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MRI-guided lung SBRT: Present and future developments

Open AccessPublished:February 24, 2017DOI:https://doi.org/10.1016/j.ejmp.2017.02.003

      Highlights

      • MRI-guidance for lung SBRT promises superior soft-tissue contrast.
      • The functional imaging capabilities of MRI could aid tumour and OAR delineation.
      • Novel treatment machines with on-board MRI-guidance capabilities are emerging.
      • Better targeting could increase the number of lung patients treatable with SBRT.

      Abstract

      Stereotactic body radiotherapy (SBRT) is rapidly becoming an alternative to surgery for the treatment of early-stage non-small cell lung cancer patients. Lung SBRT is administered in a hypo-fractionated, conformal manner, delivering high doses to the target. To avoid normal-tissue toxicity, it is crucial to limit the exposure of nearby healthy organs-at-risk (OAR).
      Current image-guided radiotherapy strategies for lung SBRT are mostly based on X-ray imaging modalities. Although still in its infancy, magnetic resonance imaging (MRI) guidance for lung SBRT is not exposure-limited and MRI promises to improve crucial soft-tissue contrast. Looking beyond anatomical imaging, functional MRI is expected to inform treatment decisions and adaptations in the future.
      This review summarises and discusses how MRI could be advantageous to the different links of the radiotherapy treatment chain for lung SBRT: diagnosis and staging, tumour and OAR delineation, treatment planning, and inter- or intrafractional motion management. Special emphasis is placed on a new generation of hybrid MRI treatment devices and their potential for real-time adaptive radiotherapy.

      Keywords

      1. Introduction

      1.1 The clinical rationale for lung SBRT

      Lung cancer is the most common type of cancer, with non-small cell lung cancer (NSCLC) representing the majority of cases [
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      ]. Within this patient cohort, roughly 15–20% present with an early and localised form of the disease (stage I), indicating a lack of nodal involvement and metastatic spread. The recent roll-out of wide-scale, low-dose computed tomography (CT)-assisted screening might further increase the number of patients diagnosed at an early disease stage. Traditionally, surgery is the treatment method of choice for these patients [
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      ]. However, some patients are classified as medically inoperable due to comorbidities, or they decline surgery for other reasons.
      In the past, the alternative treatment option of prescribing conventionally fractioned radiotherapy resulted in worse outcome compared to surgery, mainly due to the lack of local control [
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      ]. Taking heed from cranial radiosurgery, stereotactic body radiotherapy (SBRT) aims at delivering fewer, but more intense radiotherapy fractions (hypo-fractionation). Several studies have shown that increasing the biologically effective dose above 100 Gy decreases the number of patients with local failures and increases overall survival in early-stage NSCLC patients compared to conventionally fractionated radiotherapy [
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      ], leading to SBRT being the new standard of care for inoperable early-stage NSCLC patients.
      Traditionally, only patients with tumours located at least 2 cm away from the proximal bronchial tree are considered for SBRT [
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      ]. This pre-selection of eligible patients intends to minimise bronchial toxicities, but it also severely limits treatment options for inoperable early-stage NSCLC patients with more centrally located tumours [
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      Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.
      ]. More recently, trials were set up to identify a slightly milder form of hypo-fractionation suitable for these patients [
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      • Mornex F.
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      ]. Furthermore, SBRT is being investigated for the treatment of oligometastatic lung cancer [
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      Stereotactic body radiotherapy for oligometastatic lung tumors.
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      Simulated online adaptive magnetic resonance guided stereotactic body radiation therapy for the treatment of oligometastatic disease of the abdomen and central thorax: characterization of potential advantages.
      ] and small cell lung cancer [
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      Multi-institutional retrospective study of stereotactic body radiation therapy for stage I small cell lung cancer: Japan radiation oncology study group (JROSG).
      ].

      1.2 Current clinical workflow for lung SBRT

      While SBRT aims at delivering high doses to the target, it is crucial to limit the exposure of nearby healthy organs-at-risk (OAR), including surrounding lung tissue, the brachial plexus, spinal cord, trachea, proximal bronchial tree, oesophagus, heart and great aortic vessels, liver and ribs [
      • Kong F.M.
      • Ritter T.
      • Quint D.J.
      • Senan S.
      • Gaspar L.E.
      • Komaki R.U.
      • et al.
      Consideration of dose limits for organs at risk of thoracic radiotherapy: atlas for lung, proximal bronchial tree, esophagus, spinal cord, ribs, and brachial plexus.
      ]. An additional challenge for the radiotherapy of lung tumours are inter- and intrafractional anatomical changes [
      • Keall P.J.
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      • Jiang S.B.
      • et al.
      The management of respiratory motion in radiation oncology report of AAPM task group 76.
      ].
      After diagnosis, staging and treatment decision, the clinical radiotherapy workflow begins with the acquisition of a planning CT scan. Accurate delineation of the tumour and nearby OAR in this image is crucial, as a treatment plan is created based on these contours. Today, many institutions utilise modern delivery techniques for SBRT, such as intensity-modulated radiotherapy and volumetric-modulated arc radiotherapy [
      • Verbakel W.F.
      • Senan S.
      • Cuijpers J.P.
      • Slotman B.J.
      • Lagerwaard F.J.
      Rapid delivery of stereotactic radiotherapy for peripheral lung tumors using volumetric intensity-modulated arcs.
      ,
      • Navarria P.
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      • Mancosu P.
      • Alongi F.
      • Clerici E.
      • Tozzi A.
      • et al.
      Volumetric modulated arc therapy with flattening filter free (FFF) beams for stereotactic body radiation therapy (SBRT) in patients with medically inoperable early stage non small cell lung cancer (NSCLC).
      ,
      • Rossi M.M.
      • Peulen H.M.
      • Belderbos J.S.
      • Sonke J.J.
      Intrafraction motion in stereotactic body radiation therapy for non-small cell lung cancer: Intensity modulated radiation therapy versus volumetric modulated arc therapy.
      ]. In conjunction with inverse treatment plan optimization it is possible to design highly conformal dose distributions, even in inhomogeneous anatomies [
      • Ong C.L.
      • Palma D.
      • Verbakel W.F.
      • Slotman B.J.
      • Senan S.
      Treatment of large stage I-II lung tumors using stereotactic body radiotherapy (SBRT): planning considerations and early toxicity.
      ,
      • Giglioli F.R.
      • Strigari L.
      • Ragona R.
      • Borzi G.R.
      • Cagni E.
      • Carbonini C.
      • et al.
      Lung stereotactic ablative body radiotherapy: a large scale multi-institutional planning comparison for interpreting results of multi-institutional studies.
      ].
      In order to ensure correct delivery of the treatment plan, utmost attention is paid to precise patient positioning for each fraction, for example by using body frames for fixation [
      • Nagata Y.
      • Negoro Y.
      • Aoki T.
      • Mizowaki T.
      • Takayama K.
      • Kokubo M.
      • et al.
      Clinical outcomes of 3D conformal hypofractionated single high-dose radiotherapy for one or two lung tumors using a stereotactic body frame.
      ]. About 10–15 years ago, volumetric X-ray imaging started being integrated with modern linear accelerators (linacs) [
      • Mackie T.R.
      • Balog J.
      • Ruchala K.
      • Shepard D.
      • Aldridge S.
      • Fitchard E.
      • et al.
      Tomotherapy.
      ,
      • Jaffray D.A.
      • Siewerdsen J.H.
      • Wong J.W.
      • Martinez A.A.
      Flat-panel cone-beam computed tomography for image-guided radiation therapy.
      ,
      • Pouliot J.
      • Bani-Hashemi A.
      • Josephine C.
      • Svatos M.
      • Ghelmansarai F.
      • Mitschke M.
      • et al.
      Low-dose megavoltage cone-beam CT for radiation therapy.
      ]. Utilising the provided imaging information, the patient can be rigidly shifted to position the target inside the treatment beam [
      • Purdie T.G.
      • Bissonnette J.P.
      • Franks K.
      • Bezjak A.
      • Payne D.
      • Sie F.
      • et al.
      Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: localization, verification, and intrafraction tumor position.
      ,
      • Sonke J.J.
      • Rossi M.
      • Wolthaus J.
      • van Herk M.
      • Damen E.
      • Belderbos J.
      Frameless stereotactic body radiotherapy for lung cancer using four-dimensional cone beam CT guidance.
      ]. Implanted fiducials often support this process. In addition to rigid shifts, the patient’s body may deform between fractions due to weight loss, tumour growth or shrinkage, or volume changes of healthy organs. The volumetric images acquired prior to each fraction can be used to evaluate whether the original treatment plan is still suitable after interfractional motion. If not, a substitute plan can be created, either based on a newly acquired simulation CT scan or using the in-room images themselves [
      • Di Y.
      • Frank V.
      • John W.
      • Alvaro M.
      Adaptive radiation therapy.
      ,
      • Bhatt A.D.
      • El-Ghamry M.N.
      • Dunlap N.E.
      • Bhatt G.
      • Harkenrider M.M.
      • Schuler J.C.
      • et al.
      Tumor volume change with stereotactic body radiotherapy (SBRT) for early-stage lung cancer: evaluating the potential for adaptive SBRT.
      ].
      Intrafractional motion during treatment delivery, such as respiratory and cardiac movement, may cause the anatomy to shift or deform up to several centimetres [
      • Keall P.J.
      • Mageras G.S.
      • Balter J.M.
      • Emery R.S.
      • Forster K.M.
      • Jiang S.B.
      • et al.
      The management of respiratory motion in radiation oncology report of AAPM task group 76.
      ]. Using a 4D CT scan for treatment planning allows the consideration of breathing motion by deploying either an internal target volume (ITV), mid-ventilation or mid-position approach [
      • Stroom J.C.
      • Heijmen B.J.M.
      Geometrical uncertainties, radiotherapy planning margins, and the ICRU-62 report.
      ,
      • Wolthaus J.W.
      • Schneider C.
      • Sonke J.J.
      • van Herk M.
      • Belderbos J.S.
      • Rossi M.M.
      • et al.
      Mid-ventilation CT scan construction from four-dimensional respiration-correlated CT scans for radiotherapy planning of lung cancer patients.
      ,
      • Wolthaus J.W.
      • Sonke J.J.
      • van Herk M.
      • Belderbos J.S.
      • Rossi M.M.
      • Lebesque J.V.
      • et al.
      Comparison of different strategies to use four-dimensional computed tomography in treatment planning for lung cancer patients.
      ]. However, all these methods are based on extended treatment margins and the characteristics of the target motion can change over the course of the treatment [
      • Takao S.
      • Miyamoto N.
      • Matsuura T.
      • Onimaru R.
      • Katoh N.
      • Inoue T.
      • et al.
      Intrafractional baseline shift or drift of lung tumor motion during gated radiation therapy with a real-time tumor-tracking system.
      ]. Breathing protocols attempt to reproduce a certain anatomical state during treatment delivery by having the patient hold its breath, either voluntarily [
      • Kimura T.
      • Matsuura K.
      • Murakami Y.
      • Hashimoto Y.
      • Kenjo M.
      • Kaneyasu Y.
      • et al.
      CT appearance of radiation injury of the lung and clinical symptoms after stereotactic body radiation therapy (SBRT) for lung cancers: are patients with pulmonary emphysema also candidates for SBRT for lung cancers?.
      ] or aided by an active breathing control device [
      • Cheung P.C.F.
      • Sixel K.E.
      • Tirona R.
      • Ung Y.C.
      Reproducibility of lung tumor position and reduction of lung mass within the planning target volume using active breathing control (ABC).
      ]. Gating turns off the treatment beam if the target leaves a previously defined volume [
      • Shirato H.
      • Shimizu S.
      • Kitamura K.
      • Nishioka T.
      • Kagei K.
      • Hashimoto S.
      • et al.
      Four-dimensional treatment planning and fluoroscopic real-time tumor tracking radiotherapy for moving tumor.
      ]. Both these strategies result in an increased treatment time and reduced patient comfort. More advanced techniques aim at adapting the treatment in real-time by either moving the entire linac [
      • Adler Jr, J.R.
      • Chang S.D.
      • Murphy M.J.
      • Doty J.
      • Geis P.
      • Hancock S.L.
      The Cyberknife: a frameless robotic system for radiosurgery.
      ], tilting the treatment head [
      • Kamino Y.
      • Takayama K.
      • Kokubo M.
      • Narita Y.
      • Hirai E.
      • Kawawda N.
      • et al.
      Development of a four-dimensional image-guided radiotherapy system with a gimbaled X-ray head.
      ], repositioning the patient using a robotic treatment couch [
      • D’Souza W.D.
      • Naqvi S.A.
      • Yu C.X.
      Real-time intra-fraction-motion tracking using the treatment couch: a feasibility study.
      ,
      • Wilbert J.
      • Meyer J.
      • Baier K.
      • Guckenberger M.
      • Herrmann C.
      • He R.
      • et al.
      Tumor tracking and motion compensation with an adaptive tumor tracking system (ATTS): system description and prototype testing.
      ], or by changing the treatment beam’s position and shape by moving the leaves of the linac’s multi-leaf collimator (MLC) [
      • Keall P.
      • Kini V.
      • Vedam S.
      • Mohan R.
      Motion adaptive X-ray therapy: a feasibility study.
      ,
      • Tacke M.B.
      • Nill S.
      • Krauss A.
      • Oelfke U.
      Real-time tumor tracking: automatic compensation of target motion using the Siemens 160 MLC.
      ,
      • Fast M.F.
      • Nill S.
      • Bedford J.L.
      • Oelfke U.
      Dynamic tumor tracking using the Elekta Agility MLC.
      ]. Most of these techniques have been used to deliver real-time adapted lung SBRT [
      • Nuyttens J.J.
      • van de Pol M.
      The CyberKnife radiosurgery system for lung cancer.
      ,
      • Matsuo Y.
      • Ueki N.
      • Takayama K.
      • Nakamura M.
      • Miyabe Y.
      • Ishihara Y.
      • et al.
      Evaluation of dynamic tumour tracking radiotherapy with real-time monitoring for lung tumours using a gimbal mounted linac.
      ,
      • Booth J.T.
      • Caillet V.
      • Hardcastle N.
      • O’Brien R.
      • Szymura K.
      • Crasta C.
      • et al.
      The first patient treatment of electromagnetic-guided real time adaptive radiotherapy using MLC tracking for lung SABR.
      ]. They all require real-time information about the patient’s anatomy. This can be obtained by monitoring either internal or external surrogates and correlating them with the tumour motion [
      • Ozhasoglu C.
      • Murphy M.J.
      Issues in respiratory motion compensation during external-beam radiotherapy.
      ]. The tumour can also be localised using MV portal imaging [
      • Keall P.J.
      • Todor A.D.
      • Vedam S.S.
      • Bartee C.L.
      • Siebers J.V.
      • Kini V.R.
      • et al.
      On the use of EPID-based implanted marker tracking for 4D radiotherapy.
      ,
      • Richter A.
      • Wilbert J.
      • Baier K.
      • Flentje M.
      • Guckenberger M.
      Feasibility study for markerless tracking of lung tumors in stereotactic body radiotherapy.
      ] or kV fluoroscopy [
      • Shimizu S.
      • Shirato H.
      • Ogura S.
      • Akita-Dosaka H.
      • Kitamura K.
      • Nishioka T.
      • et al.
      Detection of lung tumor movement in real-time tumor-tracking radiotherapy.
      ,
      • Cui Y.
      • Dy J.G.
      • Sharp G.C.
      • Alexander B.
      • Jiang S.B.
      Multiple template-based fluoroscopic tracking of lung tumor mass without implanted fiducial markers.
      ]. Automated localisation is often aided by fiducial markers, surgically inserted in or near the target. Another marker-based method detects implanted resonant circuits using an electromagnetic array [
      • Balter J.M.
      • Wright J.N.
      • Newell L.J.
      • Friemel B.
      • Dimmer S.
      • Cheng Y.
      • et al.
      Accuracy of a wireless localization system for radiotherapy.
      ].

      1.3 MRI-guided lung SBRT

      Despite these advances in lung SBRT delivery technique, there are still residual uncertainties. MRI offers better soft-tissue contrast than CT or cone-beam CT (CBCT), does not expose the patient to additional imaging dose, and offers a larger variety of functional imaging capabilities. For this reason, there has been an increased interest in harnessing MRI for radiotherapy of different cancer sites, including lung. This has the potential to enhance several aspects of the lung SBRT workflow, including:
      • diagnosis and staging (Section 3.1),
      • delineation of the tumour and OAR for treatment planning (Section 3.2),
      • accurate patient setup and adaptation of the treatment to interfractional anatomy changes (Section 3.3),
      • monitoring of intrafractional motion and real-time adaptation of the delivery (Section 3.4).
      Decreasing the uncertainties in these areas allows shrinking the treatment margins while maintaining dose coverage of the target. Consequently, reduced toxicities in normal-tissue for lung SBRT, and, ultimately, the expansion of the SBRT to more central lung tumours can be surmised.
      This review first introduces the various technical implementations of MRI scanners into the radiotherapy workflow (Section 2). Afterwards, it discusses the different areas where MRI is already enhancing lung SBRT treatments or might do so in the future (Section 3). It is important to keep in mind that MRI-guided lung SBRT is still in its infancy and that the number of directly related publications is therefore limited.

      2. Technical implementations of MRI scanners into the radiotherapy workflow

      2.1 Offline MRI

      To employ MRI for diagnostic, staging and treatment simulation purposes, having a stand-alone MRI scanner at the same institution can suffice. However, when using MRI for patient setup and interfractional treatment adaptation, identical patient positioning during imaging and treatment becomes crucial. One way to ensure this relies on the transport of the patient between linac and MRI scanner, located in different rooms, on a trolley system using a shared table top and immobilisation device (see Fig. 1) [
      • Karlsson M.
      • Karlsson M.G.
      • Nyholm T.
      • Amies C.
      • Zackrisson B.
      Dedicated magnetic resonance imaging in the radiotherapy clinic.
      ,
      • Bostel T.
      • Nicolay N.H.
      • Grossmann J.G.
      • Mohr A.
      • Delorme S.
      • Echner G.
      • et al.
      MR-guidance–a clinical study to evaluate a shuttle-based MR-linac connection to provide MR-guided radiotherapy.
      ]. Another option is to shuttle the MRI scanner on ceiling-mounted rails into and out of the treatment room (see Fig. 2) [
      • Jaffray D.A.
      • Carlone M.C.
      • Milosevic M.F.
      • Breen S.L.
      • Stanescu T.
      • Rink A.
      • et al.
      A facility for magnetic resonance-guided radiation therapy.
      ]. Both system designs ensure that the magnitude of electromagnetic cross-interference is reduced to a minimum by using spatial separation.
      Figure thumbnail gr1
      Fig. 1Three photographs of the shuttle-based MRI-guided radiotherapy solution at Umeå University, Sweden. A movable treatment table and patient fixation system can be attached to either imaging or treatment device. Reprinted from International Journal of Radiation Oncology*Biology*Physics, 74(2), M. Karlsson, M.G. Karlsson, T. Nyholm, C. Amies, B. Zackrisson, Dedicated Magnetic Resonance Imaging in the Radiotherapy Clinic, pp. 644–51, Copyright (2009), with permission from Elsevier.
      Figure thumbnail gr2
      Fig. 2(A) Floor plan of the MRI-guided facility at Princess Margaret Hospital, Toronto, Canada. (B) The MRI-scanner is attached to rails on the ceiling and can be moved either into the brachytherapy or radiotherapy suite prior to treatment. Reprinted from Seminars in Radiation Oncology, 24(3), D.A. Jaffray, M.C. Carlone, M.F. Milosevic, S.L. Breen, T. Stanescu, A. Rink, H. Alasti, A. Simeonov, M.C. Sweitzer, J.D. Winter, A Facility for Magnetic Resonance–Guided Radiation Therapy, pp. 193–95, Copyright (2014), with permission from Elsevier.

      2.2 Online MRI

      Offline MRI solutions cannot monitor intrafractional anatomical changes and the patient might move between imaging and treatment. For this reason, there are considerable efforts to integrate MRI directly with the treatment unit.
      The first commercially available MRI-guided treatment system, based on irradiation with three 60Co sources, has been developed by ViewRay Inc., Cleveland, OH, USA [
      • Mutic S.
      • Dempsey J.F.
      The ViewRay system: magnetic resonance-guided and controlled radiotherapy.
      ]. The system has been used to treat patients since early 2014, including lung cancer patients with SBRT []. Several research groups/vendors have been working on combining a linac with MRI (see Fig. 3) [
      • Lagendijk J.J.W.
      • Raaymakers B.W.
      • Raaijmakers A.J.E.
      • Overweg J.
      • Brown K.J.
      • Kerkhof E.M.
      • et al.
      MRI/linac integration.
      ,
      • Fallone B.G.
      • Murray B.
      • Rathee S.
      • Stanescu T.
      • Steciw S.
      • Vidakovic S.
      • et al.
      First MR images obtained during megavoltage photon irradiation from a prototype integrated linac-MR system.
      ,

      Keall PJ, Barton M, Crozier S, on behalf of the Australian MRI-Linac Program, including contributors from Ingham Institute Illawarra Cancer Care Centre Liverpool Hospital Stanford University Universities of Newcastle Queensland Sydney Western Sydney and Wollongong, The Australian magnetic resonance imaging-linac program, Seminars Radiat Oncol 24 (3) (2014) 203–6. doi: https://doi.org/10.1016/j.semradonc.2014.02.015.

      ,
      • Mutic S.
      • Low D.
      • Chmielewski T.
      • Fought G.
      • Hernandez M.
      • Kawrakow I.
      • et al.
      TU-H-BRA-08: The design and characteristics of a novel compact linac-based MRI guided radiation therapy (MR-IGRT) system.
      ].
      Figure thumbnail gr3
      Fig. 3MRI-guided treatment units developed by different research groups/vendors. (A) The ViewRay MRIdian, the first clinical system at Washington University, St. Louis, MO, USA (image courtesy of P.J. Parikh), (B) the 1.5 T MR-linac developed by Elekta AB installed at NKI-AvL, Amsterdam, The Netherlands, (C) the linac-MR prototype (v1) at Cross Cancer Institute, Edmonton, Canada (image courtesy of B.G. Fallone, www.linacMR.ca), and (D) the MRI-linac prototype developed by the Australian MR-linac program, located at the Ingham Institute, Liverpool, Australia (image courtesy of G.P. Liney on behalf of the Australian MRI-Linac Program).
      Machine design has to warrant correct functioning of both imaging and treatment system in the presence of electromagnetic cross-interference. The choice of beam source and main magnet as well as the orientation and movement of all the components relative to each other directly influences the dose delivery and imaging capabilities. There are considerable differences between systems with regard to treatment beam properties, such as beam energy, penumbra, field-of-view and MLC leaf width at isocenter, and the strength and orientation of the main magnetic field (see Table 1). In addition to beam properties, the dose delivered to the patient is affected by the B0 magnetic field, which is present at all times. While the primary photon beam is not influenced, the Lorentz force deflects secondary electrons onto a curved trajectory. This electron return effect (ERE) is more pronounced at higher B0 field strengths and distorts the dose especially at air-tissue-interfaces, which present themselves manifold in thoracic anatomy [
      • Raaijmakers A.J.
      • Raaymakers B.W.
      • Lagendijk J.J.
      Integrating a MRI scanner with a 6 MV radiotherapy accelerator: dose increase at tissue-air interfaces in a lateral magnetic field due to returning electrons.
      ]. Signal- and contrast-to-noise ratio as well as spatial fidelity of the images are affected by the strength and homogeneity of the B0 magnetic field as these govern the relaxation times of the MRI signal. Due to lung tissue’s inherently low T2* relaxation time, lower field strengths can be beneficial when attempting to image thoracic anatomies [
      • Wachowicz K.
      • De Zanche N.
      • Yip E.
      • Volotovskyy V.
      • Fallone B.G.
      CNR considerations for rapid real-time MRI tumor tracking in radiotherapy hybrid devices: effects of B0 field strength.
      ].
      Table 1System characteristics of the most common hybrid MRI radiotherapy machines. B0 orientation is specified relative to the treatment beam direction.
      Treatment unitTreatment beam(s)Magnet designB0 [T]B0 orientationAdditional comments
      ViewRay MRIdian
      • Mutic S.
      • Dempsey J.F.
      The ViewRay system: magnetic resonance-guided and controlled radiotherapy.
      Three 60Co sourcesSplit0.35PerpendicularReplacement of 60Co sources with a linac under development
      Elekta MR-linac
      • Lagendijk J.J.W.
      • Raaymakers B.W.
      • Raaijmakers A.J.E.
      • Overweg J.
      • Brown K.J.
      • Kerkhof E.M.
      • et al.
      MRI/linac integration.
      7 MV linacClosed1.5PerpendicularBeam traverses cryostat and magnet
      Canadian linac-MR (v2)
      • Keyvanloo A.
      • Burke B.
      • Aubin J.S.
      • Baillie D.
      • Wachowicz K.
      • Warkentin B.
      • et al.
      Minimal skin dose increase in longitudinal rotating biplanar linac-MR systems: examination of radiation energy and flattening filter design.
      6 or 10 MV linacSplit0.5InlineMagnet rotates with gantry
      Australian MRI-linac

      Keall PJ, Barton M, Crozier S, on behalf of the Australian MRI-Linac Program, including contributors from Ingham Institute Illawarra Cancer Care Centre Liverpool Hospital Stanford University Universities of Newcastle Queensland Sydney Western Sydney and Wollongong, The Australian magnetic resonance imaging-linac program, Seminars Radiat Oncol 24 (3) (2014) 203–6. doi: https://doi.org/10.1016/j.semradonc.2014.02.015.

      4 or 6 MV linacSplit1.0
      The current research version uses a 1.5 T closed magnet [62].
      Inline or perpendicularBoth B0 orientations under investigation
      The current research version uses a 1.5 T closed magnet
      • Liney G.P.
      • Dong B.
      • Begg J.
      • Vial P.
      • Zhang K.
      • Lee F.
      • et al.
      Technical note: experimental results from a prototype high-field inline MRI-linac.
      .

      3. Opportunities for MRI to enhance the lung SBRT workflow

      Table 2 provides an overview of the most commonly employed sequences for lung MRI. The table is condensed from the recommendations in [
      • Ohno Y.
      • Koyama H.
      • Dinkel J.
      • Hintze C.
      Lung cancer.
      ,
      • Biederer J.
      • Beer M.
      • Hirsch W.
      • Wild J.
      • Fabel M.
      • Puderbach M.
      • et al.
      MRI of the lung (2/3). why when how?, Insights into.
      ] and annotated with radiotherapy application in mind. Fast spin echo (FSE) sequences are typically acquired using respiratory gating, which is prone to artefacts caused by irregular breathing or cardiac motion. Balanced steady-state free precession (bSSFP) sequences exhibit a T2/T1-weighted contrast and a high signal-to-noise ratio, but can suffer from banding artefacts in peripheral areas of the image, which is problematic if body contours are needed for treatment planning. The traditional limitations of diffusion-weighted (DW) MRI could be overcome by moving away from the echoplanar imaging readout to a segmented readout scheme [
      • Liney G.P.
      • Holloway L.
      • Harthi T.M.A.
      • Sidhom M.
      • Moses D.
      • Juresic E.
      • et al.
      Quantitative evaluation of diffusion-weighted imaging techniques for the purposes of radiotherapy planning in the prostate.
      ].
      Table 2MRI sequences for lung cancer imaging (adapted from
      • Ohno Y.
      • Koyama H.
      • Dinkel J.
      • Hintze C.
      Lung cancer.
      ,
      • Biederer J.
      • Beer M.
      • Hirsch W.
      • Wild J.
      • Fabel M.
      • Puderbach M.
      • et al.
      MRI of the lung (2/3). why when how?, Insights into.
      ).
      SequenceStrengthAcquisition typeSpatial resolutionDistortion riskVariantsComments
      Volumetric T1w GRENodulesBreath-holdHighLowDixon, 4DLow contrast
      T2w single-shot FSEInfiltrative diseaseBreath-holdLow – moderateLowCine
      T2w gated FSEMediastinal structures, infiltrative diseaseRespiratory gatedModerate – highModerateDixon, volumetricLong acquisitions
      T2/T1w bSSFPLung functionFree-breathingModerate – highModerateCine, 4DBanding artefacts
      T1w FSEMediastinal lymph nodesMultiple breath-holdModerateModerateDCE
      DWIDose paintingMultiple breath-holdLowHighDistortion risk reduction possible
      Abbreviations: GRE  = gradient echo; DCE = dynamic contrast-enhanced; FSE  = fast spin echo; T1w/ T2w  = T1/ T2-weighted; bSSFP  = balanced steady-state free precession; DWI  = diffusion-weighted imaging.

      3.1 Diagnosis and staging

      In order to be eligible for lung SBRT, patients must present at an early disease stage, meaning that only small, localised lesions are existant without any nodal or metastatic spread. Currently, combined multi-slice CT and 18Fludeoxyglucose (FDG) positron emission tomography (PET), in addition to biopsies, are considered the gold standard for staging [
      • De Ruysscher D.
      • Belderbos J.
      • Reymen B.
      • van Elmpt W.
      • van Baardwijk A.
      • Wanders R.
      • et al.
      State of the art radiation therapy for lung cancer 2012: a glimpse of the future.
      ]. However, biopsy procedures pose an additional burden to the patient and their execution is challenging for small, peripheral tumours [
      • Vansteenkiste J.
      • De Ruysscher D.
      • Eberhardt W.E.E.
      • Lim E.
      • Senan S.
      • Felip E.
      • et al.
      Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up.
      ]. Although the use of PET-CT is well established, the relatively low spatial resolution and motion artefacts, resulting from long acquisition times, are prevalent issues [
      • Devaraj A.
      • Cook G.J.
      • Hansell D.M.
      PET/CT in non-small cell lung cancer staging-promises and problems.
      ,
      • Cheebsumon P.
      • Boellaard R.
      • de Ruysscher D.
      • van Elmpt W.
      • van Baardwijk A.
      • Yaqub M.
      • et al.
      Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology.
      ]. Furthermore, inflammatory areas in the lung can lead to increased FDG uptake and the diagnosis of false positives. MRI could play a role in staging [

      Hochhegger B, Marchiori E, Sedlaczek O, Irion K, Heussel C, Ley S, Ley-Zaporozhan J, Souza AS Jr, Kauczor H. MRI in lung cancer: a pictorial essay. Br J Radiol. doi:https://doi.org/10.1259/bjr/24661484.

      ,
      • Cobben D.C.P.
      • de Boer H.C.J.
      • Tijssen R.H.
      • Rutten E.G.G.M.
      • van Vulpen M.
      • Peerlings J.
      • et al.
      Emerging role of MRI for radiation treatment planning in lung cancer.
      ] and MRI-derived motion information in hybrid PET-MRI devices could be used to mitigate PET motion artefacts [
      • Rank C.M.
      • Heusser T.
      • Wetscherek A.
      • Freitag M.
      • Sedlaczek O.
      • Schlemmer H.-P.
      • et al.
      Respiratory motion compensation for simultaneous PET/MR based on highly undersampled MR data.
      ,
      • Munoz C.
      • Kolbitsch C.
      • Reader A.J.
      • Marsden P.
      • Schaeffter T.
      • Prieto C.
      MR-based cardiac and respiratory motion-compensation techniques for PET-MR imaging.
      ].
      In order to determine size and extent of tumour growth with MRI, a range of acquisition techniques has been deployed, for example standard T1- or T2-weighted acquisitions, 2D cine MRI, or single-shot FSE MRI [
      • Kajiwara N.
      • Akata S.
      • Uchida O.
      • Usuda J.
      • Ohira T.
      • Kawate N.
      • et al.
      Cine MRI enables better therapeutic planning than CT in cases of possible lung cancer chest wall invasion.
      ,
      • Chang S.
      • Hong S.R.
      • Kim Y.J.
      • Hong Y.J.
      • Hur J.
      • Choi B.W.
      • et al.
      Usefulness of thin-section single-shot turbo spin echo with half-fourier acquisition in evaluation of local invasion of lung cancer.
      ]. T2-weighted, dynamic contrast-enhanced (DCE), or DW MRI have proven promising in their ability to distinguish between benign and malignant tumours [
      • Puderbach M.
      • Hintze C.
      • Ley S.
      • Eichinger M.
      • Kauczor H.U.
      • Biederer J.
      MR imaging of the chest: a practical approach at 1.5T.
      ,
      • Zou Y.
      • Zhang M.
      • Wang Q.
      • Shang D.
      • Wang L.
      • Yu G.
      Quantitative investigation of solitary pulmonary nodules: dynamic contrast-enhanced MRI and histopathologic analysis.
      ,
      • Ohba Y.
      • Nomori H.
      • Mori T.
      • Ikeda K.
      • Shibata H.
      • Kobayashi H.
      • et al.
      Is diffusion-weighted magnetic resonance imaging superior to positron emission tomography with fludeoxyglucose F 18 in imaging non-small cell lung cancer?.
      ,
      • Chen L.
      • Zhang J.
      • Bao J.
      • Zhang L.
      • Hu X.
      • Xia Y.
      • et al.
      Meta-analysis of diffusion-weighted MRI in the differential diagnosis of lung lesions.
      ].
      Identifying disease spread to lymph nodes is difficult using PET-CT due to its limited spatial resolution [
      • Cheebsumon P.
      • Boellaard R.
      • de Ruysscher D.
      • van Elmpt W.
      • van Baardwijk A.
      • Yaqub M.
      • et al.
      Assessment of tumour size in PET/CT lung cancer studies: PET- and CT-based methods compared to pathology.
      ]. Several MRI sequences have been investigated to stage mediastinal and hilar lymph node metastases [
      • Hasegawa I.
      • Eguchi K.
      • Kohda E.
      • Tanami Y.
      • Mori T.
      • Hatabu H.
      • et al.
      Pulmonary hilar lymph nodes in lung cancer: assessment with 3D-dynamic contrast-enhanced MR imaging.
      ,
      • Ohno Y.
      • Hatabu H.
      • Takenaka D.
      • Higashino T.
      • Watanabe H.
      • Ohbayashi C.
      • et al.
      Metastases in mediastinal and hilar lymph nodes in patients with non–small cell lung cancer: quantitative and qualitative assessment with STIR turbo spin-echo MR imaging 1.
      ,
      • Nakayama J.
      • Miyasaka K.
      • Omatsu T.
      • Onodera Y.
      • Terae S.
      • Matsuno Y.
      • et al.
      Metastases in mediastinal and hilar lymph nodes in patients with non-small cell lung cancer: quantitative assessment with diffusion-weighted magnetic resonance imaging and apparent diffusion coefficient.
      ]. A recent meta-analysis of twelve studies has concluded that MRI offers an improved sensitivity and accuracy over PET-CT [
      • Peerlings J.
      • Troost E.G.C.
      • Nelemans P.J.
      • Cobben D.C.P.
      • de Boer J.C.J.
      • Hoffmann A.L.
      • et al.
      The diagnostic value of MR imaging in determining the lymph node status of patients with nonsmall cell lung cancer: a meta-analysis.
      ].
      It remains to be seen whether MRI can complement the ubiquitous FDG-PET for diagnosis and staging of lesions. The higher spatial resolution of MRI could prove beneficial for staging and detection of smaller nodes and metastases that could go undetected in PET-CT.

      3.2 Delineation, dose calculation and treatment planning

      Currently, treatment simulation for lung SBRT is mostly based on CT images. The introduction of PET-CT for target definition has led to a significant decline in delineation uncertainties compared to CT-only contouring [
      • Steenbakkers R.J.
      • Duppen J.C.
      • Fitton I.
      • Deurloo K.E.
      • Zijp L.J.
      • Comans E.F.
      • et al.
      Reduction of observer variation using matched CT-PET for lung cancer delineation: a three-dimensional analysis.
      ]. It remains to be seen whether the introduction of MRI for target delineation purposes will result in any additional benefit. Delineation uncertainties are larger for OAR as CT features relatively poor soft-tissue contrast (see Fig. 4), resulting in uncertainties of up to a few centimetres for the oesophagus and spinal cord [
      • Cui Y.
      • Chen W.
      • Olsen L.A.
      • Beatty R.E.
      • Maxim P.G.
      • Ritter T.
      • et al.
      Contouring variations and the role of atlas in non-small cell lung cancer radiation therapy: analysis of a multi-institutional preclinical trial planning study.
      ]. The improved soft-tissue contrast of MRI may lead to a reduction in contouring variability for these structures.
      Figure thumbnail gr4
      Fig. 4(A) CT image and (B) T1-weighted MR image acquired with an ultra-fast gradient echo sequence of a NSCLC patient with a tumour located in the left upper lobe. While the bones and lung tissue are better recognizable on the CT image, the soft-tissue contrast of the MR image is superior, especially with respect to the mediastinum.
      When using MRI for treatment planning purposes, it is crucial to ensure spatial fidelity of the image data [
      • Moerland M.
      • Beersma R.
      • Bhagwandien R.
      • Wijrdeman H.
      • Bakker C.
      Analysis and correction of geometric distortions in 1.5 T magnetic resonance images for use in radiotherapy treatment planning.
      ]. One potentially critical issue is the local differences in tissue susceptibility that can induce geometric distortions. For lung tissue, this effect can result in maximum distortions of up to 4 mm, depending on main magnetic field strength, orientation and gradient field strength [
      • Stanescu T.
      • Wachowicz K.
      • Jaffray D.
      Characterization of tissue magnetic susceptibility-induced distortions for MRIgRT.
      ]. However, mean geometric distortions were found to be substantially lower (⩽1 mm). It should be noted that these errors are in addition to other distortions induced by non-linearities in the main magnetic and gradient field. Recently, the composite 4D distortion effect induced by scanner and susceptibility distortions was investigated for mobile lung tumours of different sizes [
      • Stanescu T.
      • Jaffray D.
      Investigation of the 4D composite MR image distortion field associated with tumor motion for MR-guided radiotherapy.
      ]. Composite distortions were considered manageable (⩽1 mm), even for high-field MRI scanners as long as these were operated in combination with high readout bandwidth at the cost of increased noise [
      • Schmidt M.A.
      • Payne G.S.
      Radiotherapy planning using MRI.
      ]. While not available on all vendor platforms, non-cartesian k-space trajectories, such as a radial or PROPELLER acquisition, can be employed for robustness against motion artefacts [
      • Block K.T.
      • Chandarana H.
      • Milla S.
      • Bruno M.
      • Mulholland T.
      • Fatterpekar F.
      • et al.
      Towards routine clinical use of radial stack-of-stars 3D gradient-echo sequences for reducing motion sensitivity.
      ,
      • Pipe J.G.
      • Gibbs W.N.
      • Li Z.
      • Karis J.P.
      • Schar M.
      • Zwart N.R.
      Revised motion estimation algorithm for PROPELLER MRI.
      ].
      Similarly to 4D CT and 4D CBCT – albeit not as established – 4D MRI can be used to evaluate periodic anatomical changes due to breathing. 4D MRI can be either obtained based on repeated acquisition of slices covering the whole volume and respiratory cycle [
      • Tryggestad E.
      • Flammang A.
      • Han-Oh S.
      • Hales R.
      • Herman J.
      • McNutt T.
      • et al.
      Respiration-based sorting of dynamic MRI to derive representative 4D-MRI for radiotherapy planning.
      ,
      • Liu Y.
      • Yin F.-F.
      • Czito B.G.
      • Bashir M.R.
      • Cai J.
      T2-weighted four dimensional magnetic resonance imaging with result-driven phase sorting.
      ,
      • Stemkens B.
      • Tijssen R.H.N.
      • de Senneville B.D.
      • Lagendijk J.J.W.
      • van den Berg C.A.T.
      Image-driven, model-based 3D abdominal motion estimation for MR-guided radiotherapy.
      ] or using a continuous 3D acquisition with sophisticated reconstruction techniques [
      • Feng L.
      • Grimm R.
      • Block K.T.
      • Chandarana H.
      • Kim S.
      • Xu J.
      • et al.
      Golden-angle radial sparse parallel MRI: combination of compressed sensing, parallel imaging, and golden-angle radial sampling for fast and flexible dynamic volumetric MRI.
      ,
      • Rank C.M.
      • Heuer T.
      • Buzan M.T.A.
      • Wetscherek A.
      • Freitag M.T.
      • Dinkel J.
      • et al.
      4D respiratory motion-compensated image reconstruction of free-breathing radial MR data with very high undersampling.
      ,

      Mickevicius NJ, Paulson E. Investigation of undersampling and reconstruction algorithm dependence on respiratory correlated 4D-MRI for online MR-guided radiation therapy. Phys Med Biol. doi:https://doi.org/10.1088/1361-6560/aa54f2.

      ]. While 4D MRI based on 2D acquisitions is more easily available, the 3D-based techniques offer higher resolution and allow for a full 3D distortion correction. A conceptual limitation of 4D scans is that they average over several respiratory cycles and thus cannot accurately depict baseline shifts of breathing motion [
      • Tryggestad E.
      • Flammang A.
      • Hales R.
      • Herman J.
      • Lee J.
      • McNutt T.
      • et al.
      4D tumor centroid tracking using orthogonal 2D dynamic MRI: implications for radiotherapy planning.
      ,
      • Takao S.
      • Miyamoto N.
      • Matsuura T.
      • Onimaru R.
      • Katoh N.
      • Inoue T.
      • et al.
      Intrafractional baseline shift or drift of lung tumor motion during gated radiation therapy with a real-time tumor-tracking system.
      ]. MRI could be utilised to acquire 2D cine MR images that provide a better visualisation of the patient’s breathing, especially with regard to irregularities. Combining 4D MRI with 2D cine MRI using a PCA-based approach allows generation of 3D deformable vector fields with a temporal resolution of 476 ms [
      • Stemkens B.
      • Tijssen R.H.N.
      • de Senneville B.D.
      • Lagendijk J.J.W.
      • van den Berg C.A.T.
      Image-driven, model-based 3D abdominal motion estimation for MR-guided radiotherapy.
      ]. In the future, this temporally resolved observation of the tumour motion could be used to define adequate treatment margins.
      One obstacle for the widespread introduction of MRI for treatment planning is the absence of electron density and attenuation coefficient information in the MR images. Commonly, this lack of information is circumvented by either generating synthetic (referred to as pseudo from here on) CT images from MR images employing Dixon methods, or by (deformably or rigidly) registering the MR image to a treatment planning CT. The accuracy of the latter approach depends on the quality of the registration. While the generation of pseudo-CT images works well for relatively homogeneous treatment sites, such as prostate or brain [
      • Nyholm T.
      • Jonsson J.
      Counterpoint: opportunities and challenges of a magnetic resonance imaging-only radiotherapy work flow.
      ], it is more problematic in the thoracic region, where both lung and bone feature very little MR signal. Correctly accounting for bone and lung tissue during treatment planning is key for achieving the desired dose distribution in the patient. With very limited published data available for thoracic anatomies – one exception being a study on ten patients using a segmentation/bulk density overwrite method [
      • Jonsson J.H.
      • Karlsson M.G.
      • Karlsson M.
      • Nyholm T.
      Treatment planning using MRI data: an analysis of the dose calculation accuracy for different treatment regions.
      ] – further investigations are necessary to establish the feasibility of pseudo-CT images for treatment planning in lung cancer. Useful experiences may be gained from research on PET-MRI scanners, where electron density information is needed to correctly account for attenuation [
      • Mehranian A.
      • Arabi H.
      • Zaidi H.
      Vision 20/20: magnetic resonance imaging-guided attenuation correction in PET/MRI: challenges, solutions, and opportunities.
      ].
      Several groups have investigated the influence of the electron return effect on MRI-guided lung SBRT treatments [
      • Kirkby C.
      • Murray B.
      • Rathee S.
      • Fallone B.G.
      Lung dosimetry in a linac-MRI radiotherapy unit with a longitudinal magnetic field.
      ,
      • Yang Y.M.
      • Geurts M.
      • Smilowitz J.B.
      • Sterpin E.
      • Bednarz B.P.
      Monte Carlo simulations of patient dose perturbations in rotational-type radiotherapy due to a transverse magnetic field: a tomotherapy investigation.
      ,
      • Oborn B.
      • Ge Y.
      • Hardcastle N.
      • Metcalfe P.
      • Keall P.
      Dose enhancement in radiotherapy of small lung tumors using inline magnetic fields: a Monte Carlo based planning study.
      ,
      • Menten M.J.
      • Fast M.F.
      • Nill S.
      • Kamerling C.P.
      • McDonald F.
      • Oelfke U.
      Lung stereotactic body radiotherapy with an MR-linac – quantifying the impact of the magnetic field and real-time tumor tracking.
      ,
      • Merna C.
      • Rwigema J.-C.M.
      • Cao M.
      • Wang P.-C.
      • Kishan A.U.
      • Michailian A.
      • et al.
      A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator–based stereotactic body radiotherapy for central early-stage non- small cell lung cancer.
      ,
      • Park J.M.
      • Park S.Y.
      • Kim H.J.
      • Wu H.G.
      • Carlson J.
      • Kim J.I.
      A comparative planning study for lung SABR between tri-Co-60 magnetic resonance image guided radiation therapy system and volumetric modulated arc therapy.
      ]. Although machine specifications, magnetic field orientations and strengths differ in these studies, all have found that the dose is distorted by the magnetic field, especially at air-tissue-interfaces in lung and skin. However, dedicated dose calculation algorithms, which are based either on Monte Carlo methods or on solving of the linear Boltzmann transport equation, are able to account for the presence of magnetic fields [
      • Hissoiny S.
      • Ozell B.
      • Bouchard H.
      • Després P.
      GPUMCD: a new GPU-oriented Monte Carlo dose calculation platform.
      ,
      • St Aubin J.
      • Keyvanloo A.
      • Vassiliev O.
      • Fallone B.G.
      A deterministic solution of the first order linear Boltzmann transport equation in the presence of external magnetic fields.
      ,
      • Bouchard H.
      • Bielajew A.
      Lorentz force correction to the Boltzmann radiation transport equation and its implications for monte carlo algorithms.
      ]. Several studies have shown that using such dose calculation algorithms to account for the ERE during treatment plan optimization allows for the design of clinically acceptable lung SBRT treatments [
      • Menten M.J.
      • Fast M.F.
      • Nill S.
      • Kamerling C.P.
      • McDonald F.
      • Oelfke U.
      Lung stereotactic body radiotherapy with an MR-linac – quantifying the impact of the magnetic field and real-time tumor tracking.
      ,
      • Merna C.
      • Rwigema J.-C.M.
      • Cao M.
      • Wang P.-C.
      • Kishan A.U.
      • Michailian A.
      • et al.
      A treatment planning comparison between modulated tri-cobalt-60 teletherapy and linear accelerator–based stereotactic body radiotherapy for central early-stage non- small cell lung cancer.
      ,
      • Park J.M.
      • Park S.Y.
      • Kim H.J.
      • Wu H.G.
      • Carlson J.
      • Kim J.I.
      A comparative planning study for lung SABR between tri-Co-60 magnetic resonance image guided radiation therapy system and volumetric modulated arc therapy.
      ].
      In hybrid MRI treatment machines the magnetic field also affects machine and treatment plan quality assurance (QA) procedures as the ERE influences the readings of ionization chambers, solid state detectors and radiosensitive films [
      • Meijsing I.
      • Raaymakers B.W.
      • Raaijmakers A.J.E.
      • Kok J.G.M.
      • Hogeweg L.
      • Liu B.
      • Lagendijk J.J.W.
      Dosimetry for the MRI accelerator: the impact of a magnetic field on the response of a farmer NE2571 ionization chamber.
      ,
      • Reynolds M.
      • Fallone B.G.
      • Rathee S.
      Dose response of selected solid state detectors in applied homogeneous transverse and longitudinal magnetic fields.
      ,
      • Reynoso F.J.
      • Curcuru A.
      • Green O.
      • Mutic S.
      • Das I.J.
      • Santanam L.
      Technical note: magnetic field effects on Gafchromic-film response in MR-IGRT.
      ]. Awareness of the dependence of the detector readout on its orientation relative to the magnetic field, as well as the use of dedicated detectors and phantoms are necessary for dosimetry inside a magnetic field [
      • Smit K.
      • van Asselen B.
      • Kok J.G.M.
      • Aalbers A.H.L.
      • Lagendijk J.J.W.
      • Raaymakers B.W.
      Towards reference dosimetry for the MR-linac: magnetic field correction of the ionization chamber reading.
      ,
      • Smit K.
      • Sjöholm J.
      • Kok J.G.M.
      • Lagendijk J.J.W.
      • Raaymakers B.W.
      Relative dosimetry in a 1.5 T magnetic field: an MR-linac compatible prototype scanning water phantom.
      ,
      • Li H.H.
      • Rodriguez V.L.
      • Green O.L.
      • Hu Y.
      • Kashani R.
      • Wooten H.O.
      • et al.
      Patient-specific quality assurance for the delivery of 60Co intensity modulated radiation therapy subject to a 0.35-T lateral magnetic field.
      ,
      • van Zijp H.M.
      • van Asselen B.
      • Wolthaus J.W.H.
      • Kok J.M.G.
      • de Vries J.H.W.
      • Ishakoglu K.
      • et al.
      Minimizing the magnetic field effect in MR-linac specific QA-tests: the use of electron dense materials.
      ]. Furthermore, gel-based dosimeters and a shift towards software-based QA procedures are being investigated on MRI-guided treatment units [
      • Alnaghy S.J.
      • Gargett M.
      • Liney G.
      • Petasecca M.
      • Begg J.
      • Espinoza A.
      • et al.
      Initial experiments with gel-water: towards MRI-linac dosimetry and imaging.
      ,
      • Chen G.-P.
      • Ahunbay E.
      • Li X.A.
      Technical note: development and performance of a software tool for quality assurance of online replanning with a conventional linac or MR-linac.
      ]. An electronic portal imaging device integrated with the hybrid MRI treatment unit could also be used for treatment beam QA [
      • Raaymakers B.W.
      • de Boer J.C.J.
      • Knox C.
      • Crijns S.P.M.
      • Smit K.
      • Stam M.K.
      • et al.
      Integrated megavoltage portal imaging with a 1.5 T MRI linac.
      ].
      Functional MRI offers the promise of identifying regions of the tumour that would benefit from additional dose (boosting or dose painting). While DCE MRI is expected to correlate with the oxygenation level of the tumour, DW MRI could indicate regions of increased tumour cell density [
      • van der Heide U.A.
      • Houweling A.C.
      • Groenendaal G.
      • Beets-Tan R.G.
      • Lambin P.
      Functional MRI for radiotherapy dose painting.
      ]. Functional MRI can also identify critical OAR substructures and help minimizing dose to these. For example, for pancoast tumours DW MRI can be used to localise the brachial plexus [
      • Andreou A.
      • Sohaib A.
      • Collins D.J.
      • Takahara T.
      • Kwee T.C.
      • Leach M.O.
      • et al.
      Diffusion-weighted MR neurography for the assessment of brachial plexopathy in oncological practice.
      ]. Lung ventilation can be assessed with a variety of gaseous contrast agents [
      • Biederer J.
      • Heussel C.P.
      • Puderbach M.
      • Wielpuetz M.O.
      Functional magnetic resonance imaging of the lung.
      ], among which hyperpolarised 3He was employed to identify well-ventilated, healthy parts of the lung for OAR sparing in advanced NSCLC [
      • Ireland R.H.
      • Bragg C.M.
      • McJury M.
      • Woodhouse N.
      • Fichele S.
      • Van Beek E.J.
      • et al.
      Feasibility of image registration and intensity-modulated radiotherapy planning with hyperpolarized helium-3 magnetic resonance imaging for non–small-cell lung cancer.
      ]. 129Xe has also been used to assess lung function in NSCLC patients [
      • Qing K.
      • Mugler J.
      • Chen Q.
      WE-FG-206-07: assessing the lung function of patients with non-small cell lung cancer using hyperpolarized Xenon-129 dissolved-phase MRI.
      ] and is more widely available than 3He, but maximal hyperpolarisation is lower [
      • Biederer J.
      • Heussel C.P.
      • Puderbach M.
      • Wielpuetz M.O.
      Functional magnetic resonance imaging of the lung.
      ]. Due to its solubility in blood, 129Xe could enable assessment of gas exchange [
      • Driehuys B.
      • Möller H.E.
      • Cleveland Z.I.
      • Pollaro J.
      • Hedlund L.W.
      Pulmonary perfusion and xenon gas exchange in rats: MR imaging with intravenous injection of hyperpolarized 129Xe.
      ]. A competing method that does not use hyperpolarized gases has emerged in Fourier decomposition MRI, which promises simultaneous characterisation of lung perfusion and ventilation [
      • Bauman G.
      • Puderbach M.
      • Deimling M.
      • Jellus V.
      • Chefd’hotel C.
      • Dinkel J.
      • et al.
      Non-contrast-enhanced perfusion and ventilation assessment of the human lung by means of fourier decomposition in proton MRI.
      ]. It can be employed for functional lung avoidance mapping [
      • Capaldi D.
      • Sheikh K.
      • Hoover D.
      • Yaremko B.
      • Palma D.
      • Parraga G.
      TH-CD-202-09: free-breathing proton MRI functional lung avoidance maps to guide radiation therapy.
      ], but is free from the infrastructural requirements associated with the application of hyperpolarised noble gases.
      MRI has the potential to improve OAR delineation accuracy and may allow functional evaluation of healthy tissue. It remains to be seen whether target delineation in early-stage NSCLC patients treated with SBRT will benefit from MRI, where the tumour is typically very localised with only limited involvement in adjacent soft-tissue. Issues affecting treatment planning arise from MR images not inherently containing electron density information and, on hybrid MRI treatment devices, the B0 magnetic field distorting the dose distribution and thereby affecting treatment planning and QA procedures. While the latter issue can be accounted for with dedicated dose calculation algorithms and QA protocols, the generation of pseudo CTs for the thoracic region is still under investigation.

      3.3 Patient setup and interfractional adaptations

      On conventional linacs accurate patient setup is often achieved by shifting the treatment couch based on the position of the lung tumour as derived from an average or 4D CBCT [
      • Sonke J.-J.
      • Belderbos J.
      Adaptive radiotherapy for lung cancer.
      ]. Using MRI-guided delivery systems, this workflow could be replicated using 3D or 4D MR images. Potential advantages of MRI are the improved soft-tissue contrast and a larger field-of-view resulting in superior discrimination of soft-tissue structures [
      • Noel C.E.
      • Parikh P.J.
      • Spencer C.R.
      • Green O.L.
      • Hu Y.
      • Mutic S.
      • et al.
      Comparison of onboard low-field magnetic resonance imaging versus onboard computed tomography for anatomy visualization in radiotherapy.
      ].
      It should also be noted that on hybrid MRI treatment machines, the ability to apply couch corrections is usually limited to the superior-inferior direction due to the restricted bore dimensions [
      • Bol G.
      • Lagendijk J.
      • Raaymakers B.
      Virtual couch shift (VCS): accounting for patient translation and rotation by online IMRT re-optimization.
      ]. To correct for shifts in other directions or rotations, the treatment plan segments are morphed according to the position of the target immediately prior to treatment. To validate the safety of this relatively simple plan adaptation, the dose needs to be (re-)calculated on the anatomy of the day. For flattening-filter-free beams, large target shifts can introduce systematic dose deviations compared to the original treatment plan due to the sloped nature of the beam profile [
      • Ates O.
      • Ahunbay E.E.
      • Moreau M.
      • Li X.A.
      Technical note: a fast online adaptive replanning method for VMAT using flattening filter free beams.
      ]. Compensation for this may require more complex adaptations of segment shapes and weights.
      A more advanced method aims at generating a treatment plan based on the observed anatomy of the day using the initial simulation treatment plan as a starting point (warm-start optimization) [
      • Ates O.
      • Ahunbay E.E.
      • Moreau M.
      • Li X.A.
      Technical note: a fast online adaptive replanning method for VMAT using flattening filter free beams.
      ,
      • Acharya S.
      • Fischer-Valuck B.W.
      • Kashani R.
      • Parikh P.
      • Yang D.
      • Zhao T.
      • et al.
      Online magnetic resonance image guided adaptive radiation therapy: first clinical applications.
      ]. This requires a physician, or otherwise trained member of the treatment team to check the contours, which were automatedly deformed onto the daily MR image from the treatment planning CT/MR. Re-delineation may be necessary following visual assessment [
      • Henke L.
      • Kashani R.
      • Yang D.
      • Zhao T.
      • Green O.
      • Olsen L.
      • et al.
      Simulated online adaptive magnetic resonance guided stereotactic body radiation therapy for the treatment of oligometastatic disease of the abdomen and central thorax: characterization of potential advantages.
      ]. This approach minimises computational costs and is expected to mitigate some of the issues related to quality control and plan approval. In the future, full re-planning based on the daily MR image (cold-start optimization) might result in even better plan quality.
      The use of MRI in order to account for interfractional anatomical changes has just recently gained traction with the emergence of systems allowing MRI near or inside the treatment room. The development and automation of workflows that adapt the treatment plan to the anatomy of the day is increasingly being investigated with clinical outcome results not being available yet.

      3.4 Intrafractional motion management

      In the past, different methods to monitor intrafractional lung tumour motion have been developed, each with their own individual shortcomings. Internal or external surrogates do not necessarily correlate with the target motion and their relation may change over the course of a fraction [
      • Korreman S.S.
      • Juhler-Nottrup T.
      • Boyer A.L.
      Respiratory gated beam delivery cannot facilitate margin reduction, unless combined with respiratory correlated image guidance.
      ,
      • Malinowski K.
      • McAvoy T.J.
      • George R.
      • Dietrich S.
      • D’Souza W.D.
      Incidence of changes in respiration-induced tumor motion and its relationship with respiratory surrogates during individual treatment fractions.
      ,
      • Tryggestad E.
      • Flammang A.
      • Hales R.
      • Herman J.
      • Lee J.
      • McNutt T.
      • et al.
      4D tumor centroid tracking using orthogonal 2D dynamic MRI: implications for radiotherapy planning.
      ]. Invasive marker-based localisation methods pose an additional burden to the patient. Additionally, marker migration as well as induced pneumonia have been reported [
      • Matsuo Y.
      • Ueki N.
      • Takayama K.
      • Nakamura M.
      • Miyabe Y.
      • Ishihara Y.
      • et al.
      Evaluation of dynamic tumour tracking radiotherapy with real-time monitoring for lung tumours using a gimbal mounted linac.
      ]. Neither surrogates, nor marker-based methods are able to monitor nearby OAR or deformations of the target. Markerless tumour or OAR localisation with X-ray imaging is limited by poor soft-tissue contrast [
      • Dieterich S.
      • Gibbs I.C.
      The CyberKnife in clinical use: current roles, future expectations.
      ,
      • Menten M.J.
      • Fast M.F.
      • Nill S.
      • Oelfke U.
      Using dual-energy x-ray imaging to enhance automated lung tumor tracking during real-time adaptive radiotherapy.
      ]. All X-ray based imaging methods result in an additional dose to the patient.
      The promise of continuously monitoring the tumour as well as nearby healthy organs with high soft-tissue contrast MR images was a strong driving force behind the development of MRI-guided treatment units. For real-time adaptive radiotherapy systems, which adjust the delivery after detecting a change in tumour position, the AAPM Task Group report 76 recommends a total system latency of less than 500 ms [
      • Keall P.J.
      • Mageras G.S.
      • Balter J.M.
      • Emery R.S.
      • Forster K.M.
      • Jiang S.B.
      • et al.
      The management of respiratory motion in radiation oncology report of AAPM task group 76.
      ]. Currently, it is not feasible to acquire, reconstruct and post-process 3D MR images with sufficient resolution and signal-to-noise-ratio in this time frame. MRI allows acquisition of navigator echoes and use of them as a motion surrogate [
      • Crijns S.P.
      • Raaymakers B.W.
      • Lagendijk J.J.
      Proof of concept of MRI-guided tracked radiation delivery: tracking one-dimensional motion.
      ]. Visualisation of fast moving lung tumours is therefore usually based on 2D cine acquisition techniques, especially bSSFP sequences. Strategies to further increase the imaging rate have been investigated. Several techniques are based on an undersampled acquisition of the k-space data and subsequent reconstruction of the missing data using compressed sensing or viewsharing [
      • Yip E.
      • Yun J.
      • Wachowicz K.
      • Heikal A.A.
      • Gabos Z.
      • Rathee S.
      • et al.
      Prior data assisted compressed sensing: a novel MR imaging strategy for real time tracking of lung tumors.
      ,
      • Lee D.
      • Greer P.B.
      • Pollock S.
      • Kim T.
      • Keall P.
      Quantifying the accuracy of the tumor motion and area as a function of acceleration factor for the simulation of the dynamic keyhole magnetic resonance imaging method.
      ]. Others have deployed motion prediction to create a new image through extrapolation at a rate higher then the imaging frequency [
      • Seregni M.
      • Paganelli C.
      • Lee D.
      • Greer P.B.
      • Baroni G.
      • Keall P.J.
      • et al.
      Motion prediction in MRI-guided radiotherapy based on interleaved orthogonal cine-MRI.
      ]. While coils with more than 30 individual channels are commercially available on standard clinical MRI scanners, equivalent hardware still needs to be developed for MRI-guided delivery systems. These enable advanced parallel imaging techniques [
      • Wright K.L.
      • Harrell M.W.
      • Jesberger J.A.
      • Landeras L.
      • Nakamoto D.A.
      • Thomas S.
      • et al.
      Clinical evaluation of CAIPIRINHA: comparison against a GRAPPA standard.
      ,
      • Uecker M.
      • Lai P.
      • Murphy M.J.
      • Virtue P.
      • Elad M.
      • Pauly J.M.
      • et al.
      ESPIRiTan eigenvalue approach to autocalibrating parallel MRI: Where SENSE meets GRAPPA.
      ] and simultaneous multi-slice imaging [
      • Farah R.
      • Park S.
      • Shea S.
      • Tryggestad E.
      • Wong J.
      • Hales R.
      • et al.
      TH-CD-207A-01: evaluation of lung tumor motion management strategy with dynamic MRI.
      ].
      Several groups have shown that it is feasible to localise lung tumours in these images using template matching [
      • Cervino L.I.
      • Du J.
      • Jiang S.B.
      MRI-guided tumor tracking in lung cancer radiotherapy.
      ,
      • Tryggestad E.
      • Flammang A.
      • Hales R.
      • Herman J.
      • Lee J.
      • McNutt T.
      • et al.
      4D tumor centroid tracking using orthogonal 2D dynamic MRI: implications for radiotherapy planning.
      ,
      • Shi X.
      • Diwanji T.
      • Mooney K.E.
      • Lin J.
      • Feigenberg S.
      • D’Souza W.D.
      • et al.
      Evaluation of template matching for tumor motion management with cine-MR images in lung cancer patients.
      ]. More advanced algorithms deploy artificial neural networks [
      • Cervino L.I.
      • Du J.
      • Jiang S.B.
      MRI-guided tumor tracking in lung cancer radiotherapy.
      ,
      • Yun J.
      • Yip E.
      • Gabos Z.
      • Wachowicz K.
      • Rathee S.
      • Fallone B.G.
      Neural-network based autocontouring algorithm for intrafractional lung-tumor tracking using linac-MR.
      ], scale-invariant feature transforms [
      • Paganelli C.
      • Lee D.
      • Greer P.B.
      • Baroni G.
      • Riboldi M.
      • Keall P.
      Quantification of lung tumor rotation with automated landmark extraction using orthogonal cine MRI images.
      ,
      • Mazur T.R.
      • Fischer-Valuck B.W.
      • Wang Y.
      • Yang D.
      • Mutic S.
      • Li H.H.
      SIFT-based dense pixel tracking on 0.35 T cine-MR images acquired during image-guided radiation therapy with application to gating optimization.
      ], or particle filtering [
      • Bourque A.E.
      • Bedwani S.
      • Filion E.
      • Carrier J.F.
      A particle filter based autocontouring algorithm for lung tumor tracking using dynamic magnetic resonance imaging.
      ] to quickly delineate the tumour in each image. The orientation of these 2D imaging planes with respect to the tumour motion can be freely set and even altered during image acquisition. Studies have looked at different strategies to optimise the positioning of these planes to determine kidney or liver tumour motion [
      • Bjerre T.
      • Crijns S.
      • af Rosenschold P.M.
      • Aznar M.
      • Specht L.
      • Larsen R.
      • et al.
      Three-dimensional MRI-linac intra-fraction guidance using multiple orthogonal cine-MRI planes.
      ,
      • Brix L.
      • Ringgaard S.
      • Srensen T.
      • Poulsen P.
      Three-dimensional liver motion tracking using real-time two-dimensional MRI.
      ], but are yet to be extended to monitoring of lung tumours. Additionally, 4D patient models built based on 4D pre-treatment scans may be updated using MR images acquired during delivery [
      • McClelland J.R.
      • Blackall J.M.
      • Tarte S.
      • Chandler A.C.
      • Hughes S.
      • Ahmad S.
      • et al.
      A continuous 4D motion model from multiple respiratory cycles for use in lung radiotherapy.
      ].
      The acquired real-time imaging information can support automated gating of the treatment beam on MRI-guided treatment units (see Fig. 5) [
      • Crijns S.P.
      • Kok J.G.
      • Lagendijk J.J.
      • Raaymakers B.W.
      Towards MRI-guided linear accelerator control: gating on an MRI accelerator.
      ,
      • Green O.P.
      • Goddu S.
      • Mutic S.
      SU-E-T-352: commissioning and quality assurance of the first commercial hybrid MRI-IMRT system.
      ]. Proof-of-concept MLC tracking has been implemented on MRI-linac prototypes [
      • Crijns S.P.
      • Raaymakers B.W.
      • Lagendijk J.J.
      Proof of concept of MRI-guided tracked radiation delivery: tracking one-dimensional motion.
      ,
      • Yun J.
      • Wachowicz K.
      • Mackenzie M.
      • Rathee S.
      • Robinson D.
      • Fallone B.G.
      First demonstration of intrafractional tumor-tracked irradiation using 2D phantom MR images on a prototype linac-MR.
      ]. Besides not prolonging the treatment time like gating, MLC tracking could adapt the beam aperture to tumour deformations monitored with MRI [
      • Ge Y.
      • O’Brien R.T.
      • Shieh C.C.
      • Booth J.T.
      • Keall P.J.
      Toward the development of intrafraction tumor deformation tracking using a dynamic multi-leaf collimator.
      ]. It has been shown that the presence of a magnetic field does not hinder the effectiveness of MLC tracking, which is able to reduce exposure of healthy lung tissue when compared to an ITV approach [
      • Menten M.J.
      • Fast M.F.
      • Nill S.
      • Kamerling C.P.
      • McDonald F.
      • Oelfke U.
      Lung stereotactic body radiotherapy with an MR-linac – quantifying the impact of the magnetic field and real-time tumor tracking.
      ].
      Figure thumbnail gr5
      Fig. 5An MR image acquired on the ViewRay system of a patient undergoing SBRT for oligometastatic cancer in the thorax at Siteman Cancer Center, St. Louis, USA. Continuous sagital cine imaging allows automated localization of the gross tumour volume (inner contour) and gating of the treatment beam if the planning target volume leaves the gating boundary (outer contour). Image courtesy of P.J. Parikh.
      A stream of volumetric imaging information may also be used for (real-time) dose reconstruction for online quality assurance purposes [
      • Kamerling C.P.
      • Fast M.F.
      • Ziegenhein P.
      • Menten M.J.
      • Nill S.
      • Oelfke U.
      Real-time 4D dose reconstruction for tracked dynamic MLC deliveries for lung SBRT.
      ]. Ultimately, real-time images and dosimetric information might be used to adapt the treatment plan during delivery itself, for example after the completion of each treatment beam, treatment segment or even in real-time [
      • Kamerling C.
      • Fast M.
      • Ziegenhein P.
      • Nill S.
      • Oelfke U.
      TH-CD-202-12: online inter-beam replanning based on real-time dose reconstruction.
      ]. In addition to an up-to-date 3D patient dataset, this requires ultra-fast dose calculation algorithms [
      • Hissoiny S.
      • Ozell B.
      • Bouchard H.
      • Després P.
      GPUMCD: a new GPU-oriented Monte Carlo dose calculation platform.
      ,
      • Jia X.
      • Gu X.
      • Graves Y.J.
      • Folkerts M.
      • Jiang S.B.
      GPU-based fast Monte Carlo simulation for radiotherapy dose calculation.
      ,
      • Ziegenhein P.
      • Pirner S.
      • Ph Kamerling C.
      • Oelfke U.
      Fast CPU-based Monte Carlo simulation for radiotherapy dose calculation.
      ] and treatment plan optimisation strategies [
      • Bol G.H.
      • Hissoiny S.
      • Lagendijk J.J.
      • Raaymakers B.W.
      Fast online Monte Carlo-based IMRT planning for the MRI linear accelerator.
      ,
      • Ziegenhein P.
      • Kamerling C.P.
      • Bangert M.
      • Kunkel J.
      • Oelfke U.
      Performance-optimized clinical IMRT planning on modern CPUs.
      ,
      • Kontaxis C.
      • Bol G.H.
      • Lagendijk J.J.
      • Raaymakers B.W.
      Towards adaptive IMRT sequencing for the MR-linac.
      ].
      Intrafractional tumour and OAR monitoring using MRI might be able to overcome some of the shortcomings of systems based on X-ray imaging, electromagnetic markers or surrogates. However, hybrid MRI treatment devices allowing real-time MRI of the patient undergoing treatment are just becoming available. As of today, intrafractional treatment monitoring and adaptation – MRI-based or not – are only being put into practice by few institutions world-wide and most technologies described in this section are still in a research phase.

      4. Conclusion and outlook

      This review has highlighted elements of the clinical workflow where the integration of MRI may enhance the quality of lung SBRT. It is expected that MRI will contribute most in the areas of OAR delineation, patient setup, online motion monitoring and plan adaptations. As for most disease sites, the exploitation of MRI for lung radiotherapy is rather new. Therefore, it remains to be seen how far the technical realisation, refinement and integration into the clinical workflow can progress.
      Ultimately, it has to be proven whether these conceptual advantages translate into any measurable increase in patient survival or reduction of treatment toxicities, which warrant the additional financial cost of MRI. As it stands, the 5-year absence of local recurrences for early-stage NSCLC patients being treated with lung SBRT is approximately 90% – an already very high value that rivals that of surgery, the current treatment method of choice.
      If the integration of MRI is able to substantially increase delivery accuracy and, consequently, allow for higher dose conformality due to treatment margin reduction, it may be possible to deliver higher biologically effective doses to more centrally located lung tumours. Even though there has been an interest to deliver SBRT to patients affected by these tumours, dose escalation has often been limited by normal-tissue toxicities.

      Acknowledgements

      The Institute of Cancer Research is part of the Elekta Atlantic MR-linac Research Consortium and we acknowledge financial and technical support from Elekta AB under a research agreement. Research at The Institute of Cancer Research is supported by Cancer Research UK under Programme C33589/A19727. Dr. Fast is supported by Cancer Research UK under Programme C33589/A19908. We acknowledge NHS funding to the NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research .

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