetic Resonance Imaging (MRI)-Linear Accelerator (MR-Linac) radiotherapy requires special consideration for secondary electron interactions within the magnetic eld, which can alter dose deposition at air-tissue interfaces. Thirty-seven consecutive glioma patients treated during their radiotherapy course with at least one fraction delivered on MR-Linac or Cone Beam CT (CBCT)-guided Linac, were analyzed. Treatment planning for both systems were completed prior to radiotherapy initiation and approved for clinical delivery using commercial treatment planning systems (TPS): a Monte Carlo calculation-based or convolution calculation-based TPS for MR-Linac or CBCT-Linac, respectively. Dosimetric parameters for planning target volume (PTV), organs-at-risk (OARs), and air-tissue interface were compared. In vivo skin dose during a single fraction of MR-Linac and CBCT-Linac treatment was measured using an Optically Stimulated Luminescent Dosimeter (OSLD) and correlated with TPS skin dose. CBCT-Linac


Introduction
Modern radiotherapy with selective incorporation of Magnetic Resonance Imaging (MRI) during the treatment course has shown promise for evaluating glioma tumor dynamics [1], predicting glioma treatment response [2] and identifying regions for dose escalation based on functional imaging. Typically, Loading [MathJax]/jax/output/CommonHTML/jax.js no more than 2 to 3 MR images were obtained during a 6-week radiation treatment course due to practicalities and cost of obtaining repeat MRIs. With the advent of integrated MRI-linear accelerator (MR-Linac) delivery systems, this technology has the potential for the rst time to allow daily acquisition of high eld strength (1.5 Tesla) diagnostic quality MRI to enable adaptive radiotherapy, to individualize the radiation treatment plan and to incorporate functional imaging. At our institution, we have been developing the application of the Unity MR-Linac (Elekta AB, Stockholm, Sweden) to brain tumors, and have treated ~ 150 glioma patients with either 3 or 6 weeks of daily fractionated standard radiotherapy with concurrent temozolomide.
The challenge of delivering radiation within a high MRI eld strength environment is the in uence of the Lorentz force on dose deposition. The Electron Return Effect (ERE) refers to secondary electrons exiting tissue into air being curved back to deposit dose at the tissue surface due to the Lorentz Effect, which results from the presence of the strong magnetic eld placed perpendicularly to the beam direction [3][4][5][6][7][8][9][10][11].
Until now, the ERE has been investigated in phantom studies [12], as well as in simulated dosimetric studies [13][14][15][16][17] with research versions of MR-Linac planning software prior to the release of the current clinical treatment planning version. The purpose of the current study is to report on those glioma patients treated on the MOMENTUM prospective registry study (Clinicaltrials.gov: NCT04075305) [18] who received at least one fraction of radiotherapy on both the MR-Linac and a Cone Beam CT (CBCT)-guided Linac: 1) the dosimetric impact of the magnetic eld on the target, organs-at-risk (OARs), skin and tissues surrounding air cavities, and; 2) to compare skin dose modelled from the treatment planning software with in vivo skin dose measurements.

Patient Population
This consecutive case series of glioma patients treated between July 2019 and February 2021 consented to the institutional research ethics board approved prospective MOMENTUM trial. Patients were treated on the Unity MR-Linac (Elekta AB, Stockholm, Sweden) and our practice was to create a clinical backup conventional CBCT-Linac plan during treatment planning. On days when the MR-Linac was scheduled for maintenance or had a service issue such that treatment would otherwise be delayed, patients were irradiated on an Elekta CBCT-Linac (Elekta AB, Stockholm, Sweden) for that particular radiotherapy fraction. Thirty-seven glioma patients treated with at least one fraction on both the MR-Linac and CBCT-Linac for their adjuvant radiotherapy at our institution met these criteria. All patients completed maximal safe surgical resection followed by either 3 or 6 weeks of adjuvant radiotherapy according to standard practices [19][20].

Radiotherapy Simulation and Target De nition
Loading [MathJax]/jax/output/CommonHTML/jax.js All patients were simulated with a treatment planning CT (Brilliance, Philips Healthcare, Best, Netherlands) with a slice thickness of 1.0 mm, and immobilized with a thermoplastic head immobilization device (CIVCO Medical Solutions, Kalona, Iowa, USA). MRI simulation at 1.5 Tesla (Ingenia, Philips Healthcare, Best, Netherlands) was also performed in the treatment position with the immobilization device applied. Standard volumetric axial T1 gadolinium-enhanced and T2 FLAIR sequences with a slice thickness of 1.0 mm were acquired. CT images and MRI sequences were registered and fused based on rigid mutual information registration within a region of interest box de ned around the tumor [21].
Delineation of OARs, gross tumor volume (GTV), and clinical target volume (CTV) were de ned based on glioma consensus contouring guidelines [22]. Planning target volume (PTV) was generated as a 0.4-cm isotropic expansion of the CTV.

Radiotherapy Planning
Treatment planning for the MR-Linac was completed on the Monaco treatment planning system (TPS) (Monaco v5.40, Elekta AB, Stockholm, Sweden). The Monte Carlo algorithm [23] accounts for magnetic eld effects for the MR-Linac. A TPS based on a convolution-superposition dose calculation algorithm (Pinnacle v9.8, Philips Healthcare, Eindhoven, Netherlands) was used for planning on the CBCT-Linac (Fig. 1). All MR-Linac plans used ≥ 9 coplanar non-opposing Intensity-Modulated Radiation Therapy (IMRT) beams, and were optimized to achieve at least 90% of the prescription dose covering 99% of PTV (D99%>90%), less than 5% of PTV getting 105% of the prescription dose (V105%<5%), and less than 110% of the prescription dose to 0.1cc volume of PTV (D0.1cc < 110%), as outlined by the MR-Linac consortium clinical treatment planning document. All CBCT-Linac plans used ≥ 7 coplanar non-opposing IMRT beams, and were optimized to achieve at least 95% of PTV covered by 95% of the prescription dose (V95%≥95%), and at most 1% of PTV getting 105% of the prescription dose (V105%≤1%). Dose to OARs were constrained according to our institutional protocols (Supplementary Material,

Skin Dosimetry Assessment
Skin volumes were generated as a 5 mm rim of tissue contracted from the patient body surface (Supplementary Material, Fig. 1). Tissues around air cavities were generated as a 5mm rim of tissue expanded from air cavity volumes (e.g. nasopharynx, paranasal sinuses). Dosimetric parameters analyzed included: Mean dose and Maximum dose to 2cc volumes of tissues surrounding air cavities and skin contours (Air cavity Dmean, Air cavity D2cc, Skin Dmean, Skin D2cc), as well as the volume of skin receiving 20 Gy (Skin V20Gy).
For 10 randomly selected patients, in vivo skin dose measurements during one fraction of MR-Linac treatment and one fraction of CBCT-Linac treatment were obtained using Optically Stimulated Luminescent Dosimeters (OSLDs; nanoDots, Landauer, Glenwood, IL, USA) placed in a de ned location on the patient's skin near the PTV (Supplementary Material, Fig. 2). OSLD dose point in the TPS was de ned as the placement location on the treatment unit, at 0.6 mm depth from the patient surface. In the TPS, the patient surface was de ned as the 0.6 g/cc boundary between tissue and air. The 0.6 mm depth is the water equivalent depth of an OSLD taking into account its plastic casing, and the accuracy was rated to be ± 3% [12]. Dose delivered to skin, as measured by the OSLD, were correlated to both corresponding clinical treatment plans to determine which TPS best predicted the in vivo dose measurement.

Statistical Analysis
Descriptive statistics were used to summarize the dosimetric parameters. Assumption of normality was assessed using the Smirnov-Kolmogorov test. Student's t-paired test or Wilcoxon signed-rank test, as appropriate based on normality assumption, were used to compare dosimetric parameters between MR-Linac plans and CBCT-Linac plans. Spearman's correlation was used to assess the relationship between in vivo OSLD measurements and TPS skin dose. All statistical tests were two-sided, and threshold used for statistical signi cance was p < 0.05. Statistical analyses were performed using version 9.4 of the SAS system for Windows (2002-2012 SAS Institute, Inc., Cary, NC, USA).

Tissues around Air Cavities and at Skin Surface
The difference in dosimetric parameters for tissues surrounding air cavities and skin between MR-Linac and CBCT-Linac are shown in Fig. 2b, and summarized in   more accurately (Spearman's correlation ρ = 0.9500, p < 0.0001). By comparison, there was a weaker association between CBCT-Linac Pinnacle modelled skin dose and in vivo OSLD skin dose (Spearman's correlation ρ = 0.8000, p < 0.0096).

Discussion
We demonstrate that Monaco is able to accurately generate safe MR-Linac radiotherapy treatment plans for glioma patients that achieve planning objectives. We observed that for coplanar beam arrangements, MR-Linac treatments have lower homogeneity, but higher dose conformity and equivalent dose falloff outside of the target, when compared with CBCT-Linac. Conventional CBCT-Linac with non-coplanar beams can potentially achieve better dose falloff than MR-Linac, but only coplanar beam arrangements were used to standardize comparisons. MR-Linac treatment plans had more heterogenous dose distributions, which is consistent with the observed small but statistically signi cant increase in PTV D50%, D5%, and D2%. This is also consistent with previous reports showing higher heterogeneity and higher median V100% for MR-Linac plans compared with CBCT-Linac [24]. Similarly, a very small but statistically signi cant increase in Brainstem D0.1cc, each Globe D0.03cc, and each Lens D0.03cc was observed in MR-Linac plans. Over the course of a patient's entire radiotherapy regimen, the absolute summed dose difference was < 1 Gy for PTV parameters, < 1 Gy for brainstem, approximately 3 Gy for each globe, and approximately 2 Gy for each lens. Since MR-Linac treatment plans are adapted to position every fraction [25], the exact location of these minimally higher dose regions varies geospatially every fraction, which may negate their effects when accumulated over the treatment course. Nonetheless, all MR-Linac treatments achieved standard planning objectives and dose constraints, and it is unlikely that these small differences translate into clinically relevant outcomes.
We also quantitatively characterized the impact of the MR-Linac's magnetic eld on delivered dose to skin and tissue surrounding air cavities. Compared to CBCT-Linac, we observed that MR-Linac treatments showed 1.52 Gy higher Dmean (p < 0.0001), and 1.23 Gy higher D2cc (p = 0.0007) for tissues surrounding air cavities. Skin D2cc was not statistically different (p > 0.05), skin Dmean was 1.10 Gy higher (p < 0.0001), and skin V20Gy was 19.04 cm3 higher (p = 0.0001) with MR-Linac treatment. This is consistent with recent preliminary studies investigating the effect of the MR-Linac's magnetic eld on radiotherapy treatment [12][13][14][15][16][17]. Tseng et al. used Monaco to retrospectively generate MR-Linac plans with 9 coplanar non-opposing IMRT beams on 24 patients with intact single brain metastases, and found MR-Linac had 0.08 Gy higher Dmean and 0.6 Gy higher D2cc for skin, and 0.07 Gy higher Dmean and 0.3 Gy higher D2cc for tissues around air cavities [13]. Schrenk et al. used an open-source Monte Carlo-based TPS to retrospectively generate plans in the presence of a magnetic eld with ≥ 7 coplanar non-opposing 3D-CRT and IMRT beams on 4 patients with non-small cell lung cancer, and found that the presence of the perpendicular magnetic eld increased mean dose to tissues surrounding the lung air cavity by 0.5 Gy (18.5%) [14]. Nachbar  opposing equally-spaced IMRT beams on 10 patients with locally advanced rectal cancer, and found MR-Linac had higher skin dose and higher PTV V105% (14.8%) compared with CBCT-Linac VMAT with two full coplanar arcs (5.0%) and CBCT-Linac IMRT using 5 coplanar beams (7.3%) [17]. Taken together, these studies demonstrated that MR-Linac plans have small increases in dose to skin and tissues surrounding air cavities, and are consistent with our ndings. However, the present study is unique in that the selected patient population represents a large cohort of glioma patients who received at least one fraction on both MR-Linac and CBCT-Linac based on clinically approved radiotherapy plans. Second, the plans were prospectively generated prior to treatment and delivered on both MR-Linac and CBCT-Linac, in contrast to previous studies of simulated plans that were retrospectively generated for dosimetric comparison. Lastly and importantly, we performed in vivo measurements to correlate the skin dose calculated on Monaco and Pinnacle, with measured patient skin dose via OSLD on MR-Linac and CBCT-Linac.
A potential limitation of our study is the variability in dose fractionations used. However, plan evaluation was performed with pairwise comparisons between MR-Linac and CBCT-Linac treatments for each patient and are independent of absolute values. Second, there may be potential uncertainty in OSLD measurements caused by placement, air gaps, and surface effects. To mitigate this, a single OSLD measurement was obtained from each patient's MR-Linac and CBCT-Linac treatments using standardized technique [12], although we acknowledge that reproducibility could be assessed by performing additional measurements. Third, since there are differences in how each TPS models patient surface, calculates surface dosimetry, and uses voxel sizes for TPS dose evaluation, we recognize the di culty in quantifying the magnitude of these effects and their contribution to the dose differences observed.
Finally, each patient's clinically delivered treatment plan was analyzed on the latest version of clinical

Declarations
Funding: The authors did not receive nancial support from any organization for the submitted work.

Con icts of Interest:
MR is a co-inventor/owns intellectual property speci c to the image-guidance system on the Gamma Knife Icon outside the submitted work.
HS has received travel accommodations/expenses and honoraria from Elekta AB outside the submitted work.
SM has provided research support to Novartis AG and has received honoraria from Novartis AG and Ipsen and travel accommodations/expenses from Elekta outside the submitted work.
BK has received previous grant funding from Elekta AB outside of the submitted work and has also received travel accommodations/expenses from Elekta AB outside of this work.
AS is an advisor/consultant for AbbVie, Merck, Roche, Varian, Elekta AB, BrainLAB, and VieCure; is a board member of the International Stereotactic Radiosurgery Society; is cochair of the AO Spine

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. SupplementalMaterial.docx