MRI-guided Prostate adaptive radiotherapy – the future is ...
MRI-guided prostate adaptive radiotherapy – a systematic reviewMcPartlin AJ FRCR*1, Li XA PhD*2, Kershaw LE PhD1, Heide U4, Kerkmeijer L5, Lawton C MD2, Mahmood U MD3, Pos F4, van As N6,7, van Herk M1, Vesprini D8, van der Voort van Zyp J5, Tree A MD(res) FRCR*6, Choudhury A PhD FRCR*1$ on behalf of the MR-Linac consortium.1.The Christie NHS Foundation Trust and Manchester Cancer Research Centre, University of Manchester, Manchester Academic Health Sciences Centre, UK2.Medical College of Wisconsin, U.S.A., 3.MD Anderson Cancer Center, Houston, herlands Cancer Institute, Antoni van Leeuwenhoek Hospital, The Netherlands5.University Medical Center Utrecht, The Netherlands6.Royal Marsden Hospital, UK7. Institute of Cancer Research, UK8.Sunnybrook Health Sciences Centre, University of Toronto, Canada*These authors contributed equally to this manuscriptConflicts of interest: Alison Tree has received funding from Elekta to support a research fellowSource of funding: Not applicable Ethics committee approval: Not applicableCorresponding author:$Dr A Choudhury MA PhD MRCP FRCRDept of Clinical Oncology,The Christie NHS Foundation Trust, Wilmslow Rd, Manchester.M20 4BX. Email: Ananya.choudhury@christie.nhs.uk Telephone: +1 161-446-3000 Contribution of authors: McPartlin, Li, Tree, Choudhury contributed equally to the literature review, article selection and manuscript preparation.Kershaw, van der Heide, Kerkmeijer, Lawton, Mahmood, van As, van Herk, Vesprini, and van der Voort van Zpy all reviewed the manuscript, contributed to its amended final form, and suggested additional references where appropriate.Total pages 19, Total Tables 3, total figures 4Running title: MRI-linac and prostate motion reviewKeywords: Prostate, MRI, MR-Linac, adaptive radiotherapy, IGRTAbstractDose escalated radiotherapy improves outcomes for men with prostate cancer. A plateau for benefit from dose escalation using EBRT may not have been reached for some patients with higher risk disease. The use of increasingly conformal techniques, such as step and shoot IMRT or more recently VMAT, has allowed treatment intensification to be achieved while minimizing associated increases in toxicity to surrounding normal structures. To support further safe dose escalation, the uncertainties in the treatment target position will need be minimised using optimal planning and image-guided radiotherapy (IGRT). In particular the increasing usage of profoundly hypo-fractionated stereotactic therapy is predicated on the ability to confidently direct treatment precisely to the intended target for the duration of each treatment. This article reviews published studies on the influences of varies types of motion on daily prostate position and how these may be mitigated to improve IGRT in future. In particular the role that MRI has played in the generation of data is discussed and the potential role of the MR-linac in next-generation IGRT is discussed.MRI-guided prostate adaptive radiotherapy – a systematic reviewA consensus statement from the MR-linac consortium.IntroductionRandomised trials have demonstrated that dose escalated radiotherapy improves outcomes for men with prostate cancer PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWxiYXNpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA [2]. The accuracy of any radiotherapy delivery is however limited by multiple factors: organ delineation, set up error and inter-/intra-fraction organ motion, rotation and deformation ADDIN EN.CITE <EndNote><Cite><Author>Kupelian</Author><Year>2011</Year><RecNum>334</RecNum><DisplayText>[3]</DisplayText><record><rec-number>334</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1437605682">334</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kupelian, P.</author><author>Meyer, J. L.</author></authors></contributors><auth-address>Department of Radiation Oncology, University of California School of Medicine, Los Angeles, Calif., USA. pkupelian@mednet.ucla.edu</auth-address><titles><title>Image-guided, adaptive radiotherapy of prostate cancer: toward new standards of radiotherapy practice</title><secondary-title>Front Radiat Ther Oncol</secondary-title><alt-title>Frontiers of radiation therapy and oncology</alt-title></titles><periodical><full-title>Front Radiat Ther Oncol</full-title><abbr-1>Frontiers of radiation therapy and oncology</abbr-1></periodical><alt-periodical><full-title>Front Radiat Ther Oncol</full-title><abbr-1>Frontiers of radiation therapy and oncology</abbr-1></alt-periodical><pages>344-68</pages><volume>43</volume><edition>2011/06/01</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>Motion</keyword><keyword>Prostatic Neoplasms/*radiotherapy</keyword><keyword>Radiation Oncology/*methods/*standards</keyword><keyword>Radiotherapy Planning, Computer-Assisted/methods</keyword><keyword>Radiotherapy, Computer-Assisted/*methods/*standards</keyword></keywords><dates><year>2011</year></dates><isbn>1662-3789 (Electronic)
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ADDIN EN.CITE.DATA [5]. Much work has been carried out over the past 20 years quantifying the degree of prostate motion, rotation and deformation that occurs during a course of radiotherapy, allowing rationalization of treatment margins based on expansion “recipes” ADDIN EN.CITE <EndNote><Cite><Author>van Herk</Author><Year>2004</Year><RecNum>1646</RecNum><DisplayText>[6]</DisplayText><record><rec-number>1646</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1440338671">1646</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Herk, M.</author></authors></contributors><auth-address>Department of Radiotherapy, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.</auth-address><titles><title>Errors and margins in radiotherapy</title><secondary-title>Semin Radiat Oncol</secondary-title><alt-title>Seminars in radiation oncology</alt-title></titles><periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></periodical><alt-periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></alt-periodical><pages>52-64</pages><volume>14</volume><number>1</number><edition>2004/01/31</edition><keywords><keyword>Humans</keyword><keyword>*Motion</keyword><keyword>Radiotherapy Dosage</keyword><keyword>*Radiotherapy Planning, Computer-Assisted</keyword><keyword>Radiotherapy, Conformal</keyword><keyword>Respiration</keyword><keyword>*Tomography, X-Ray Computed</keyword></keywords><dates><year>2004</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1053-4296 (Print)
1053-4296</isbn><accession-num>14752733</accession-num><urls></urls><electronic-resource-num>10.1053/j.semradonc.2003.10.003</electronic-resource-num><remote-database-provider>Nlm</remote-database-provider><language>eng</language></record></Cite></EndNote>[6]. The use of increasingly sophisticated real time imaging has enabled monitoring of the prostate and OAR’s through treatment delivery and has provided extensive data on their behaviour. MRI, with its unrivalled soft tissue delineation, has contributed to this data but has not, as yet, emerged as a routine part of daily radiotherapy delivery. The long anticipated arrival of a fully integrated MR-Linac may change this PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWdlbmRpams8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy
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ADDIN EN.CITE.DATA [7].The ideal scenario is to guide prostate radiotherapy with MR imaging, identifying the prostate in real time while delivering radiation. Two systems (ViewRay and the Elekta MR Linac) hope to demonstrate improvement in patient outcomes with this technique. This article reviews data on target uncertainties when treating prostate cancer and in particular the work performed using MRI. Available techniques to reduce this uncertainty, and the potential benefits an MR-Linac may offer for IGRT are discussed. These data underpin the clinical work which will be undertaken on the MR-Linac to establish its utility in treating localized prostate cancer. Search strategy and selection criteriaReferences for this review were identified through PubMed with the search terms “prostate”, “adaptive”, “radiation”, “radiotherapy”, “motion”, “MRI”, “MR”. The literature review was performed between June and September 2015. The titles/abstracts were screened and full text copies of all potentially relevant studies obtained. References within identified papers were reviewed for relevance. A final reference list was generated on the basis of originality and relevance to the scope of this Review.Non-MR studies of inter- and intra-fractional prostate motionThe prostate experiences inter- and intra-fractional motion during a course of radiotherapy, as reported from an extensive body of work carried out over the past twenty years (supplement- figure 1). A comprehensive review of early studies indicates that the inter-fraction motion appears to have a standard deviation (SD) of around 1 – 4 mm, with one study finding motion with SD as high as 7.3 mm ADDIN EN.CITE <EndNote><Cite><Author>Byrne</Author><Year>2005</Year><RecNum>286</RecNum><DisplayText>[8]</DisplayText><record><rec-number>286</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1437584483">286</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Byrne, T. E.</author></authors></contributors><auth-address>Department of Radiation Oncology, Thompson Cancer Survival Center, Knoxville, TN 37916, USA.</auth-address><titles><title>A review of prostate motion with considerations for the treatment of prostate cancer</title><secondary-title>Med Dosim</secondary-title><alt-title>Medical dosimetry : official journal of the American Association of Medical Dosimetrists</alt-title></titles><periodical><full-title>Med Dosim</full-title><abbr-1>Medical dosimetry : official journal of the American Association of Medical Dosimetrists</abbr-1></periodical><alt-periodical><full-title>Med Dosim</full-title><abbr-1>Medical dosimetry : official journal of the American Association of Medical Dosimetrists</abbr-1></alt-periodical><pages>155-61</pages><volume>30</volume><number>3</number><edition>2005/08/23</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Movement</keyword><keyword>Prostate/*radiation effects</keyword><keyword>Prostatic Neoplasms/*radiotherapy</keyword></keywords><dates><year>2005</year><pub-dates><date>Fall</date></pub-dates></dates><isbn>0958-3947 (Print)
1873-4022 (Linking)</isbn><accession-num>16112467</accession-num><work-type>Research Support, Non-U.S. Gov't
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ADDIN EN.CITE.DATA [9-14]. A minority of patients experience more pronounced changes, as illustrated in a series of 427 patients assessed using fiducial markers (FM) and portal imaging, with motion > 3mm in 28% of treatment fractions over a ten minute period PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3R0ZTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl
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dGU+AG==
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3R0ZTwvQXV0aG9yPjxZZWFyPjIwMDc8L1llYXI+PFJl
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dGU+AG==
ADDIN EN.CITE.DATA [15]. Multiple modalities been used to demonstrate that two general types of intra-fraction motion are seen: non-resolving slow drift, predominantly in the posterior direction due to rectal changes, and sudden transient motion, largely in the superior and anterior direction, likely a result of peristaltic visceral motion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXRsZXI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [9, 16-18]. Constant assessment also identifies greater intra-fraction motion; one study using Calypso 4-D tracking of 7738 records in 200 patients over 12 minutes showed the percentage of fractions with prostate shift >2 ,3, 5, and 7 mm for > 30 seconds was 56.8%, 27.2%, 4.6% and 0.7% ADDIN EN.CITE <EndNote><Cite><Author>Tong</Author><Year>2015</Year><RecNum>184</RecNum><DisplayText>[19]</DisplayText><record><rec-number>184</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1437049115">184</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tong, X.</author><author>Chen, X.</author><author>Li, J.</author><author>Xu, Q.</author><author>Lin, M. H.</author><author>Chen, L.</author><author>Price, R. A.</author><author>Ma, C. M.</author></authors></contributors><auth-address>Third-Affiliated Hospital of Qiqihar Medical University. cn_tongxu@.</auth-address><titles><title>Intrafractional prostate motion during external beam radiotherapy monitored by a real-time target localization system</title><secondary-title>J Appl Clin Med Phys</secondary-title><alt-title>Journal of applied clinical medical physics / American College of Medical Physics</alt-title></titles><periodical><full-title>J Appl Clin Med Phys</full-title><abbr-1>Journal of applied clinical medical physics / American College of Medical Physics</abbr-1></periodical><alt-periodical><full-title>J Appl Clin Med Phys</full-title><abbr-1>Journal of applied clinical medical physics / American College of Medical Physics</abbr-1></alt-periodical><pages>5013</pages><volume>16</volume><number>2</number><edition>2015/06/24</edition><dates><year>2015</year></dates><isbn>1526-9914 (Electronic)
1526-9914 (Linking)</isbn><accession-num>26103174</accession-num><urls><related-urls><url>;[19]. For the worst 10 patients, 5% of the total, these percentages increased to 91.3%, 72.4%, 36.3% and 6%. Cohorts of patients assessed using multiple continuous imaging techniques have also found significant proportions experiencing movements >2-5mm, demonstrating the consistency of this finding within differing imaging modalities PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGltaXp1PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA [20-23]. Intra-fraction motion has generally been found to be patient specific and predominantly random, although this has been challenged PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BZGFtc29uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA [27-29]. Numerous studies have quantified the systematic and random components of inter- and intra-fraction motion to allow application of margin expansion formulas (Table 1 and 2).Table SEQ Table \* ARABIC 1: Inter-fraction systematic and random motionAuthorPt no. (fractions analysed)ImagingInter-fraction motion SD (mm)RegistrationPreparationSystematic motionRandom motionAPLRSIAPLRSIZelefsky 1999PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aZWxlZnNreTwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA [36]10 (243)CT3.91.63.43.62.52.0Skin markersEmpty rectum, full bladder at simulationSoete 2007 ADDIN EN.CITE <EndNote><Cite><Author>Soete</Author><Year>2007</Year><RecNum>2330</RecNum><DisplayText>[37]</DisplayText><record><rec-number>2330</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1446501798">2330</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soete, Guy</author><author>De Cock, Mieke</author><author>Verellen, Dirk</author><author>Michielsen, Dirk</author><author>Keuppens, Frans</author><author>Storme, Guy</author></authors></contributors><titles><title>X-ray–assisted positioning of patients treated by conformal arc radiotherapy for prostate cancer: Comparison of setup accuracy using implanted markers versus bony structures</title><secondary-title>International Journal of Radiation Oncology*Biology*Physics</secondary-title></titles><periodical><full-title>International Journal of Radiation Oncology*Biology*Physics</full-title></periodical><pages>823-827</pages><volume>67</volume><number>3</number><keywords><keyword>Prostate cancer</keyword><keyword>Implanted markers</keyword><keyword>Conformal radiotherapy</keyword></keywords><dates><year>2007</year><pub-dates><date>3/1/</date></pub-dates></dates><isbn>0360-3016</isbn><urls><related-urls><url>;[37]12 (120)kV EPID + FM4.31.34.22.81.62.3BoneHead and knee supportVan der Heide 2007 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIEhlaWRlPC9BdXRob3I+PFllYXI+MjAwNzwv
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0031-9155 (Linking)</isbn><accession-num>23798642</accession-num><work-type>Research Support, N.I.H., Extramural</work-type><urls><related-urls><url>;[50]105 (775)EM0.60.30.51.20.51.15 minNot specifiedChoi 2015 ADDIN EN.CITE <EndNote><Cite><Author>Choi</Author><Year>2015</Year><RecNum>871</RecNum><DisplayText>[51]</DisplayText><record><rec-number>871</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1438874671">871</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Choi, Y.</author><author>Kwak, D. W.</author><author>Lee, H. S.</author><author>Hur, W. J.</author><author>Cho, W. Y.</author><author>Sung, G. T.</author><author>Kim, T. H.</author><author>Kim, S. D.</author><author>Yun, S. G.</author></authors></contributors><auth-address>Departments of Radiation Oncology, School of Medicine, Dong-A University Hospital, Busan, South Korea.</auth-address><titles><title>Effect of rectal enema on intrafraction prostate movement during image-guided radiotherapy</title><secondary-title>J Med Imaging Radiat Oncol</secondary-title><alt-title>Journal of medical imaging and radiation oncology</alt-title></titles><periodical><full-title>J Med Imaging Radiat Oncol</full-title><abbr-1>Journal of medical imaging and radiation oncology</abbr-1></periodical><alt-periodical><full-title>J Med Imaging Radiat Oncol</full-title><abbr-1>Journal of medical imaging and radiation oncology</abbr-1></alt-periodical><pages>236-42</pages><volume>59</volume><number>2</number><edition>2014/09/18</edition><dates><year>2015</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1754-9485 (Electronic)
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ADDIN EN.CITE.DATA [26]184 (5778)kV EPID + FM0.80.50.71.20.81.2< 6 minNot specifiedSoete 2007 ADDIN EN.CITE <EndNote><Cite><Author>Soete</Author><Year>2007</Year><RecNum>2330</RecNum><DisplayText>[37]</DisplayText><record><rec-number>2330</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1446501798">2330</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Soete, Guy</author><author>De Cock, Mieke</author><author>Verellen, Dirk</author><author>Michielsen, Dirk</author><author>Keuppens, Frans</author><author>Storme, Guy</author></authors></contributors><titles><title>X-ray–assisted positioning of patients treated by conformal arc radiotherapy for prostate cancer: Comparison of setup accuracy using implanted markers versus bony structures</title><secondary-title>International Journal of Radiation Oncology*Biology*Physics</secondary-title></titles><periodical><full-title>International Journal of Radiation Oncology*Biology*Physics</full-title></periodical><pages>823-827</pages><volume>67</volume><number>3</number><keywords><keyword>Prostate cancer</keyword><keyword>Implanted markers</keyword><keyword>Conformal radiotherapy</keyword></keywords><dates><year>2007</year><pub-dates><date>3/1/</date></pub-dates></dates><isbn>0360-3016</isbn><urls><related-urls><url>;[37]12 (120)MV EPID + FM0.81.31.11.61.42.47.5 minHead and knee supportKron 2010 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lcm9uPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [52]105 (775)EM0.80.30.81.60.71.410-20 minNot specifiedBadakhshi 2013 ADDIN EN.CITE <EndNote><Cite><Author>Badakhshi</Author><Year>2013</Year><RecNum>1671</RecNum><DisplayText>[53]</DisplayText><record><rec-number>1671</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre">1671</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Badakhshi, H.</author><author>Wust, P.</author><author>Budach, V.</author><author>Graf, R.</author></authors></contributors><auth-address>Department for Radiation Oncology, Charite School of Medicine and University Hospital Berlin, Augustenburger Platz 1, 13353 Berlin, Germany, Harun.Badakhshi@charite.de.</auth-address><titles><title>Image-guided radiotherapy with implanted markers and kilovoltage imaging and 6-dimensional position corrections for intrafractional motion of the prostate</title><secondary-title>Anticancer Res</secondary-title><alt-title>Anticancer research</alt-title></titles><periodical><full-title>Anticancer Res</full-title><abbr-1>Anticancer research</abbr-1></periodical><alt-periodical><full-title>Anticancer Res</full-title><abbr-1>Anticancer research</abbr-1></alt-periodical><pages>4117-21</pages><volume>33</volume><number>9</number><edition>2013/09/12</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Motion</keyword><keyword>Prostatic Neoplasms/*radiotherapy</keyword><keyword>Radiotherapy Dosage</keyword><keyword>Radiotherapy, Image-Guided/*methods</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1791-7530 (Electronic)
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ADDIN EN.CITE.DATA [54-65].The first work with MRI to quantify prostatic motion used axial cine-MRI on 55 patients to evaluate intra-fraction motion of the rectum and prostate centre of mass every 10 seconds over a 6-7 minute period, representative of a radiotherapy treatment delivery time. This identified a median anterior shift of 4.2mm, which in 16% of patients was > 5 mm PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYWRoYW5pPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48
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ADDIN EN.CITE.DATA [61]. This increase in motion appears to occur predominantly in the first few minutes of treatment with another study using cine-MRI imaging over 12-15 minutes finding motion at 3, 5, 10 and 15 minutes with an SD of 1mm, 1.3 mm, 2.1 mm and 1.9 mm in the AP plane and 0.7 mm, 1.8 mm, 1.5 mm and 1.6 mm in the SI plane ADDIN EN.CITE <EndNote><Cite><Author>Gill</Author><Year>2014</Year><RecNum>593</RecNum><DisplayText>[65]</DisplayText><record><rec-number>593</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1437671651">593</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gill, S.</author><author>Dang, K.</author><author>Fox, C.</author><author>Bressel, M.</author><author>Kron, T.</author><author>Bergen, N.</author><author>Ferris, N.</author><author>Owen, R.</author><author>Chander, S.</author><author>Tai, K. H.</author><author>Foroudi, F.</author></authors></contributors><auth-address>Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. suki.gill@.</auth-address><titles><title>Seminal vesicle intrafraction motion analysed with cinematic magnetic resonance imaging</title><secondary-title>Radiat Oncol</secondary-title><alt-title>Radiation oncology</alt-title></titles><periodical><full-title>Radiat Oncol</full-title><abbr-1>Radiation oncology</abbr-1></periodical><alt-periodical><full-title>Radiat Oncol</full-title><abbr-1>Radiation oncology</abbr-1></alt-periodical><pages>174</pages><volume>9</volume><edition>2014/08/12</edition><keywords><keyword>*Artifacts</keyword><keyword>Humans</keyword><keyword>Image Interpretation, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging/*methods</keyword><keyword>Male</keyword><keyword>Motion</keyword><keyword>Prostatic Neoplasms/*pathology</keyword><keyword>Seminal Vesicles/*pathology</keyword></keywords><dates><year>2014</year></dates><isbn>1748-717X (Electronic)
1748-717X (Linking)</isbn><accession-num>25106679</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[65]. The increasing intra-fractional motion seen initially over time shows the potential benefit of shortened treatments associated with VMAT compared to that with IMRT. Other studies using non-MR based imaging have also shown this increase and that it is the strongest predictor of observed displacements PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5nZW48L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [68, 71]. Shortened treatment times, such as those achievable by VMAT, have been shown to achieve a marked reduction in the SD of intra-fraction motion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGVsdG9uPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA [19, 50, 66]. Stereotactic radiotherapy is challenging both due to the potential increase in treatment time compared to conventional VMAT and the implications of a geographical miss for even a single fraction. The necessity to avoid this obliges caution in margin reduction although it has been shown using Cyberknife that repeat imaging every 60 -180 seconds may be sufficient to allow correction for the increased prostate motion of longer treatments PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGUgV2F0ZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9Z
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ADDIN EN.CITE.DATA [72]. Even with regular repeat imaging 6-dimensional correction for rotation and translation is required if margins as small as 3mm are to be achievable.Deformation and rotationMany studies of prostatic motion have assumed rigid motion of the prostate. Analyses of prostate changes have shown this to be a simplification although the degree of deformation identified has varied substantially. For example a study comparing the contoured prostate to an average CTV on 8-12 CT images for 19 patients matched for rotation and translation found “real” shape variation, correcting for inter-observer variation, of 1.6 mm at the SV tip and 0.9 mm at the posterior prostate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZXVybG9vPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48
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ADDIN EN.CITE.DATA [73]. Another group used three repeat CT scans with prostate and SV contoured and matched to a planning CT and non-rigidly registered to represent deformation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGVyIFdpZWxlbjwvQXV0aG9yPjxZZWFyPjIwMDg8
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ADDIN EN.CITE.DATA [75]. Again SV deformation was larger, with changes in the posterior direction of >5 mm and >3 mm in 7.5% and 44.9% of cases. For this analysis three clinicians delineated contours which were averaged in an attempt to reduce error however the SD of the mean centre of mass of the contours was up to 2.2 mm. It may therefore be that the inferior CBCT image quality, limiting contouring accuracy, contributed to the larger changes identified.MRI, which may mitigate delineation errors associated with CT imaging, has also been used to assess deformation. A study of 10 patients using sagittal and axial cine MRI of the prostate to assess changes in the volume of contoured prostate over six minutes found similar results to those obtained using CT imaging with a deformation with a SD 1.7 mm in the AP plane shown ADDIN EN.CITE <EndNote><Cite><Author>Khoo</Author><Year>2002</Year><RecNum>2449</RecNum><DisplayText>[76]</DisplayText><record><rec-number>2449</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1442670524">2449</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Khoo, V.S.</author><author>Bedford, J.L.</author><author>Padhani, A. R.</author><author>Leach, M.</author><author>Husband, J. E.</author><author>Dearnaley, D.</author></authors></contributors><titles><title>Prostate and rectal deformation assessed using cine magnetic resonance imaging (MRI) during a course of radical prostate radiotherapy</title><secondary-title>Radiother Oncol</secondary-title></titles><periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></periodical><pages>S285</pages><volume>64</volume><number>Sup1</number><dates><year>2002</year></dates><urls></urls></record></Cite></EndNote>[76]. Interestingly it has been suggested through tracking points of movement in sagittal MRI imaging that deformation is only seen with a full rectum, and is most marked at the level of mid-prostate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaGlsZXphbjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA [57]. The cause of deformation is due both to mass effect from surrounding structures and as a consequence of treatment itself with the prostate being shown to change in volume during radiotherapy. For example 25 patients underwent MR imaging pre-radiation and at one time point during therapy to assess prostate motion and deformation through treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNob2w8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [58]. Scans were compared using finite element modelling aligned on the centroid of three FM. An increase in prostate volume by up to 34% was seen in those scanned early in treatment whilst a decrease of up to 24% was seen later in the course. The degree of shrinkage seen over a course of radiotherapy is affected by the use of neo-adjuvant hormone therapy and pre-treatment volume but may be generally of the order of 10-15% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuazwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [77-80]. This has implications for further development of MR-guided radiotherapy, which can account for the intra-fraction motion described above, but would need further technical developments to adapt for deformation. The effect of systematic and random inter-fraction rotations on prostate motion has been assessed by various groups using CT, kV and MVCT or EM imaging. These rotations predominate in the sagittal plane and appear to correlate with rectal filling; this moves the prostate in the AP direction, causing rotation due to apex tethering ADDIN EN.CITE <EndNote><Cite><Author>Boda-Heggemann</Author><Year>2007</Year><RecNum>1587</RecNum><DisplayText>[81]</DisplayText><record><rec-number>1587</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1439992711">1587</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boda-Heggemann, J.</author><author>Kohler, F.</author><author>Wertz, H.</author><author>Welzel, G.</author><author>Riesenacker, N.</author><author>Schafer, J.</author><author>Lohr, F.</author><author>Wenz, F.</author></authors></contributors><auth-address>Department of Radiation Oncology, Mannheim Medical Center, University of Heidelberg, Germany.</auth-address><titles><title>Fiducial-based quantification of prostate tilt using cone beam computer tomography (CBCT)</title><secondary-title>Radiother Oncol</secondary-title><alt-title>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</alt-title></titles><periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></periodical><alt-periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></alt-periodical><pages>247-50</pages><volume>85</volume><number>2</number><keywords><keyword>*Cone-Beam Computed Tomography</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Prostate/*radiography</keyword><keyword>Prostatic Neoplasms/radiography</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0167-8140 (Print)
0167-8140 (Linking)</isbn><accession-num>17935807</accession-num><urls><related-urls><url>;[81]. The differing bowel preparations employed by various groups may affect rectal volumes and contribute to the variation in degree of rotation identified. Intra-fractional rotation has been less well characterised and although appearing smaller, it remains relevant (table 3). A study using continuous kV imaging with FM during the treatment of 10 patients with prostate cancer found for 35% of treatment time the prostate rotated more than 5? around the lateral axis PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdWFuZzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [82]. These intra-fraction rotations may be clinically significant. For example even with daily translations the intra-fraction rotation during RT can cause significant under-dosing, and margins of 3mm may be required to account for rotations of up to 5? PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gZGUgV2F0ZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9Z
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Tm90ZT4A
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Tm90ZT4A
ADDIN EN.CITE.DATA [72, 83]. The significance of prostatic rotation is only likely to increase as treatment margins further reduce.Table 3: Studies of intra- and inter-fraction rotationAuthorPt no.( Fractions analysed)ImagingInter-fraction rotation SD (degrees) around each axisRegistrationPreparationSystematicRandomAPLRSIAPLRSIStroom 1999 PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TdHJvb208L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [10]7 (44)MV EPID + FM0.31.00.80.61.81.1<5 minutesFull bladder, empty rectumBadakhshi 2013 ADDIN EN.CITE <EndNote><Cite><Author>Badakhshi</Author><Year>2013</Year><RecNum>1671</RecNum><DisplayText>[53]</DisplayText><record><rec-number>1671</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre">1671</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Badakhshi, H.</author><author>Wust, P.</author><author>Budach, V.</author><author>Graf, R.</author></authors></contributors><auth-address>Department for Radiation Oncology, Charite School of Medicine and University Hospital Berlin, Augustenburger Platz 1, 13353 Berlin, Germany, Harun.Badakhshi@charite.de.</auth-address><titles><title>Image-guided radiotherapy with implanted markers and kilovoltage imaging and 6-dimensional position corrections for intrafractional motion of the prostate</title><secondary-title>Anticancer Res</secondary-title><alt-title>Anticancer research</alt-title></titles><periodical><full-title>Anticancer Res</full-title><abbr-1>Anticancer research</abbr-1></periodical><alt-periodical><full-title>Anticancer Res</full-title><abbr-1>Anticancer research</abbr-1></alt-periodical><pages>4117-21</pages><volume>33</volume><number>9</number><edition>2013/09/12</edition><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Motion</keyword><keyword>Prostatic Neoplasms/*radiotherapy</keyword><keyword>Radiotherapy Dosage</keyword><keyword>Radiotherapy, Image-Guided/*methods</keyword></keywords><dates><year>2013</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1791-7530 (Electronic)
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ADDIN EN.CITE.DATA [88]. It is therefore generally necessary to include this area in the intended CTV for radiotherapy planning. The base of the SV is the region most likely to harbour occult disease, with one pathological series finding disease 2cm beyond this in only 1% of all patients ADDIN EN.CITE <EndNote><Cite><Author>Kestin</Author><Year>2002</Year><RecNum>1642</RecNum><DisplayText>[89]</DisplayText><record><rec-number>1642</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1440188991">1642</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kestin, L.</author><author>Goldstein, N.</author><author>Vicini, F.</author><author>Yan, D.</author><author>Korman, H.</author><author>Martinez, A.</author></authors></contributors><auth-address>Department of Radiation Oncology, William Beaumont Hospital, Royal Oak, MI 48073, USA. lkestin@beaumont.edu</auth-address><titles><title>Treatment of prostate cancer with radiotherapy: should the entire seminal vesicles be included in the clinical target volume?</title><secondary-title>Int J Radiat Oncol Biol Phys</secondary-title><alt-title>International journal of radiation oncology, biology, physics</alt-title></titles><periodical><full-title>Int J Radiat Oncol Biol Phys</full-title><abbr-1>International journal of radiation oncology, biology, physics</abbr-1></periodical><alt-periodical><full-title>Int J Radiat Oncol Biol Phys</full-title><abbr-1>International journal of radiation oncology, biology, physics</abbr-1></alt-periodical><pages>686-97</pages><volume>54</volume><number>3</number><keywords><keyword>Aged</keyword><keyword>Biopsy</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Multivariate Analysis</keyword><keyword>Prostate-Specific Antigen/blood</keyword><keyword>Prostatectomy</keyword><keyword>Prostatic Neoplasms/blood/*pathology/radiotherapy</keyword><keyword>Seminal Vesicles/*pathology/radiography</keyword></keywords><dates><year>2002</year><pub-dates><date>Nov 1</date></pub-dates></dates><isbn>0360-3016 (Print)
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ADDIN EN.CITE.DATA [78, 92]. Inter-fraction SV motion appears more significant than that of the prostate gland with a SD in the order of 2.9 – 7.3 mm, 1.9 - 3.1 mm and 2.1 - 5.5 mm in the AP, LR and SI planes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYXdzb248L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [30, 43, 79, 91, 93, 94]. Despite direct tumour invasion reducing SV mobility, this motion may remain considerable ADDIN EN.CITE <EndNote><Cite><Author>van der Burgt</Author><Year>2015</Year><RecNum>2416</RecNum><DisplayText>[95]</DisplayText><record><rec-number>2416</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1450028521">2416</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van der Burgt, M.</author><author>Bergsma, L.</author><author>de Vries, J.</author><author>Pos, F. J.</author><author>Kalisvaart, R.</author><author>Heemsbergen, W.</author><author>Remeijer, P.</author><author>van der Heide, U. A.</author></authors></contributors><auth-address>Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Radiation Oncology, Academic Medical Center, Amsterdam, The Netherlands.
Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: u.vd.heide@nki.nl.</auth-address><titles><title>Impact of tumour invasion on seminal vesicles mobility in radiotherapy of prostate cancer</title><secondary-title>Radiother Oncol</secondary-title><alt-title>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</alt-title></titles><periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></periodical><alt-periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></alt-periodical><dates><year>2015</year><pub-dates><date>Oct 14</date></pub-dates></dates><isbn>1879-0887 (Electronic)
0167-8140 (Linking)</isbn><accession-num>26476561</accession-num><urls><related-urls><url>;[95]. Allowing for intra-fractional motion is also problematic. Overall intra-fractional displacement of the SV appears greater than for the prostate and increases over time. In one series using cine-MRI it was found that for 95 % of the images SV centroid movement at 3, 5, 10 and 15 minutes was 4.7 mm, 5.8 mm, 6.5 mm and 7.2 mm respectively in the SI plane and 4.0 mm, 4.5 mm, 6.5 mm and 7.0 mm in the AP plane ADDIN EN.CITE <EndNote><Cite><Author>Gill</Author><Year>2014</Year><RecNum>593</RecNum><DisplayText>[65]</DisplayText><record><rec-number>593</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1437671651">593</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gill, S.</author><author>Dang, K.</author><author>Fox, C.</author><author>Bressel, M.</author><author>Kron, T.</author><author>Bergen, N.</author><author>Ferris, N.</author><author>Owen, R.</author><author>Chander, S.</author><author>Tai, K. H.</author><author>Foroudi, F.</author></authors></contributors><auth-address>Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. suki.gill@.</auth-address><titles><title>Seminal vesicle intrafraction motion analysed with cinematic magnetic resonance imaging</title><secondary-title>Radiat Oncol</secondary-title><alt-title>Radiation oncology</alt-title></titles><periodical><full-title>Radiat Oncol</full-title><abbr-1>Radiation oncology</abbr-1></periodical><alt-periodical><full-title>Radiat Oncol</full-title><abbr-1>Radiation oncology</abbr-1></alt-periodical><pages>174</pages><volume>9</volume><edition>2014/08/12</edition><keywords><keyword>*Artifacts</keyword><keyword>Humans</keyword><keyword>Image Interpretation, Computer-Assisted</keyword><keyword>Magnetic Resonance Imaging/*methods</keyword><keyword>Male</keyword><keyword>Motion</keyword><keyword>Prostatic Neoplasms/*pathology</keyword><keyword>Seminal Vesicles/*pathology</keyword></keywords><dates><year>2014</year></dates><isbn>1748-717X (Electronic)
1748-717X (Linking)</isbn><accession-num>25106679</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[65]. The correlation between prostate and SV intra-fraction movement was shown to vary greatly with no relationship between the two for most patientsThe lack of correlation between prostate and SV inter- and intra-fractional motion has implications for the use of prostate tracking devices, such as calypso transponders, when simultaneously treating the SV. Caution must be employed when considering reducing treatment margins on the basis of an assumed confidence about exact CTV location.Contributing factors to prostate motionRectal and bladder volumes Rectal distension is a major contributor to, and correlates with, prostate motion (supplement- figure 2). This likely relationship was identified in some of the earliest prostate motion analyses PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UZW4gSGFrZW48L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFy
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ADDIN EN.CITE.DATA [54, 55, 57, 98-100]. This relationship has also been demonstrated with MRI. A small study of seven patients measured the prostate midpoint relative to bony anatomy on pre and post treatment MRI and found variation in rectal filling that correlated strongly with anterior displacement and a lesser correlation between bladder filling and superior motion PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaWxsZWlyczwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+
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ADDIN EN.CITE.DATA [56]. A larger study of 42 patients used cine-MRI scans every nine seconds for nine minutes at baseline without any bowel preparation, before CT planning with bowel preparation and at a random point during RT with bowel preparation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OaWNob2w8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [101-103]. The increased motion associated with initial large rectal volumes may also negatively influence treatment outcome. In one series of 127 patients those with a mean rectal cross sectional area greater than the group average of 11.2cm2 at the time of planning experienced greater biochemical failure rates (HR 3.89) and more toxicity from treatment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBDcmV2b2lzaWVyPC9BdXRob3I+PFllYXI+MjAwNTwv
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBDcmV2b2lzaWVyPC9BdXRob3I+PFllYXI+MjAwNTwv
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ADDIN EN.CITE.DATA [104]. Another study examined outcomes for 549 patients, stratified by anorectal volumes ≥90cm3 at time of planning CT, and found that in patients with a risk of SV involvement >25% those with a larger rectal volume had a 15% reduction in freedom from failure at five years (p=0.01) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IZWVtc2JlcmdlbjwvQXV0aG9yPjxZZWFyPjIwMDc8L1ll
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ADDIN EN.CITE.DATA [106]. The use of effective daily image guidance may mitigate any effects of initial rectal distension. Although the potential effect of rectal volume on prostate motion appears clear, the effects of changes in bladder volume appear at most to be minimal. Various studies have provided some limited evidence suggesting a weak relationship between the two PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWxpYW48L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [108-111]. It would therefore seem likely that simple bladder filling protocols are sufficient to minimise any bladder volume effects. However, for prone patients or patients with restricted abdominal movement, e.g. due to MR coils, bladder filling may affect prostate motion and such setups should be avoided.Target delineationInter- and intra- operator variation in target delineation, particularly at the SV and apex, can be significant PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PZWhsZXI8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [49, 112, 113]. This is in part due to poor soft tissue definition on CT imaging making identification of the boundaries of the prostate challenging. It is known that CT delineated prostates are routinely larger than the true anatomical site. One study comparing the CT delineation by six radiation oncologists with photographic anatomical images found that the contoured prostate was on average 30% larger that the true gland but only included 84% of its volume, such that posterior portions were always missed and anterior normal tissue always included ADDIN EN.CITE <EndNote><Cite><Author>Gao</Author><Year>2007</Year><RecNum>1866</RecNum><DisplayText>[114]</DisplayText><record><rec-number>1866</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1442195641">1866</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gao, Z.</author><author>Wilkins, D.</author><author>Eapen, L.</author><author>Morash, C.</author><author>Wassef, Y.</author><author>Gerig, L.</author></authors></contributors><auth-address>Department of Physics, Carleton University, Ottawa, Canada.</auth-address><titles><title>A study of prostate delineation referenced against a gold standard created from the visible human data</title><secondary-title>Radiother Oncol</secondary-title><alt-title>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</alt-title></titles><periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></periodical><alt-periodical><full-title>Radiother Oncol</full-title><abbr-1>Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology</abbr-1></alt-periodical><pages>239-46</pages><volume>85</volume><number>2</number><keywords><keyword>Humans</keyword><keyword>Male</keyword><keyword>Organ Size</keyword><keyword>Prostate/*anatomy & histology/radiography</keyword><keyword>Tomography, X-Ray Computed</keyword><keyword>United States</keyword><keyword>*Visible Human Projects</keyword></keywords><dates><year>2007</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0167-8140 (Print)
0167-8140 (Linking)</isbn><accession-num>17825447</accession-num><urls><related-urls><url>;[114]. MRI provides better distinction between adjacent soft tissue structures and has been shown to be superior at identifying the prostate apex, SV and posterior border (supplement-figure 3). Multiple studies have demonstrated a reduction in volume of contoured prostate, of between 30-35% in the three largest series, when MR imaging is used to provide addition information for planning PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXNjaDwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [115-117]. These reductions are primarily due to reduced variation at the superior and inferior extent of the prostate and translate into reductions in delivered dose to the rectum PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EZWJvaXM8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [122]. A final benefit from use of MRI for prostate delineation comes from the reduced metal artefact degradation from prosthetic hips which may significantly affect CT imaging and subsequent contour consistency PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb3Nld2FsbDwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA [124, 125]. Therefore it appears MR-based contouring of the prostate can be done more consistently and with higher fidelity than CT, leading to reduced treatment volumes and radiation to surrounding structures.Recently work has focused on the use of multi-parametric (MP) MR to identify areas of high grade tumour within the prostate gland PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJlbnRzejwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+
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ADDIN EN.CITE.DATA [126]. The use of modelling for voxelwise prediction of disease presence on MR imaging has been shown to have promise PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm9lbmVuZGFhbDwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll
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ADDIN EN.CITE.DATA [128]. MPMR guided targeted dose escalation is the subject of the ongoing phase III FLAME study and results are awaited with interest ADDIN EN.CITE <EndNote><Cite><Author>Lips</Author><Year>2011</Year><RecNum>2434</RecNum><DisplayText>[129]</DisplayText><record><rec-number>2434</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1452649543">2434</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lips, I. M.</author><author>van der Heide, U. A.</author><author>Haustermans, K.</author><author>van Lin, E. N.</author><author>Pos, F.</author><author>Franken, S. P.</author><author>Kotte, A. N.</author><author>van Gils, C. H.</author><author>van Vulpen, M.</author></authors></contributors><auth-address>Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands. i.m.lips@umcutrecht.nl</auth-address><titles><title>Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial</title><secondary-title>Trials</secondary-title><alt-title>Trials</alt-title></titles><periodical><full-title>Trials</full-title><abbr-1>Trials</abbr-1></periodical><alt-periodical><full-title>Trials</full-title><abbr-1>Trials</abbr-1></alt-periodical><pages>255</pages><volume>12</volume><keywords><keyword>Aged</keyword><keyword>*Clinical Protocols</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Outcome Assessment (Health Care)</keyword><keyword>Prostatic Neoplasms/psychology/*radiotherapy</keyword><keyword>Quality of Life</keyword><keyword>Radiotherapy Dosage</keyword><keyword>Single-Blind Method</keyword></keywords><dates><year>2011</year></dates><isbn>1745-6215 (Electronic)
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ADDIN EN.CITE.DATA [130]. In a study using collimator adjustments to account for prostate rotations, patients with and without focal boost were equally sensitive to rotations, indicating a limited effect of prostate rotations on boost dose PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5kZSBCb2VyPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA [131].Adaptive radiotherapy for inter-fraction motionThe current standard practice to manage inter-fraction variations is to use IGRT by repositioning the patient based on the rigid-body registration of the planning image and the image of the day acquired just before treatment, followed by delivery of the original (unchanged) plan. IGRT addresses the translational motions, including set-up errors, but cannot completely account for the organ deformation, rotation, and independent motion between different organs. The ideal method to fully account for the inter-fractional variations is to adapt the treatment plan based on the anatomy of the day. Such adaptive planning process may be performed in an online or offline manner PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5ZYW48L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [45, 134, 135].Online adaptive radiotherapy (ART), on the other hand, is capable of addressing both systematic and random variations and is the most effective strategy for precisely irradiating concurrent targets that move independently. Online planning must be fast enough to be completed within a few minutes while the patient is lying on the table waiting for treatment. Although such fast planning is generally challenging using conventional planning technologies, adaptive re-planning does not need to start completely from scratch. For example, it can start with an initial plan fully optimized from the planning images for the same patient and adapt for the anatomy of the day (‘warm start’ optimization). Technologies to facilitate this, such as the quality of in-room imaging, image registration and segmentation, plan optimization algorithm and computing hardware, are advancing significantly and rapidly. For example, integration of diagnostic-quality MRI in the treatment room, graphic-processing unit (GPU) accelerated auto-segmentation and dose calculation, rapid plan modification algorithms, and plan adaptation based on previous knowledge or a previously-created plan library are among the technology advances that can speed up adaptive planning significantly. In particular, among a number of online planning algorithms PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3VydDwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl
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AG==
ADDIN EN.CITE.DATA [136-139], an online adaptive planning scheme ADDIN EN.CITE <EndNote><Cite><Author>Ahunbay</Author><Year>2008</Year><RecNum>2173</RecNum><DisplayText>[138]</DisplayText><record><rec-number>2173</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1444841221">2173</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahunbay, E. E.</author><author>Peng, C.</author><author>Chen, G. P.</author><author>Narayanan, S.</author><author>Yu, C.</author><author>Lawton, C.</author><author>Li, X. A.</author></authors></contributors><auth-address>Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.</auth-address><titles><title>An on-line replanning scheme for interfractional variations</title><secondary-title>Med Phys</secondary-title><alt-title>Medical physics</alt-title></titles><periodical><full-title>Med Phys</full-title><abbr-1>Medical physics</abbr-1></periodical><alt-periodical><full-title>Med Phys</full-title><abbr-1>Medical physics</abbr-1></alt-periodical><pages>3607-15</pages><volume>35</volume><number>8</number><keywords><keyword>Automation</keyword><keyword>Dose Fractionation</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>*Pancreatic Neoplasms/pathology/radiography/radiotherapy</keyword><keyword>Prostate/pathology/radiography</keyword><keyword>*Prostatic Neoplasms/pathology/radiography/radiotherapy</keyword><keyword>Radiation Dosage</keyword><keyword>Radiography, Abdominal/*radiation effects</keyword><keyword>Radiotherapy, Computer-Assisted/*methods</keyword><keyword>Rectum/pathology/radiography</keyword><keyword>Tomography, X-Ray Computed/*methods</keyword><keyword>Urinary Bladder/pathology/radiography</keyword></keywords><dates><year>2008</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0094-2405 (Print)
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ADDIN EN.CITE.DATA [140]. It has been demonstrated that the online SAM+SWO scheme can adequately account for all inter-fraction variations and can be completed within 10 minutes for prostate RT PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BaHVuYmF5PC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA [145, 146].With online ART, a CTV-PTV margin can reach as low as 3 mm, depending mainly on intra-fraction variations. Such a small margin would be highly desirable to reduce treatment-related toxicities and/or to allow dose escalation. Online ART is particularly important for hypo-fractionated RT or SBRT where the penalty of a geographical miss and/or over dosing of normal tissue for a single fraction is significant. However, with such small margins, target definition accuracy becomes much more critical to avoid the risk of compromising clinical outcome PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbmdlbHM8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [147]MRI-guided adaptive radiotherapy for inter- and intra-fractional motionsThe high soft tissue contrast makes MRI an ideal imaging modality for online ART. MRI-guided RT delivery systems that integrate MR scanners with radiation delivery machines are being introduced into the clinic ADDIN EN.CITE <EndNote><Cite><Author>Mutic</Author><Year>2014</Year><RecNum>2246</RecNum><DisplayText>[148]</DisplayText><record><rec-number>2246</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1445437692">2246</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mutic, S.</author><author>Dempsey, J. F.</author></authors></contributors><auth-address>Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO. Electronic address: mutic@wustl.edu.
ViewRay Incorporated, Oakwood Village, OH.</auth-address><titles><title>The ViewRay system: magnetic resonance-guided and controlled radiotherapy</title><secondary-title>Semin Radiat Oncol</secondary-title><alt-title>Seminars in radiation oncology</alt-title></titles><periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></periodical><alt-periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></alt-periodical><pages>196-9</pages><volume>24</volume><number>3</number><keywords><keyword>Equipment Design</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/*instrumentation</keyword><keyword>Magnetic Resonance Imaging, Interventional</keyword><keyword>Missouri</keyword><keyword>Radiation Oncology/*instrumentation</keyword><keyword>Radiotherapy Planning, Computer-Assisted/instrumentation</keyword><keyword>Radiotherapy, Image-Guided/*instrumentation</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1532-9461 (Electronic)
1053-4296 (Linking)</isbn><accession-num>24931092</accession-num><urls><related-urls><url>;[148]. For example, ViewRay system (Oakwood Village, OH) combines a 0.35 T MRI scanner with three 60Co sources with multi-leaf collimators (MLC). Integration of a diagnostic MRI scanner with a Linac (MR-Linac) is also under development. The MR-Linac proposed by Lagendijk et al at the University Medical Center Utrecht ADDIN EN.CITE <EndNote><Cite><Author>Lagendijk</Author><Year>2014</Year><RecNum>2247</RecNum><DisplayText>[149]</DisplayText><record><rec-number>2247</rec-number><foreign-keys><key app="EN" db-id="as29rft002ffvfep5d0xrpe80atdx5aeevre" timestamp="1445437795">2247</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lagendijk, J. J.</author><author>Raaymakers, B. W.</author><author>van Vulpen, M.</author></authors></contributors><auth-address>Department of Radiotherapy, Imaging Division, UMC Utrecht, Utrecht, The Netherlands. Electronic address: j.j.w.lagendijk@umcutrecht.nl.
Department of Radiotherapy, Imaging Division, UMC Utrecht, Utrecht, The Netherlands.</auth-address><titles><title>The magnetic resonance imaging-linac system</title><secondary-title>Semin Radiat Oncol</secondary-title><alt-title>Seminars in radiation oncology</alt-title></titles><periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></periodical><alt-periodical><full-title>Semin Radiat Oncol</full-title><abbr-1>Seminars in radiation oncology</abbr-1></alt-periodical><pages>207-9</pages><volume>24</volume><number>3</number><keywords><keyword>Equipment Design</keyword><keyword>Humans</keyword><keyword>Magnetic Resonance Imaging/*instrumentation</keyword><keyword>Magnetic Resonance Imaging, Interventional</keyword><keyword>Particle Accelerators</keyword><keyword>Radiation Oncology/*instrumentation</keyword><keyword>Radiotherapy Planning, Computer-Assisted/instrumentation</keyword><keyword>Radiotherapy, Image-Guided/*instrumentation</keyword></keywords><dates><year>2014</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1532-9461 (Electronic)
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ADDIN EN.CITE.DATA [7]. With CT based IGRT, image quality adversely affects the CTV-to-PTV margins required for targeting and ART, mainly due to the residual uncertainties from the soft-tissue contrast for the image modality PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3Jyb3c8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [150]. It is anticipated that the residual uncertainty with diagnostic quality MRI will be drastically smaller than those with CT or CBCT, allowing a smaller CTV-to-PTV margin.The design of the MR-Linac system comprises a 6 MV Linac (Elekta Inc) mounted on a ring around a modified 1.5 T MRI scanner (Achieva, Philips Healthcare, Best, The Netherlands) and an online ART planning system PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYWdlbmRpams8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFy
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ADDIN EN.CITE.DATA [7]. The system is designed to be able to simultaneously image and irradiate the patient. The radiation beam is shaped by a 160-leaf MLC system and travels through the closed-bore MRI before it enters the patient. The accelerator and MRI are designed to be magnetically decoupled so that the MR images are not distorted by the presence of magnetized accelerator components, and the operation of the accelerator is not hampered by the magnetic field. A series of MR sequences can be scanned to produce pre-, during- and post-treatment images. Once the MR-Linac is fully developed, the pre- and post-treatment MRI can include both morphological (T1, T2...) and functional (DWI, DCE etc.) images. The during-treatment MRIs include cine MRI (2D), morphological 3D (e.g., T1, T2) and 4D images. The online planning system integrated in the MR-Linac should be designed to generate an adaptive plan based on the pre-treatment MRI in the following steps: 1) deformably register the pre-treatment MRI with the planning images, 2) rapidly generate a plan by modifying or re-optimizing the original plan or by fast adaptive re-planning to account for the different anatomy based on the registered images, and 3) quickly perform a software-based QA check on the new plan. To be successful the system should complete this 3-step online process within 5 minutes while the patient is still lying on the couch. Then, the new adaptive plan is delivered simultaneously with the during-treatment images acquired. The MR-Linac system is designed to able to track/monitor organ (e.g., prostate gland) motion in real-time on 2D (cine) MRI during the radiation delivery. Because of superior soft tissue contrast, this tracking should be very accurate and effective. The radiation beam can be paused, via the capability of exception gating, if prostate motion is detected outside a pre-defined range, and can be resumed if the prostate moves back to the range. Alternatively, it is anticipated that with technical enhancements, the radiation beam may be dynamically shaped to trace the prostate motion detected from the cine MRI acquired on the plane perpendicular to the beam orientation. Either way, the intra-fractional variations can be managed effectively, thus the margin required to account for intra-fraction variation can be reduced. The superior soft tissue contrast along with function/physiological information with MRI will significantly improve the performance and implementation of the online ART strategy (e.g., improved target definition, image registration, auto-segmentation). In addition, with the availability of real-time MR imaging during RT delivery to measure and monitor intra-fraction motion, the motion management techniques (gating or tracking) can be improved. With both inter- and intra-fractional variations being accounted for, the CTV-to-PTV margin may be safely reduced to ≤3 mm. Because the PTV often overlaps with rectum and bladder, such a drastic reduction in PTV margin should reduce toxicities or allow RT doses to be safely escalated to eradicate the tumour, thus improving treatment outcomes. ConclusionExtensive literature demonstrates that substantial inter- and intra-fractional variations occur in radiation therapy for prostate cancer. These variations include translational and rotational motions, deformations, and independent motions between the structures, and consist of both random and systematic components. While the current standard practice of IGRT based on CT or CBCT can only address translational motion, adaptive radiotherapy has the potential to fully account for these variations. The superior soft-tissue contrast and the continuous imaging capability of MRI are highly desirable for the management of inter- and intra-fraction variations. Integration of MRI radiotherapy delivery and ART capability, such as with the MR-Linac, holds the promise to optimize radiotherapy to the prostate. Using this approach the improved delineation of target and OARs in both planning and delivery, will mean inter- and intra-fractional variations may be confidently accounted for, permitting use of a decreased CTV-to-PTV margin. Conflict of Interest:Dr Tree has received funding from Elekta for a Research FellowAcknowledgements:Dr van As and Dr Tree gratefully acknowledge the support of the Royal Marsden/Institute of Cancer NIHR Biomedical Research Centre. 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