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Contents

Best of BJR

Introduction from the Honorary Editors Commentaries Doctor, is a CT scan safe for my child? M J Goske

Dreams, themes and particle beams—an oncologist’s perspective on technology trickle-down from the LHC R Jena

Review article Imaging in head and neck squamous cell carcinoma: the potential role of PET/MRI Minerva Becker and Habib Zaidi

Full papers Simultaneous integrated boost to intraprostatic lesions using different energy levels of intensity-modulated radiotherapy and volumetric-arc therapy C Onal, S Sonmez, G Erbay, O C Guler and G Arslan

Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI S A Milgrom, H Alberto Vargas, E Sala, J Frankel Kelvin, H Hricak and K A Goodman

Detection of ischaemic myocardial lesions with coronary CT angiography and adenosine-stress dynamic perfusion imaging using a 128-slice dual-source CT: diagnostic performance in comparison with cardiac MRI S M Kim, J-H Choi, S-A Chang and Y H Choe

Evaluation of 99mTc-peptide-ZHER2:342 Affibody® molecule for in vivo molecular imaging J-M Zhang, X-M Zhao, S-J Wang, X-C Ren, N Wang, J-Y Han and L-Z Jia

Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy W B Hyland, S J McMahon, K T Butterworth, A J Cole, R B King, K M Redmond, K M Prise, A R Hounsell and C K McGarry

Cone beam CT guidance provides superior accuracy for complex needle paths compared with CT guidance W M H Busser, S J Braak, J J Fütterer, M J L van Strijen, Y L Hoogeveen, F de Lange and L J Schultze Kool

Walking on thin ice! Identifying methamphetamine “drug mules” on digital plain radiography S N Abdul Rashid, S B Mohamad Saini, S Abdul Hamid, S J Muhammad, R Mahmud, M J Thali and P M Flach

Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? X Wang, X Zhang, X Li, R A Amos, S F Shaitelman, K Hoffman, R Howell, M Salehpour, S X Zhang, T L Sun, B Smith, W Tereffe, G H Perkins, T A Buchholz, E A Strom and W A Woodward To read these articles in full, go to birpublications.org/bjr. If you are a BIR member you can access these articles by going to www.bir.org.uk, accessing the member’s area and then selecting “Read BJR”. © 2014 The Authors. Published by The British Institute of Radiology. This publication is copyright under the Berne Convention and the Universal Copyright Convention. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means without the prior permission of the copyright owner. Permission is not, however, required to copy abstracts of papers or articles on condition that a full reference to the source is shown. Multiple copying of the publication without permission is illegal—address enquiries regarding photocopying to the Copyright Licensing Agency, Saffron House, 6-10 Kirby Street, London EC1N 8TS, UK (Tel. +44 (0)20 7400 3100; E-mail: licence@cla.co.uk). All opinions expressed in the British Journal of Radiology are those of the respective authors and not the publisher. The publisher has taken the utmost care to ensure that the information and data contained in this journal are as accurate as possible at the time of going to press. Nevertheless, the publisher cannot accept any responsibility for errors, omissions or misrepresentations howsoever caused. All liability for loss, disappointment, or damage caused by reliance on the information contained in this journal or the negligence of the publisher is hereby excluded.

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BJR is essential reading for radiologists, medical physicists, radiotherapists, radiographers and radiobiologists. Articles included in BJR cover a wide range of subjects, including diagnostic radiology, radiotherapy, oncology, nuclear medicine, ultrasound, radiation physics, radiation protection and radiobiology.

Introduction from the Honorary Editors

David Bradley Honorary Editor (Scientific)

Nigel Hoggard Honorary Editor (Medical)

We hope you enjoy reading this collection of influential articles from recent issues of BJR. BJR is an international, multidisciplinary journal covering the clinical and technical aspects of medical imaging, radiotherapy, oncology, medical physics, radiobiology and the underpinning sciences. This collection contains a cross-section of the broad, multidisciplinary content that can be found in BJR. Two commentaries and one review are reproduced in full and there are excerpts from eight other articles to give you a taster of the great content you can find in the journal. To read the articles in full, go to the BJR website, www.birpublications.org/bjr, where they have been made free. Featured articles include a commentary by 2012 RSNA award winner Dr Marilyn Goske “Doctor, is a CT scan safe for my child?”, an oncologist's perspective on technology trickle-down from the Large Hadron Collider by Dr Raj Jena and a comprehensive review article on the potential role of PET/MRI in imaging head and neck squamous cell carcinoma by Professors Minerva Becker and Habib Zaidi.

Articles are published in their final version within only three weeks! As the oldest scientific journal in the field of radiology and related sciences, BJR has published a number of pioneering articles, including the first description of Computed Tomography, “Computerized transverse axial tomography” by Godfrey Hounsfield in 1973.1 The full BJR archive has been digitized from 1896, and launched in January 2014 as a valuable historical resource. January 2014 also saw the relaunch of our journal website, www.birpublications.org, for enhanced and more user-friendly content delivery and the first of our winning entries for the BJR 2014 cover competition. BJR is at the cutting edge of modern publishing with our flexible open access option, BIR|Open, for any author who chooses or is mandated to publish in this way, and continuous publication model: once an article is in its final form, it is immediately published online in its final citable form. BJR articles are published quicker than ever before—after a paper is accepted for publication, it appears in its final version within only three weeks! BJR is a competitive, accessible, high-quality journal for 21st century radiological sciences. We hope you will contribute to the continuing success of BJR by reading BJR articles, reviewing papers and submitting your work.

Reference 1.

Hounsfield GN. Computerized transverse axial scanning (tomography): Part I. Description of system. Br J Radiol 1973;46:1016–22. doi:10.1259/0007-1285-46-552-1016

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BJR Received: 14 August 2013

Accepted: 17 December 2013

doi: 10.1259/bjr.20130517

Cite this article as: Goske MJ. Doctor, is a CT scan safe for my child?. Br J Radiol 2014;87:20130517.

COMMENTARY

Doctor, is a CT scan safe for my child? M J GOSKE, MD Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA Address correspondence to: Dr Marilyn J. Goske E-mail: Marilyn.Goske@cchmc.org

Medical professionals and international organizations have promoted radiation protection for patients since the early 1900s when organizations such as the British Roentgen Society and American Roentgen Ray Society were founded.1 However, it was the 2007 article by Brenner and Hall2 and the release of such publications as the National Council on Radiation Protection and Measurement’s Report 160 that prompted the much needed public debate in the media and by the public on increasing radiation exposure from CT scans.3,4 Within the past 15 months, three large epidemiological studies, including the most recent one by Miglioretti et al,5 have assessed the risk of cancer due to CT imaging in children.6,7 The purpose of this commentary is to consider whether the Miglioretti article and the other two research studies on radiation protection in children should impact parents’ perception of CT safety for their child. Do these articles help answer a parent’s most common and difﬁcult question, “Doctor, is a CT scan safe for my child?”

FINDING 2: ESTIMATES OF EFFECTIVE RADIATION DOSE Pearce et al6 estimated radiation dose based on typical CT scanner settings for young people from 1989 and 2003 to estimate absorbed dose for “reference patients” and did not obtain actual patient dose data. In the Australian study by Mathews et al,7 the primary outcome measure was cancer incidence; the study did not address radiation dose per CT scan directly. In the Miglioretti article, estimates of the number of patients with an effective dose .20 mSv were higher than the estimates for paediatric CT in the past. Because parents want their child to receive the minimal necessary radiation dose, they will sometimes ask “Did the CT scan my child received use a ‘child-sized’ dose of radiation?”10 The data from this article tell us that the answer may be “no”. Parents should be very interested in this ﬁnding because it implies that their child may receive a higher radiation dose than is warranted for the necessary examination.

The Miglioretti study had 3 main ﬁndings: estimates of the rates of CT scan use in children younger than 15 years from a population comprising 4 857 736 child-years; estimates of organ and effective doses using a credible new measure based on sex- and age-speciﬁc computational anatomic phantoms in a subpopulation of 744 randomly selected CT scans; and assessment of the projected excess lifetime cancer risk attributed to CT scans in this population.5

In addition, the Miglioretti article highlighted significant variation of CT dose among facilities. Because CT dose varied so much between sites for the same examination, between 3% and 25% (depending on the anatomic location), some patients received a larger dose of radiation than they could have received if scanned at another institution. In that regard, the Migglioretti article is noteworthy for both parents and radiologists. Parents, particularly parents with children who have chronic illness, may choose to use this information to investigate CT doses at a specific facility and choose to take their child to a facility with lower doses. Radiologists in countries with relevant statutory requirements will have their patient dose data and should be able to compare their internal data with those of reference institutions or national data. Other radiologists (in countries where there is no legal control on the amount of radiation that a patient may receive) may not. For those radiologists, it may be difficult to answer a parent’s question. Blanket assurances to parents that “the lowest dose was used” may be wrong and are inappropriate. This underscores the need for facilities throughout the world to have teams of individuals responsible for patient care in CT as part of a robust quality assurance programme, as is required by law in many

FINDING 1: ESTIMATES OF THE RATES OF CT USE Estimates of rates of CT use were relatively straightforward in the Miglioretti article.5 Rates of CT scans from 1995 to 2005 increased at a signiﬁcant rate, plateaued in 2006 and 2007 and then declined. These ﬁndings mirror several other studies on CT use in the paediatric population and are not controversial within the radiology community.8,9 The other two articles6,7 provided data on the number of CT scans within the study time frames, but did not assess utilization. CT use at a national level is not likely to be central to a parent’s interest, as they are interested in their child’s need for a CT scan and not focused on population statistics.

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MJ Goske

countries throughout the world.11 The medical imaging team shares the responsibility to ensure radiation protection for children under their care. Justification for each paediatric CT scan and the judicious use and rigorous monitoring of patient dose need to occur irrespective of whether it is required by law. Members of the team include the radiologist, medical imaging physicist, radiographer and CT manufacturer.10 Medical imaging professionals (and that includes referring physicians) who are part of the patient care team should attend training updates on an ongoing basis to learn newer concepts related to radiation biology, risk, risk communication, dose optimization and other relevant aspects of paediatric patient radiation protection. There is a significant gap in knowledge that is relevant to estimating paediatric radiation doses. While the Miglioretti report provided organ and effective doses from their study group, there are few studies that address what the organ or effective dose should be for a CT scan based on anatomic part scanned, patient size and clinical indication. The first attempt to fill this gap in paediatric patients was made in 1999 in the UK through the development of diagnostic reference levels for paediatric CT.12 Since that time, only a handful of countries have published paediatric diagnostic reference levels for CT to provide target values so that one facility can compare their practice with other similar practices. More recently, the development of diagnostic reference ranges that take into account image quality are being developed for children in the USA.13 As further research addresses this gap in knowledge, the question of a “child-sized” CT dose may be easier to answer for parents. Increasing use of registries with automatic upload of data such as that developed by the American College of Radiology will aid in providing benchmarks to be used as guidance locally. FINDING 3: ESTIMATES OF LIFETIME CANCER RISK All three articles project the lifetime attributable risk of cancer. The articles agree that the younger the patient and the higher the radiation dose for each CT scan, the greater the risk of excess cancer. This information might help inform parents generally but is not specific enough. The most consistent and most challenging question raised by parents is whether or not a CT scan will cause cancer in their child. Parental understanding of ionizing radiation and its use in medical imaging is generally minimal. Parents cannot see radiation, and the possible stochastic effects may take years to occur. Until the recent development of size-specific dose estimates, rapid estimates of individual patient dose after a CT scan were not available.14 Finally, the potential excess risk of cancer is incremental to the baseline risk of cancer. It is estimated that more than one in three people will be diagnosed with some form of cancer during their lifetime.15 It is unrealistic to expect parents to understand population statistics, laws of chance and probability, or the concept of causation. Furthermore, probability of causation (e.g. one in so many will get cancer) is not useful in any practical sense for estimating an individual’s cancer risk because the data are derived from population averages and cannot be accurately applied to an individual. The population data do not account for individual differences owing to environmental risk factors or individual biological factors. By definition, the excess cancer risk is not a true individual risk but a risk shared by the total population.

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The risk discussion is further clouded by heuristics, where a parent may simplify the risk, that is, CT is “good” or CT is “bad”. A simple definition of heuristics is that it represents the set of shortcuts people use to solve problems and make judgements rapidly and efficiently; such shortcuts may be prone to systematic errors or bias. There is a considerable body of work within the field of cognitive psychology that indicates that a discussion of risk may lead to bias in how parents would interpret information and potentially refuse indicated examinations.16,17 It is no wonder that parents and some physicians are confused. The Miglioretti article does not provide information on the potential benefits that a child may have realized by having the CT scan performed. Although that was beyond the scope of the Miglioretti study, discussion of any potential risk without discussion of the corresponding benefit is not useful. For instance, if one is buying a car and the only discussion relates to the risk of death over one’s lifetime from a motor vehicle accident (1 in 304) and not the practical benefit of car travel (getting to work or reaching a vacation destination), then the discussion of risk related to car travel is meaningless.18 So where does that leave parents and radiologists in the discussion of risk? Parents need to know about the risk of CT scans and the benefits, prior to the study, to make an informed decision. The parent also needs to know what would happen if no CT is done, and whether there are other strategies that can answer the medical questions. Some argue for a formal process of informed consent prior to CT scans, whereas others feel this would be onerous and inappropriate given the extremely low risk. One thing seems clear— parents have the right to be informed about the risks and benefits of a test involving ionizing radiation, and they have the right to this information before the test. As opposed to “informed consent”, which some view as a unidirectional and legalistic disclosure of alternatives, risks and benefits by the physician, “informed decision making” may be an alternative by providing a “meaningful dialogue between physicians and patient”.19 Parents who have not received information about risk from ionizing radiation may feel deceived by the medical profession, to whom they entrusted their child. They need to know that the CT scan is necessary, that there is a potential risk, that the risk for imaging tests is low and that the minimal necessary dose of radiation is used. Mostly, they want to understand why the scan is being performed and how it will help physicians care for their child. In this regard, the specific risk factors provided by Miglioretti, taken alone, are of minimal use to parents. Does that mean that studies such as the one by Miglioretti are not important in furthering our understanding of potential effects from CT? The answer is “no”. Their risk estimates, however accurate, however controversial, keep a focus on the need to justify every paediatric CT, to “child-size” the CT dose for paediatric patients and to closely monitor and compare results with other similar sites. The study also implies the need for continued refinement of diagnostic reference levels and, most importantly, communication with parents. For those countries where the concept of justification, optimization, diagnostic reference levels and quality improvement are gaining traction, we can learn from countries where these principles have been inherent to the definition of radiation protection since its inception.11 As Picano20

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Commentary: Doctor, is a CT scan safe for my child?

states, “better knowledge of risks will help us avoid small individual risks translating into substantial population risks”. So, when a parent asks the question “Doctor, is a CT scan safe for my child?”, we should be able to look the parent in the eyes and let them know that we have worked to ensure that their child’s CT scan is necessary and that the scan is as safe as possible. Parents, on behalf of their children, will be positioned to make informed

decisions when provided with information about the potential benefits and risks of the scan and, in most cases, the considerable magnitude of the benefits relative to the risks. It is time to add these discussions to the routine practice of paediatric radiology, so that maximum benefit can occur with the least risk. This approach is necessary to responsibly leverage the power of CT for accuracy and precision in medical diagnosis.

REFERENCES 1.

Kathern RL, Ziemer PL. The ﬁrst ﬁfty years of radiation protection—a brief sketch. In: Kathren R, Ziemer P, eds. Health physics: a backward glace. Oxford, UK: Pergamon Press; 1980 [cited 18 November 2013]. The Health Physics Society. Available from: http:// www.umich.edu/;radinfo/introduction/ 50yrs.htm#top Brenner DJ, Hall EJ. Computed tomography —an increasing source of radiation exposure. N Engl J Med 2007; 357: 2277–84. National Council on Radiation Protection and Measurements. Ionizing radiation exposure of the population of the United States 2009. NCRP report no. 160. Bethesda, MD: National Council on Radiation Protection and Measurements; 2009. doi: 10.1021/ ac902650w Sternberg S. Study: unnecessary CT scans exposing patients to excessive radiation. USA Today. November 2007 [updated 29 November 2007; cited 18 November 2013]. Available from: http://usatoday30.usatoday.com/news/ health/2007-11-28-dangerous-scans_N.htm Miglioretti D, Johnson E, Williams A, Greenlee RT, Weinmann S, Solberg L, et al. The use of computed tomography in pediatrics and the associated radiation exposure and estimated risk of cancer. JAMA Pediatr 2013; 167: 700–7. doi: 10.1001/ jamapediatrics.2013.311 Pearce MS, Salotti HA, Little MP, McHugh K, Lee C, Kim KP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumors: a retrospective cohort study. Lancet 2012; 380:

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499–505. doi: 10.1016/S0140-6736(12) 60815-0 Mathews JD, Forsythe AV, Brady Z, Butler MW, Goergen SK, Byrnes GB, et al. Cancer risk in 680,000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians. BMJ 2013; 167: 700–7. Townsend BA, Callahan MJ, Zurakowski D, Taylor GA. Has pediatric CT at children’s hospitals reached its peak. AJR Am J Roentgenol 2010; 194: 1194–6. doi: 10.2214/ AJR.09.3682 Menoch MJ, Hirsch DA, Khan NS, Simon HK, Sturm JJ. Trends in computed tomography utilization in the pediatric emergency department. Pediatrics 2012; 129: e690–7. doi: 10.1542/peds.2011-2548. Goske MJ, Applegate KE, Boylan J, Butler PF, Callahan MJ, Coley BD, et al. The image gently campaign: working together to change practice. AJR Am J Roentgenol 2008; 190: 273–4. doi: 10.2214/AJR.07.3526 European guidelines on quality criteria for computed tomography. European Union Report, EUR16262. Luxembourg: Ofﬁce for Ofﬁcial Publications of the European Communities; 1999. Shrimpton PC, Hillier MC, Lewis MA, Dunn M. Reference doses for paediatric computed tomography. Radiat Prot Dosimetry 2000; 90: 249–52. Goske MJ, Strauss KJ, Coombs LP, Mandel KE, Towbin AJ, Larson DB, et al. Diagnostic reference ranges for pediatric abdominal CT. Radiology 2013; 268: 208–18. doi: 10.1148/ radiol.13120730

14. Boone JM, Strauss KJ, Cody DD, McCollough CH, McNitt-Gray MF, Toth TL. Size speciﬁc dose estimates (SSDE) in pediatric and adult body CT examinations. College Park, MD: American Association of Physicists in Medicine; 2011 [cited 18 November 2013]. Available from: http://www.aapm.org/pubs/ reports/rpt_204.pdf. 15. Cancer Research UK [homepage on the internet]. What is the lifetime risk of developing cancer? [updated 26 July 2012; cited 18 November 2013]. Available from: http:// www.cancerresearchuk.org/cancer-info/cancerstats/incidence/risk/ 16. Lloyd AJ. The extent of patients’ understanding of the risks of treatments. Qual Health Care 2001; 10(Suppl. 1): il4–8. 17. Redelmeier DA, Rozin P, Kahneman D. Understanding patients’ decisions: cognitive and emotional persepctives. JAMA 1993; 270: 72–6. 18. Fahey FH, Treves ST, Adelstein SJ. Minimizing and communicating radiation risk in pediatric nuclear medicine. J Nucl Med 2011; 52: 1240–51. doi: 10.2967/ jnumed.109.069609 19. Brink JA, Goske MJ, Patti JA. Informed decision making trumps informed consent for medical imaging with ionizing radiation. Radiology 2012; 262: 11–14. doi: 10.1148/ radiol.11111421 20. Picano E. Informed consent and communication risk from radiological and nuclear medicine examinations: how to escape from a communication inferno. BMJ 2004; 329: 849–51. doi: 10.1136/ bmj.329.7470.849

Br J Radiol;87:20130517

BJR Received: 18 December 2013

Accepted: 28 January 2014

doi: 10.1259/bjr.20130828

Cite this article as: Jena R. Dreams, themes and particle beams—an oncologist’s perspective on technology trickle-down from the LHC. Br J Radiol 2014;87: 20130828.

COMMENTARY

Dreams, themes and particle beams—an oncologist’s perspective on technology trickle-down from the LHC R JENA, MD, FRCR Cambridge University Hospitals NHS Foundation Trust, Addenbrooke’s Hospital, Cambridge, UK Address correspondence to: Dr Rajesh Jena E-mail: rjena@nhs.net

ABSTRACT 11 years ago, the European Network for Light Ion Therapy (ENLIGHT) was established as a multidisciplinary network of engineers, physicists and clinicians with a common interest in the development of hadron therapy in Europe. ENLIGHT is coordinated from the European Centre for Nuclear Research (CERN), the home of the Large Hadron Collider. The network has evolved into a mature platform for research, with more than 100 researchers working in CERN and its allied research centres. One of the benefits of hosting this network at CERN is the ability to translate hardware and software developments, originally developed in the High Energy Physics domain, into clinical applications. From the perspective of a clinical radiation oncologist within the network, this commentary reviews the ways in which leading edge technological developments in detectors and solid state physics, Monte-Carlo simulation, grid computing and accelerator design have trickled down into real-world clinical applications.

In March 2013, scientists at the European Centre for Nuclear Research (CERN) conﬁrmed the discovery of Higgs Boson amidst a wash of international publicity. The effort represents the culmination of decades of effort in accelerator and detector design, and represents a huge contribution to mankind’s knowledge and understanding of the physical world. However, the development of the Large Hadron Collider (LHC), A Toroidal LHC Apparatus (ATLAS) and the Compact Muon Solenoid (CMS) have driven numerous other developments in a range of domains, including those of imaging and radiation therapy. The following account is a description of some of these technologies, from the personal perspective of a clinical radiation oncologist. THE ENLIGHT NETWORK Established in February 2002 as a European Union funded project from the European Society of Therapeutic Radiology and Oncology, ENLIGHT is a contraction of the term “European Network for Light Ion Therapy”. The ENLIGHT network is coordinated by Professor Manjit Dosanjh from CERN. At its inaugural meeting, it included 70 members from the ﬁelds of radiation biology, medical physics, engineering, accelerator physics and radiation oncology, sharing a common interest in the implementation of hadron therapy (HT) in Europe. 11 years on, the network has matured considerably. Over 100 researchers belong to the network, which has accrued over V26 million in funding across four

Framework 7 grants (Box 1). The research output of the network focusses on a range of biomedical applications in fields coherent to CERN’s main areas of research. At the outset, the consortium also included research representatives from two companies with interest in the HT market, namely Siemens (Erlangen, Germany) and IBA (LouvainLa-Neuve, Belguim). Siemens have since withdrawn from the HT field, but IBA remains a committed partner to our research endeavours. Within the consortium, I am one of three radiation oncologists, and although we are small in number, our contribution to discussions and strategic planning is always highly welcomed. The clinicians in the consortium share an interest in clinical radiation biology and have advised on the design of experiments investigating cellular response to hadron irradiation and novel drug and radiation combinations. We have provided input into tumour modelling projects and also provided clinical relevance to the data and informatics projects undertaken by the consortium. DETECTORS AND IMAGING A significant part of the research effort for the creation of ATLAS and CMS has been the development of fast, highsensitivity detectors to map collision events. Exactly the same requirements apply in the medical imaging domain for gamma cameras, specifically for positron emission tomography (PET) imaging. The “Crystal Clear” collaboration

Commentary: An oncologist’s perspective on technology trickle-down from the LHC

Box 1. CERN is derived from the acronym for “Conseil Europ´een pour la Recherche Nucl´eaire” or European Council for Nuclear Research. It was founded in 1952 with the mandate of establishing a world-class fundamental physics research organization in Europe. For more details, see http://home.web. cern.ch/ ENLIGHT is derived from the term for “European Network for Light Ion Therapy”. It was founded in 2002 and consists of four major research programmes: PARTNER (Particle Training Network for European Radiotherapy). PARTNER is a Framework 7 Marie Curie initial training network in particle therapy, which was established in 2008. For more details, see http://partner.web.cern.ch/ ULICE (Union of Light Ion Centres in Europe): established in 2009, ULICE is an European Union infrastructure project for the provision of beam time and informatics for hadron therapy research. For more details, see http://ulice.web.cern. ch/ ENVISION (European Novel Imaging Systems for Ion Therapy): ENVISION is a second Framework 7 research project to develop digital imaging for hadron therapy. It was established in 2010. For more details, see http://envision.web. cern.ch/ ENTERVISION (European Training Network in Digital Medical Imaging for Radiotherapy): established in 2011, ENTERVISION research training network for three-dimensional digital imaging, following on from the research collaborations that were established in ENVISION. For more details, see http://envision.web. cern.ch/

is a community of 70 physicists from 15 institutes, with interests in solid state physics and condensed matter. The members span commercial, industrial and academic domains, with a common goal of sourcing the highest quality crystals for use in calorimeters or gamma cameras. The same group also exchanges knowledge in photodetector design and readout electronics. ClearPEM® (Supersonic Imagine, Aix-en-Provence, France) is an example of such a technology arising from the Crystal Clear collaboration. The device is a high-sensitivity PET imaging device designed specifically for breast screening. The entire device, including readout electronics, is small enough to fit in the palm of my hand. Combined with ultrasound elastography, the device allows for simultaneous structural and physiological imaging of the breast, whilst keeping radiation dose exposures down in the safe range for a screening technology. Another application that is being actively developed in the European Novel Imaging Systems for Ion Therapy and European Training Network in Digital Medical Imaging for Radiotherapy programmes is the use of time-of-flight PET detection for in-beam PET auto-activation that occurs with exposure to high-energy hadrons. Whilst steep gradients of physical and biologically effective dose make HT an attractive treatment technique for radiation oncologists, the lack of exit dose makes it difficult to ascertain whether or not the planned dose distribution has been delivered to the correct location within the patient. Reconstruction of dose from PET auto-activation represents an exciting opportunity for in vivo dosimetry, but represents a challenge

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owing to the very-low counting statistics, which are several orders of magnitude lower than those observed in diagnostic PET. As a result, sophisticated time-of-flight PET detectors and extremely fast electronics with high temporal resolution are required to maximize the sensitivity, specificity and spatial resolution of the PET signal. Many of our early-stage researchers are engaged in this problem and are working on the development of crystal and resistive plate chamber sensors, fast programmable gate array electronics designs and Monte-Carlo simulations of the PET imaging devices. The same technologies have now been applied to conventional diagnostic PET-CT systems. Siemens was the first company to integrate time-of-flight PET into a commercial device with their Biograph™ Truepoint™ HD PET unit. The improvements in resolution and signal-to-noise ratio translate immediately into clinical benefit, particularly in the imaging of small intra-abdominal lymph nodes that were difficult to resolve using conventional PET-CT.1 MODELLING AND SIMULATION Development of in-beam PET solutions has relied heavily on Monte Carlo simulation of particle–matter interaction and positron emission within the patient. This was made possible by the use of particle tracking code, which had been developed for high energy physics applications. GEANT, a portmanteau from GEometry ANd Tracking, was developed in CERN in 1974 and originally written in FORTRAN. FLUKA (portmanteau of FLUktuierende KAskade) was developed jointly by the Istituto Nazionale di Fisica Nucleare and CERN. It is the second particle transport code that is being used extensively in the medical domain. Increases in computing power allow for more sophisticated simulations to be conducted using these techniques. PARTRAC (PARticle Tracking) is a separate package specifically designed to investigate particle–matter interaction at the cellular component scale, such as the interphase spread of a mammalian cell, which contains 6 billion DNA base pairs on a phosphate backbone. The package has been utilized to investigate the genotoxic effects of hadron beams of varying linear energy transfer and radiation-induced DNA fragmentation.2 At the opposite end of the length scale, the Geant Human Oncology Simulator is a full Monte Carlo simulation of the megavoltage imaging system within the TomoTherapy® (Accuracy, Inc., Sunnyvale, CA) image-guided radiotherapy (IGRT) treatment unit. It has been used to estimate the risk of radiation-induced malignancy associated with the additional imaging dose used in daily IGRT treatment. In the PARTNER (Particle Training Network for European Radiotherapy) research project, large-scale simulations of treatment hardware have been created to verify dose calculation algorithms used in proton and carbon ion planning at the recently opened HT facility at the National Centre for Oncological Hadron Therapy (CNAO) in Pavia, Italy. INFORMATICS AND GRID COMPUTING When offloading data from the ATLAS detector, the global highenergy physics grid infrastructure can consume up to 10% of the global bandwidth for internet connectivity. Medical applications are dwarfed by such endeavours, but one of the benefits of the ENLIGHT platform has been the engagement with the European grid community. As European centres started to make plans for

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HT treatment facilities, it became apparent that transnational access to highly specialized HT facilities would create its own challenges for the flow of patient data. The Hadron Therapy Information Sharing Portal (HISP) is a component of the informatics research within the PARTNER project (Figure 1). HISP provides a framework for transnational access to patient data for HT referral, treatment and follow-up, allowing diagnostic data to follow the patient as they journey to receive treatment. Furthermore, once the patient returns to his/her home clinic for follow-up, the platform provides a mechanism for staff at the treatment centre to obtain information on the outcome of treatment and for researchers to obtain censored information on treatment outcomes. I was fascinated by the way in which open-source technologies from the Grid community could be applied to problems we face in the sharing of medical data. Many web-based tools for information security, user access control, and joining of databases in different institutions, were directly applicable to the HISP project. ACCELERATOR DEVELOPMENT AND BIOMEDICAL APPLICATIONS From time to time, the clinical community receive requests to consider challenges and technologies that may be of importance over the next 5–10 years. Although this is difficult for medical doctors, it is a necessity for accelerator scientists. In 2005, 3 years before the first useable beam time on the LHC, researchers from the International Committee for Future Accelerators had already established proposals for the High Luminosity LHC to come online in 2018. Following the same paradigm, the Proton-Ion Medical Machine Study project (PIMMS) was established in 1996 by Philip Bryant from CERN. The project was a collaboration to develop a novel synchrotron design for cancer therapy

and produced a design plan for a mixed proton and carbon ion treatment centre. Two European centres formed part of the collaboration, Med-AUSTRON in Wiener Neustadt, Austria, and the TERA Foundation in Novara, Italy.3 12 years after the completion of the PIMMS project, the design has been implemented at the HT Centre for Cancer Treatment (CNAO) in Pavia, Italy, which treated its ﬁrst patient with carbon ions on 13 November 2012. EBG MedAustron, as it is now known, is the second centre to be built to the same basic design. Construction started in March 2011 and is scheduled to start treating patients in 2015. There are also plans to utilize existing hardware at CERN for biomedical applications. The Low Energy Ion Ring (LEIR) is normally used to accelerate lead ions for ﬁlling into the LHC. LEIR is capable of producing ion species from protons to neon ions with an energy spectrum that is suitable for biomedical applications. Although CERN statutes prevent experiments on whole animals, such a facility could be used for cell irradiation, tissue scaffolds, microdosimetry, radiation detector development and proton tomography. Similar biomedical end stations exist in a number of treatment facilities, but competition for beam time against clinical applications and service commitments means that experimental beam time is limited and must often be conducted overnight. LEIR could easily be adapted to operate in “time-sharing” mode during LHC operations, to provide beam time for biomedical applications during normal working hours. As an organization, CERN is extremely effective at brokering international collaboration, and in June 2012, a brainstorming meeting was held in CERN to discuss plans for a biomedical endstation for LEIR. Despite the timing and relatively short notice, the meeting was attended by .200 scientists from 26

Figure 1. Hadron therapy (HT) Information Sharing Platform is a web-based infrastructure that would allow secure access to clinical data, as a patient is referred to a HT treatment centre and returns home for their follow-up. It works by using well-established technologies for distributed data storage and access that were developed by the grid community.

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Commentary: An oncologist’s perspective on technology trickle-down from the LHC

Box 2. “CERN’s role is not to build future machines for medical applications but to co-ordinate and catalyse feasibility studies for future developments of a cost-effective accelerator facility”. Steve Myers, CERN Life Sciences Meeting, Geneva, 25th June 2012.

countries, including Australia, Canada, Colombia, Russia and India (Box 2). CONCLUDING THOUGHTS The potential health impact of the technologies mentioned in this commentary lie in areas of cancer screening and curative radiotherapy treatment. As life expectancy rises and cardiovascular mortality falls throughout Europe, the lifetime risk of developing cancer may rise beyond the current estimate of one person in three. The UK breast cancer screening programme has resulted in an 8% reduction in mortality from breast cancer since 1990, using X-ray based imaging techniques.4 The ClearPEM device, with its improved sensitivity and speciﬁcity for early tumour detection, seems attractive as a new screening technology providing the cost of implementation and radiation exposure can be minimized.

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Radiotherapy is an effective anticancer therapy and is used in the treatment of .40% of patients who are cured of cancer. My own work in Monte Carlo simulation of radiotherapy demand has shown that according to published evidence, 40.6% of patients developing cancer should receive radiotherapy treatment at some point in their cancer journey, and that a 22% rise in the number of radiotherapy treatments is projected for 2020.5 I believe that HT has the potential to deliver a high-throughput radiotherapy service for speciﬁc clinical indications, and that the lower integral doses and higher biological effectiveness might facilitate hypofractionated treatment regimens. Curative radiotherapy treatment could be delivered in 3–5 instead of 35 treatments. Advances in in-beam dosimetry and radiation biology made by our group will facilitate clinical trials of such treatment strategies in existing centres over next 10 years. However, the prohibitive capital investment costs for HT remain the biggest obstacle to widespread implementation of this technology. I look to the high-energy physics community to prototype novel particle acceleration technologies, which will be smaller and cheaper by perhaps one to two orders of magnitude. ACKNOWLEDGMENTS I would like to thank Professor Manjit Dosanjh for her effort in creating and maintaining the ENLIGHT community.

REFERENCES 1. Lois C, Jakoby BW, Long MJ, Hubner KF, Barker DW, Casey ME, et al. An assessment of the impact of incorporating time-of-ﬂight information into clinical PET/ CT imaging. J Nucl Med 2010; 51: 237–45. doi: 10.2967/jnumed.109.068098 2. Friedland W, Dingfelder M, Kundr´at P, Jacob P. Track structures, DNA targets

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and radiation effects in the biophysical Monte Carlo simulation code PARTRAC. Mutat Res 2011; 711: 28–40. doi: 10.1016/j.mrfmmm.2011.01.003 3. Bryant PJ. Progress of the Proton-Ion Medical Machine Study (PIMMS). Strahlenther Onkol 1999; 175(Suppl. 2): 1–4.

4. Sasieni P. Evaluation of the UK breast screening programmes. Ann Oncol 2003; 14: 1206–8. 5. Round CE, Williams MV, Mee T, Kirkby NF, Cooper T, Hoskin P, et al. Radiotherapy demand and activity in England 2006–2020. Clin Oncol (R Coll Radiol) 2013; 25: 522–30. doi: 10.1016/j.clon.2013.05.005

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BJR Received: 19 October 2013

doi: 10.1259/bjr.20130677 Revised: 15 January 2014

© 2014 The Authors. Published by the British Institute of Radiology under the Accepted: terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License 28 January 2014 http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted noncommercial reuse, provided the original author and source are credited.

Cite this article as: Becker M, Zaidi H. Imaging in head and neck squamous cell carcinoma: the potential role of PET/MRI. Br J Radiol 2014;87:20130677.

REVIEW ARTICLE

Imaging in head and neck squamous cell carcinoma: the potential role of PET/MRI 1

MINERVA BECKER, MD and 2HABIB ZAIDI, PhD

Department of Imaging, Division of Radiology, Geneva University Hospital, Geneva, Switzerland Department of Imaging, Division of Nuclear Medicine, Geneva University Hospital, Geneva, Switzerland

Address correspondence to: Professor Minerva Becker E-mail: Minerva.Becker@hcuge.ch

ABSTRACT In head and neck oncology, the information provided by positron emission tomography (PET)/CT and MRI is often complementary because both the methods are based on different biophysical foundations. Therefore, combining diagnostic information from both modalities can provide additional diagnostic gain. Debates about integrated PET/MRI systems have become fashionable during the past few years, since the introduction and wide adoption of software-based multimodality image registration and fusion and the hardware implementation of integrated hybrid PET/MRI systems in pre-clinical and clinical settings. However, combining PET with MRI has proven to be technically and clinically more challenging than initially expected and, as such, research into the potential clinical role of PET/MRI in comparison with PET/CT, diffusion-weighted MRI (DW MRI) or the combination thereof is still ongoing. This review focuses on the clinical applications of PET/MRI in head and neck squamous cell carcinoma (HNSCC). We first discuss current evidence about the use of combined PET/CT and DW MRI, and, then, we explain the rationale and principles of PET/MR image fusion before summarizing the state-of-the-art knowledge regarding the diagnostic performance of PET/MRI in HNSCC. Feasibility and quantification issues, diagnostic pitfalls and challenges in clinical settings as well as ongoing research and potential future applications are also discussed.

Pre-therapeutic work-up of head and neck squamous cell carcinoma (HNSCC) requires clinical evaluation, panendoscopy with biopsy and cross-sectional imaging.1–3 Crosssectional imaging is indicated to provide accurate staging at the time of diagnosis. This may be achieved using a variety of imaging modalities, including contrast-enhanced CT (CECT), MRI with or without diffusion-weighted (DW) sequences (DW MRI), ultrasonography with or without fine-needle aspiration cytology (FNAC), positron emission tomography (PET)/CT or a combination of these techniques. During recent years, the technology for both PET/CT and MRI has evolved steadily, resulting in increased image quality, robustness and rapidity of acquisition. By providing combined metabolic and morphological information, PET/ CT has significantly improved diagnostic and prognostic information in HNSCC, thereby facilitating patient management.1,2 Clinical MRI has evolved towards higher field strengths (3 T), faster sequences, whole-body imaging, as well as functional imaging capabilities, including DW MRI and perfusion imaging.4–10 Despite all these technical advances, considerable expertise is required for the diagnostic interpretation of head and neck imaging studies because of

the complex regional anatomy, the variable appearance of primary and recurrent tumours and functional phenomena mimicking disease. Since information provided by PET/CT and MRI is complementary in many clinical situations, it seems to make sense to combine the two modalities. From a technical point of view, the integration of PET with MRI in one imaging system has proven to be quite complex. However, the first software algorithms for multimodality data fusion and a first generation of hybrid PET/MRI systems are now available for clinical use. Consequently, the discussion about integrated PET/MRI systems has become fashionable, and an initial euphoria has been generated about potential applications of this new hybrid technology in oncological imaging and especially in the head and neck.11,12 To date, however, facts and scientific data assessing the clinical usefulness of hybrid PET/MRI systems remain scarce, and it appears difficult to assess where PET/MRI may be preferable over PET/ CT, DW MRI or the combination of these two powerful modalities. The purpose of the present article is to summarize current evidence about the combined use of PET/CT and MRI in HNSCC, to explain the rationale and principles of PET/MRI data fusion and to review the existing knowledge

Review article: PET/MRI in head and neck oncology

regarding the performance of hybrid PET/MRI in clinical head and neck oncology. CURRENT EVIDENCE ABOUT POSITRON EMISSION TOMOGRAPHY/CT IN HNSCC PET/CT has established itself as a robust, rapid and reliable technique providing reproducible data even in patients with limited cooperation. Acquisition of a total body CTscan takes only a few seconds and allows unparallelled detection of pulmonary nodules as well as a complete overview of all anatomic regions. The combination of PET and CT is highly synergistic, resulting in increased sensitivity and specificity for tumour staging as well as effective patient management in clinical routine.13,14 The metabolic information from PET radiotracers can be complemented by the full diagnostic capability of CECT during the same session, although this may not be done in a majority of institutions.15 Positron emission tomography radiotracers and quantification issues PET radiotracers that can be used for PET/CT examinations in HNSCC patients include 18-fludeoxyglucose (FDG) for the quantification of glucose metabolism, 18-fluorothymidine (FLT) for the quantification of tumour cell proliferation, 18fluoroethyltyrosine (FET) for the quantification of tumour growthrelated protein synthesis, as well as new tracers specifically designed for imaging of apoptosis and epidermal growth factor receptor (EGFR).2 The most commonly used PETradiotracer for HNSCC in clinical routine is FDG. It is a glucose analogue that is taken up by metabolically active tumour cells using facilitated glucose transport. Because FDG is not a specific tracer for HNSCC, it may also become trapped in other cells with high glucose metabolism, including inflammatory lymph nodes, scar tissue or certain benign salivary gland tumours, such as Whartin tumours. Quantification of tracer uptake is commonly performed in the clinical setting using the standardized uptake value (SUV). The SUV is a semi-quantitative metric defined as the ratio between the tissue radioactivity concentration (in megabecquerel per kilogram) at a time t and the injected radioactivity (in megabecquerel) extrapolated to the same t normalized to body weight (in kilograms) multiplied by a decay correction factor.16 As reported by several investigators, SUVmean and SUVmax metrics are imperfect quantification tools since they depend on a variety of factors, including data acquisition and reconstruction protocols, selection of regions of interest (ROIs) for measurements, statistical noise, partial volume effect and tumour size.17–19 Therefore, while the SUV derived from static whole-body images is simpler and more clinically feasible than more rigorous kinetic analysis, there are a number of approximations implicit in the use of uptake ratios that may lead to variability and bias. Despite these drawbacks, quantification of tracer uptake by means of SUV is widely used in clinical routine. Positron emission tomography/CT for staging and restaging of HNSCC FDG PET/CT and SUV measurements have proven to be highly accurate for the follow-up of HNSCC after radio-chemotherapy,20,21 allowing reliable exclusion of residual or recurrent disease.22–24

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Although the high sensitivity and high negative predictive value in the treated neck are consistent findings in most reported studies, the specificity and positive predictive value of FDG PET/CT can vary substantially, leading to a considerable number of false-positive assessments.25 In the T staging of primary HNSCC, most authors have reported FDG PET/CT to be as sensitive as CT/MRI.6,14 Some authors, however, have found PET/CT to be slightly superior to CT/ MRI,26,27 the reported sensitivity for oral cavity HNSCC being 96% for PET/CT, 85% for MRI and 78% for CT.27 Because CECT and MRI have a superior anatomic resolution, current practice is not in favour of routinely using PET/CT for the T staging of primary HNSCC.14 Regarding the staging of nodal disease in primary HNSCC, FDG PET/CT appears to be superior to conventional anatomic MRI sequences.28,29 However, direct comparison with DW MRI is still missing. Occult lymph nodes in the clinically negative neck (clinical N0 disease) represent a diagnostic challenge for PET/ CT and MRI, as both techniques are not sensitive enough to reliably detect subcentimetre metastatic nodes.15,26,30,31 In skilled hands, ultrasonography has been shown to be superior to CT and MRI because of its high spatial resolution and the ability to routinely perform power Doppler and ultrasonography FNAC.3 The superiority of ultrasonography FNAC over CT and MRI is indisputable when dealing with small metastatic neck nodes,32 and ultrasonography FNAC performs significantly better than any other imaging technique in the N0 neck.3,32 Nevertheless, it is important to realize that micrometastases, which may occur in up to 8% of all N0 necks, are beyond detection by any currently available imaging modality.3 Several authors have shown that FDG uptake will increase significantly over time in lymph nodes harbouring metastatic cancer lesions, whereas inflammatory neck nodes tend to show a decreased or stable FDG activity over time.33,34 However, as recently shown, the use of dynamic PET/CT examinations performed between 60 and 115 min after injection of FDG does not allow correct identification of those patients in whom elective neck dissection should be performed.35 Therefore, most authors currently agree that FDG PET/CT, CECT, MRI or ultrasonography FNAC are not reliable enough to exclude lymph node metastases in the clinical N0 neck.35,36 There is general agreement that FDG PET/CT is the method of choice to detect distant metastases and synchronous tumours.30,37 In locally advanced disease and in patients with N2 or N3 necks, PET/CT may reveal distant metastases and second primary tumours in up to 14% of cases.38 However, false-positive assessments have also been reported in up to 25% of patients.14 The utility of PET/CT to identify unknown primary tumours in patients with metastatic neck nodes has been demonstrated by several reports,14,39 and PET/CT may be currently recommended early in the work-up of these patients.14 Positron emission tomography/CT for radiotherapy planning Last but not least, with the emergence of new high-precision radiotherapy techniques, such as intensity-modulated radiation

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therapy (IMRT), three-dimensional conformal radiotherapy (3DCRT) or proton beam therapy, PET/CT may play an important role in radiation therapy planning, although contouring the outline of the tumour or metastatic lymph nodes applying PET/CT, the so-called “dose painting”, is still one of the most challenging and controversial issues in radiation therapy planning.14,30,40 Because changing the PET window level can lead to over- or underestimation of the target volume, several groups have suggested different methods for tumour volume contouring, such as normalized volumes according to liver uptake, arbitrary SUV thresholds, 50% of tumour SUVmax values, institutional contouring protocols and gradient-based methods.14 CURRENT EVIDENCE ABOUT MRI IN HNSCC Despite the advantages and popularity of PET/CT, there are some shortcomings in the use of CT as the complementary anatomical imaging modality. First of all, CT adds radiation dose to the general examination,41 particularly when used in a full diagnostic mode. Second, CT provides relatively poor soft-tissue contrasts especially when using low-dose PET/CT acquisition protocols or when intravenous contrast material is not administered. Utility of morphological MRI sequences in HNSCC MRI has been shown to be superior to CT for obtaining excellent soft-tissue contrast and for providing images of good quality even in the presence of dental hardware. Conventional MRI sequences are also superior to CT for a variety of findings that influence the therapeutic choice such as laryngeal cartilage invasion, invasion of the skull base, perineural spread, detection of retropharyngeal lymph nodes in nasopharyngeal carcinoma, extranodal spread in metastatic neck nodes and vascular and lymphatic invasion.4,5,42–44 The introduction of more refined MRI criteria based on the analysis of signal intensity and enhancement patterns after injection of gadolinium chelates has had a major impact on the assessment of deep tumour spread. In most HNSCCs, the actual invasion of bony and cartilaginous structures is often preceded by tumour-induced inflammation.45 In laryngeal and hypopharyngeal HNSCCs, careful analysis of signal intensities on T1 and T2 sequences has improved differentiation between tumour and inflammation: moderate enhancement after injection of gadolinium chelates and moderately high signal on T2 indicate tumour involvement, whereas high signal on T2 and strong enhancement correspond histologically to peritumoral inflammation.4 These diagnostic criteria thereby improve the specificity of MRI for the detection of laryngeal cartilage invasion without affecting its high sensitivity. In analogy, the same criteria can be applied to the skull base or mandible.46 As suggested by some investigators, differentiation of tumour from peritumoral inflammation can also affect prognosis after radiation therapy.5,47,48 A moderately high signal within cartilage correlates with a less favourable response to radiation therapy in glottic squamous cell carcinoma (SCC), whereas a high signal on T2 does not affect local control.47 It therefore appears that the differentiation of peritumoral inflammation from tumour on the basis of MRI signal intensity characteristics may have direct implications for patient outcome after radiation therapy.46,47 Morphological MRI also appears to provide a higher accuracy than FDG PET/CT in detecting residual and/or recurrent

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nasopharyngeal carcinoma at the primary site and, in the context of tumour restaging, the combination of PET/CT and MRI seems to be superior to either modality alone.49 Principles of diffusion-weighted MRI In addition to providing excellent anatomical detail, MRI has the capability to evaluate functional parameters in vivo. DW MRI is a functional MRI technique based on the assessment of random (Brownian) motion of water molecules. In the presence of biological barriers, such as fibres, cell membranes and macromolecules, the free displacement (diffusion) of water molecules is impaired (restricted diffusivity). DW MRI enables in vivo imaging and quantification of the diffusivity of water molecules. Images obtained with DW MRI provide a high lesion-to-background contrast, thus outperforming conventional T2 sequences.50 Cellular swelling in stroke, increased cellularity in tumours, inflammation and abscesses all lead to a restricted diffusivity. However, restricted diffusivity can also be seen in normal structures such as Waldeyer’s ring or normal lymph nodes because these structures have high cellularity.50 On the other hand, apoptosis and tumour necrosis can lead to decreased cellularity resulting in an increased diffusivity.7 A drawback of DW MRI is the lack of anatomical information at high b values because of suppressed signal in many normal tissues.7,50 Therefore, DW MRI should not be interpreted alone but in correlation with morphological sequences or by performing fusion of DW MRI and morphologic MR images (see Pitfalls in hybrid positron emission tomography/MRI). Quantification issues in diffusion-weighted MRI Diffusion in biological tissue is quantified by the apparent diffusion coefficient (ADC), which is independent of the strength of the magnetic field.51–54 Having measured at least two different b values, the logarithm of the relative signal intensity of a tissue is plotted on the y-axis against the b values on the x-axis. The slope of the line fitted through the plots describes the ADC. This monoexponential fitting represents a rough approximation of ADC and is most often used in clinical routine.7,54,55 Multiexponential models using several b values are more suitable for quantification; however, the acquisition of multiple b values increases scan duration.7,55 Mean ADC values (ADCmean) are commonly used for the characterization of HNSCC. Nevertheless, tissue characterization using ADCmean values is not appropriate when the tumour or the metastatic lymph node consist of both highly cellular and poorly cellular or necrotic portions. To overcome this drawback, one should perform ADCmean measurements in areas with high cellularity, or one can use minimum ADC values (ADCmin). Further factors that may limit the reliability of ADC measurements include patient motion, image distortion due to magnetic field heterogeneity, artefacts caused by air–soft-tissue interfaces, slice thickness and tissue perfusion. The effect of perfusion is more pronounced with low b values. To overcome the limitations of ADC measurements, the so-called lesion-to-spinal cord ratio (LSR) can be used. It is a semi-quantitative measure calculated by dividing lesion signal intensity by spinal cord signal intensity.56 LSR has been successfully applied for differentiating benign from malignant lesions in lung cancer patients;56 however, it is not often used in clinical head and neck imaging. Another approach to evaluate diffusion and perfusion is to calculate and quantify

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Review article: PET/MRI in head and neck oncology

intravoxel incoherent motion (IVIM)-derived parameters such as D (real diffusion of water molecules), D* (perfusion contribution to signal decay) or f (perfusion contribution to the diffusion signal).57–59 IVIM-derived parameters, in particular high initial f values, have been shown to predict a poor prognosis in HNSCC patients60 and may serve as potential biomarkers in the future. A detailed discussion of IVIM-derived parameters is, however, beyond the scope of this article. Despite the above-mentioned drawbacks, ADCmean measurements in HNSCC are often used in clinical routine. They have been shown to be reproducible with good to almost perfect inter- and intra-observer agreement.54,61 Although ADC values cannot predict the histological grade in HNSCC, lower values are observed in poorly differentiated lesions, whereas higher values are seen in well-differentiated tumours.54,62 Applications of diffusion-weighted MRI in HNSCC DW MRI has shown promising results for the nodal staging of primary HNSCC for the assessment of tumour response and prognosis after chemo-radiotherapy and for the detection of recurrent disease.6–10 Although morphological MRI sequences have a limited performance regarding the detection of nodal metastases,63 DW MRI with ADC measurements allows detection of subcentimetre metastatic neck nodes.8 Nevertheless, DW MRI cannot reliably depict nodal metastases ,4 mm.8 ADC values have also been shown to predict response to treatment: tumours and lymph nodes with lower ADC values are more likely to have a complete response to radio-chemotherapy than lesions with higher ADC values.64 Regarding the detection of recurrent disease in the treated neck, DW MRI has shown encouraging results mainly in the larynx and hypopharynx.10 However, no data are currently available on the value of DW MRI for the staging of recurrent HNSCC (restaging), in particular, as recent reports have suggested that MRI and CT may grossly underestimate the extent of submucosal tumour spread leading to inadequate treatment in many cases.65,66 Underestimation of submucosal spread in recurrent HNSCC is caused by post-therapeutic inﬂammation with ﬁbrosis on the one hand and by the fact that recurrent tumours show a different pattern of submucosal spread on the other hand.65,66 Recurrent tumours typically display a multicentric recurrence pattern with widespread foci of undifferentiated tumour cells as compared with the rather concentric growth pattern of primary carcinomas.65,66 PRINCIPLES OF POSITRON EMISSION TOMOGRAPHY/MR IMAGE FUSION AND HYBRID SYSTEMS When interpreting two different modalities such as MRI and PET from PET/CT, image fusion may be done either visually by the interpreting radiologist or by means of software or hardware fusion. Visual fusion implies that the reader assesses the two modalities side by side on the computer screen and combines the images in his/her mind during interpretation. Interpreting images obtained on two different modalities side by side is time consuming and logistically demanding. Although it has been

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suggested that side-by-side image interpretation results in diagnostic inaccuracy because of imperfect anatomical matching,11 there is no scientific evidence currently supporting this view. The aim of software and hardware fusion is to provide a single integrated image on which a colour-scale functional image (PET) is superimposed on the corresponding anatomical greyscale MR image (typically a contrast-enhanced T1 or T2 image). Fusion of PET and MR images requires volume data coregistration from the two modalities. Multimodal image fusion can be generated either by using computerized algorithms enabling coregistration of images obtained on separate systems (PET/CT and MRI) or by hardware coregistration achieved by the use of hybrid PET/MRI devices. Separate systems have the advantage of full temporal and spatial flexibility with independent use of the two devices. However, the challenges and inherent limitations of software-based image registration approaches in whole-body imaging motivated the emergence of hardware-based approaches for multimodality imaging. Software fusion Software fusion is technically challenging and can be classified into two categories: rigid and non-rigid. Currently available fusion software typically uses rigid transformation. In this case, the high-resolution anatomical image (reference image) remains stationary, while the low-resolution functional image (source image) is transformed mathematically using geometric parameters (resampled) to match the reference image.67 Rigid registration may be appropriate for non-moving organs, such as the brain, where the skull provides a rigid structure that preserves the geometrical relationship of structures. However, in the head and neck, rigid registration is not always optimal because of different positioning or breathing. This may result in erroneous interpretation of fused images unless each individual data set is carefully evaluated. To minimize positioning and motion-related misalignment between the two data sets, customized support devices and immobilizing masks may be used during data acquisition whenever very high fusion accuracy, such as for radiotherapy planning, is needed. Non-rigid registration68 is based on models accounting for the deformable properties of soft tissues (elastic, fluid or other deformation models). These techniques have been used in the clinic with a certain degree of success, but, in most cases, non-rigid image registration can be challenging and, at most institutions, is not used routinely for clinical procedures. In the near future, it is expected that reliable commercial fusion software may enable automatic correction of small differences in data sets caused by breathing or changes in geometrical relationships between different anatomical regions due to positioning differences, in particular in the head and neck area.69 Hybrid positron emission tomography/MRI systems Recently developed hybrid PET/MRI systems allow PET and MRI data sets to be obtained in the same session. The two separate scanners are positioned in-line at a fixed distance, allowing the calibrated data sets to be overlaid with minimal error. Three types of hybrid PET/MRI devices are currently available: simultaneous PET/MRI, sequential PET/MRI and sequential PET/CT-MRI. All

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currently available first-generation PET/MRI systems use standard clinical 3-T MRI scanners. A simultaneous PET/MRI system consists of either a PET insert located between the radiofrequency coil and gradient set of an MRI scanner or a fully integrated and compact design with the two subsystems in the same gantry, thus allowing concomitant PET and MRI data acquisition.12,70–72 Because photomultiplier tubes used in standard PET scanners do not function properly within or near the strong static magnetic field of MRI scanners, simultaneous PET/MRI scanners use new detector technologies, including avalanche photodiodes (APDs) and silicon photomultiplier tubes (SiPMTs). In addition, electronics are shielded against the static magnetic field, the changing gradients and radiofrequency pulses. Such technology based on APD photodetectors has been implemented on the Biograph mMR hybrid imager (Siemens Healthcare, Erlangen, Germany), the patient being thereby scanned only once.73,74 Because the coils needed for head and neck imaging can contain amplifier electronics impairing PET image quality, surface coils for simultaneous PET/MRI scanners need to be specifically redesigned. Another challenge in simultaneous PET/MRI is to generate a reliable attenuation map for attenuation correction. Although CT data sets can be easily scaled and used for attenuation correction of PET data since they correlate with electron density, MR image signal intensities are not directly linked to attenuation properties of biological tissues, as they originate from proton spin excitation. Therefore, various approaches have been developed to transform MRI data sets into attenuation maps for PET.75 These techniques fall into three main categories: segmentation, atlasbased and simultaneous emission/transmission scanning. The first class of techniques is based on segmentation of T1 weighted or other special MRI sequences.76–80 Although methods for MRI-based attenuation correction are still a field of intense research, segmentation methods are being utilized clinically,76–79 while the two other classes of methods are still being explored and developed. In sequential PET/MRI systems, two separate PET and MRI devices, located within the same room and positioned far enough apart, use a common rotating examination table. The patient is first scanned on one device then the table rotates, and the patient is then scanned on the second device in the same position. Data sets are then fused for clinical interpretation.81–83 This system has been implemented and is commercially available as the Ingenuity TF PET/MR system (Philips Healthcare, Cleveland, OH). Because of the distance between the two scanners, only minor modifications of PET detectors and MRI surface coils are necessary. Attenuation correction maps are derived from a T1 MRI sequence.84,85 The third option, implemented by GE Healthcare, consists of a tri-modality system composed of a PET/CT and an MRI scanner placed in two adjacent examination rooms with a transferable patient table that can be docked on either of the two systems.13,86 PET/CT and MRI are performed sequentially, and the patient is shuttled in the same position on the transferable examination table from one room to the other. The acquired PET/CT and MRI are retrospectively coregistered on a commercially

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available workstation. Images are then displayed as PET/CT, PET/MRI, CT only or PET only.86 Although this system presents a higher risk for patient motion between the two acquisitions, attenuation correction is done using CT (classical CT-based attenuation correction). PRE-CLINICAL AND CLINICAL DATA IN THE HEAD AND NECK Despite the initial excitement related to the implementation of the first PET/MRI scanners in a clinical environment, PET/ MRI is still in an early phase of development, and only very few studies have so far addressed the clinical workflow, feasibility and optimized imaging protocols in the head and neck.12,81,82 Clinical workflow and protocols Distant metastases and second primary tumours can occur in a considerable number of patients with advanced primary and recurrent HNSCC.30,37 Therefore, imaging of HNSCC should not be limited to the head and neck area alone but should additionally cover at least the chest and abdomen. In most institutions, head and neck cancer patients undergoing PET/CTare typically imaged from the head to the pelvic floor. In PET/CT, a low-dose CT is acquired first, followed by a PET acquisition. Depending on institutional protocols, a dedicated total body or regional CECTmay be additionally obtained. In analogy to PET/CT, several clinical workflows have been proposed for conducting whole-body PET/ MRI studies. One approach is to perform a rapid total body MRI sequence for attenuation correction (typically a T1 or a Dixon sequence) and to obtain corresponding PET images on bed positions covering the total body. This approach has the advantage of being rapid regardless of the scanner type used (simultaneous or sequential). The total PET/MRI acquisition time in this approach is around 20–40 min. Nevertheless, although sufficient for anatomical localization of focal uptake, this approach is not optimal for the pre-therapeutic evaluation of the head and neck region, as it does not provide the required detailed morphological and functional DW MRI information. In addition, the obtained MR images in the chest are of poorer quality than those obtained with low-dose CT (see below). The second approach consists in performing a rapid total body PET/MRI and an additional full diagnostic high-resolution MRI examination on certain bed positions depending on the clinical situation. This full diagnostic MRI with morphological and DW MRI sequences can be performed, in simultaneous systems, partly during the PET acquisition or, in sequential systems, during the required 60 min necessary for tracer uptake and before the start of the PET acquisition. The simultaneous approach is more time effective than the sequential approach because the morphological MRI can be partially performed during the PET acquisition. Nevertheless, even in the simultaneous approach, not all MRI sequences can be acquired simultaneously with the PET acquisition. Whenever a tripartite PET/CT-MRI system is used, the rapid total body PET/ CT is combined with dedicated high-resolution MRI sequences of the clinically relevant regions. Finally, the third approach is to perform a total body full diagnostic high-resolution MRI examination with dedicated sequences in addition to the total body PET acquisition. This option is difficult to implement in clinical routine today because of the unacceptably long acquisition time.

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Various PET/MRI protocols for head and neck cancer imaging have been proposed by different investigators, reflecting institutional preferences for sequences and imaging planes, ongoing research protocols, as well as time-effectiveness issues.77,81,82 Because of cost constraints and limited patient cooperation necessitating a reasonable acquisition time, PET/MRI protocols in head and neck oncology patients will continue to be a compromise between high-resolution imaging including DW MRI and the minimum time lapse necessary for a correct and complete diagnosis. Therefore, it appears desirable to develop standardized PET/MRI protocols that are reproducible across multiple institutions; such attempts are currently made by a few research groups. Last but not least, economic aspects must also be taken into account. Owing to the limited throughput, especially when the full diagnostic MRI potential is used, PET/MRI examinations are likely to be more expensive than PET/CT scans.13 Feasibility Recent studies have shown that PET/MRI is feasible in patients with head and neck tumours on both simultaneous and sequential systems.12,81,82 In a prospective study, Boss et al12 assessed the feasibility of FDG PET/MRI in eight patients with head and neck tumours. The patients underwent routine FDG PET/CT followed by PET/MRI performed on a simultaneous hybrid prototype system. No additional FDG and no gadolinium chelates were administered for the PET/MRI examination. The total acquisition time was about 40 min. MRI data sets showed excellent image quality without recognizable artefacts or distortions caused by the inserted PET system.12 Because of the higher resolution of the PET component of the PET/MRI system in comparison with the PET component of the PET/CT system, PET images from PET/ MRI had a superior spatial resolution and improved image contrast compared with images from PET/CT. The authors also performed semi-quantitative analysis, including the calculation of metabolic ratios for normal anatomical structures and for tumours. The metabolic ratios were defined as the ratio of the uptake within the ROI and the mean cerebellar uptake. Boss et al found an excellent agreement between metabolic ratios from both PET systems with correlation coefficients of 0.99 and 0.96 for normal anatomic head and neck structures and tumours, respectively.12 As the prototype used in this study had a small craniocaudal field of view (only 19 cm), only tumours located at the skull base or in the suprahyoid neck could be imaged. The evaluation of lymph nodes below Level II, of laryngeal or hypopharyngeal cancers as well as of distant metastases and second primary tumours was, however, not possible.12 In a review article,81 we have reported the feasibility of PET/MRI in 221 patients who underwent sequential whole-body FDG PET/MRI with full diagnostic MRI protocols for a variety of indications. The MRI protocols included administration of gadolinium chelates and DW MRI sequences. In 27 head and neck oncology patients, PET/MRI was performed for staging or restaging purposes or for follow-up after radio-chemotherapy.81 In 3 (11%) cases, PET/MR images could not be interpreted because of motion artefacts and poor image fusion.81 Moderate fusion quality was present in 4 (15%) cases, hampering the assessment of normal-sized metastatic lymph nodes or HNSCC ,2 cm.81 In the remaining 20 cases (75%), image quality was

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good with excellent lesion conspicuity. Nevertheless, the reported total examination time was very long (3 h for the dedicated head and neck and total body PET/MRI protocol). Platzek et al87 evaluated the feasibility of PET/MRI in the initial staging of 20 head and neck cancer patients and compared the PET images from a sequential PET/MRI system with those obtained on a stand-alone PET scanner. PET/MRI was performed after scanning on the conventional PET system using a single FDG dose. PET/MRI of the head and neck region was feasible on a whole-body PET/MRI system without impairment of PET or MR image quality.87 In a prospective study performed in our institution, Varoquaux et al82 evaluated the feasibility of sequential PET/MRI in 32 head and neck oncology patients. All patients underwent whole-body FDG PET/MRI with a dedicated head and neck examination followed by whole-body PET/CT. The total PET/MRI acquisition time was 90 min. Two experienced observers, who were blinded to clinical data, evaluated the anonymized PET/CT and PET/MRI data sets. Image and fusion quality, lesion conspicuity, anatomical localization of lesions, as well as the number and size of benign and malignant focal uptake lesions were assessed. The quantitative analysis included ROI measurements on both modalities for SUVs of lesions (in the head and neck and rest of the body) and organs. PET/MRI coregistration and image fusion was feasible in all patients initially included in the study.82 PET/MRI showed equivalent performance to PET/CT regarding rating scores for image quality, fusion quality, lesion conspicuity and anatomical localization, number of detected lesions and number of patients with and without malignant lesions.82 A high correlation was obtained for SUV values measured on PET/MRI and PET/CT for malignant lesions, benign lesions and organs (r 5 0.787–0.877, p , 0.001). Quantification in hybrid positron emission tomography/MRI Despite much worthwhile research effort, quantification is still a hot research topic because simultaneous and sequential PET/ MRI systems both use MRI-based attenuation correction methods. However, as the tri-modality PET/CT-MRI system employs classical CT-based attenuation correction, the challenges and pitfalls related to MRI-based quantification do not apply. A detailed discussion of ongoing research in the field of MRI-based quantification of tracer uptake is beyond the scope of this article. Nonetheless, performing PET/MRI examinations requires an understanding of the clinically relevant technical issues. Although several groups have demonstrated a statistically significant strong correlation between SUV measurements on PET/MRI and PET/ CT,71,82,88 it was suggested that SUVs of focal uptake and organs might be underestimated on PET/MRI as compared with PET/ CT.71,82,88 Despite differences in study design and data analysis, several investigators have reported that SUVmean for focal uptake may be underestimated by 11–13% on PET/MRI in comparison with its PET/CT counterpart, whereas SUVmax appears to be underestimated by 17–20%.71,82,88 SUVs for normal organs (liver, spleen and bone marrow) also appear to be significantly underestimated by PET/MRI.71,82,88 As reported by our group, this observed underestimation can result in a limited concordance of

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SUV measurements on PET/MRI and PET/CT.82 Differences in SUVs measured on PET/MRI and PET/CT can be partially attributed to tracer kinetics, as, in all reported studies, PET/MRI and PET/CTwere performed sequentially after the administration of a single FDG dose. In the study of Drzezga et al71 and Wiesmuller et al,88 PET/CTwas performed prior to PET/MRI, whereas in our study PET/MRI was performed first. Therefore, the observed underestimation (similar range in all three studies) cannot be explained by tracer kinetics alone.82 As MRI-based attenuation correction ignores bone in contrast to CT-based attenuation correction, the observed difference in SUV measurements appears to be particularly pronounced in areas with large bony structures, such as the pelvis and the head and neck.89 In addition, SUV measurements in malignant tumours appear to be affected by lesion size: the larger the tumour, the bigger the difference in SUVs measured on PET/MRI and PET/CT.82 Further research is required to better understand differences in SUV measurements on PET/MRI and PET/CT observed in clinical series. Pitfalls in hybrid positron emission tomography/MRI Susceptibility artefacts, attenuation correction artefacts and miscoregistration artefacts can hamper the interpretation of head and neck PET/MRI examinations. Susceptibility artefacts occur as the result of microscopic variations in the magnetic field strength near the interfaces of substances with different magnetic susceptibility. Susceptibility artefacts are commonly seen around ferromagnetic objects as contained in dental restorations or osteosynthesis material. Dephasing of spins and frequency shifts in the tissues surrounding the ferromagnetic objects lead to spatial distortion of the surrounding anatomy as well as to bright and dark areas on MRI sequences. These artefacts are more pronounced at high field strength (3 T vs 1.5 T), on gradient echo sequences, with long echo train length and DWI sequences. Although metal-based restoration materials can degrade MR image quality, they have an even stronger influence on CT image quality90 (Figure 1). As suggested by several authors, the observed artefacts are in general larger on CT than on MR images, the size of the artefact mainly depending on the composition of the ferromagnetic material used.90 A distinct problem is geometric distortion in DW MRI sequences caused by B0 susceptibility

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differences over the areas imaged. Although parallel imaging techniques reduce geometric distortion, a certain amount of distortion cannot be avoided even with newer DW MRI sequences.91 Because of miscoregistration of the k space, the geometric distortion can be particularly well appreciated when b 1000 images are fused with standard morphological sequences.92 In our experience, this diffeomorphic miscoregistration may result in erroneous interpretation of findings unless morphological MRI sequences are carefully analysed (Figure 2). Susceptibility artefacts also lead to a void signal on MRI, resulting in wrong assignment of air attenuation coefficient on the corresponding MRI-based attenuation map. It has been suggested to manually “fill the hole” on attenuation correction maps to partially compensate the bias in the estimated SUV values. This most often leads to underestimation of SUV values in PET/MRI.93 Nevertheless, it is important to point out that artefacts generated by dental implants also have a major impact on SUV values measured on PET/CT.94,95 In patients with a metal tooth prosthesis, SUVs have been reported to decrease by approximately 20% in the dark streak artefact region and increase by approximately 90% in the bright streak artefact region when compared with the artefact free region.94 Using a PET/MRI-CT system, Delso et al96 have reported on the feasibility of correcting dental streak artefacts during CT-based attenuation correction using complementary MRI data. Motion and respiratory mismatch between the acquisition of MRI and PET data can result in anatomic miscoregistration. Even the slightest degree of miscoregistration can cause diagnostic errors with respect to precise tumour localization (Figure 3) or submucosal extension having a direct impact on tumour staging. Careful analysis of data and comparison with morphological MRI sequences are crucial in order to avoid this interpretation pitfall. Diagnostic performance of positron emission tomography/MRI in the head and neck Only very few data are currently available regarding the diagnostic performance in terms of sensitivity, specificity and

Figure 1. This patient was a follow-up case of a squamous cell carcinoma of the floor of the mouth. (a) Axial positron emission tomography (PET)/CT image shows streak artefacts from bilateral dental implants hampering interpretation. Tumour recurrence could not be excluded on the basis of PET/CT. (b) Corresponding hybrid PET/MRI (PET fused with axial gadolinium-enhanced water-only Dixon image) shows the absence of tumour recurrence. In this patient, PET/MRI is less affected by dental artefacts (arrows) than PET/CT.

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Figure 2. Hybrid positron emission tomography (PET)/MRI obtained for primary staging of advanced laryngeal squamous cell carcinoma. (a) Fused T2 and b 1000 image (colour overlay) illustrate restricted diffusivity in the right Level VI region (arrow), suggesting metastatic lymph nodes. Note geometric distortion of the overlaid b 1000 image in comparison with T2. Position of the spinal cord (long dashed arrow) and T1 nerve roots (arrowheads) on b 1000. Position of the spinal cord on T2 (short dashed arrow). (b) Corresponding fused T2 and PET show hypermetabolic thyroid nodule (arrow) and absent Level VI metastatic nodes. Ultrasonography with fine-needle aspiration cytology and surgery revealed a benign thyroid nodule and absent Level VI metastases, respectively.

accuracy of PET/MRI in the head and neck.97–99 These data are based on studies evaluating software fusion of PET and morphological MRI sequences obtained on separate scanners. Nakamoto et al97 evaluated the clinical value of retrospective image fusion of morphological MRI sequences combined with FDG PET from a stand-alone PET scanner. The study comprised 65 consecutive patients with HNSCC; the standard of reference was histology in 61 patients and follow-up in 4. The sensitivity of MRI and PET/MRI was 98% and 100% for primary tumours, 85% for lymph node metastases and 67% and 92% for recurrent tumours, respectively.97 The authors concluded that PET/MRI software fusion might be useful in suspected recurrent disease, however no diagnostic gain was obtained in primary tumours. Huang et al98 compared the performance of PET/MRI software fusion with PET/CT, MRI and CT for the assessment of deep tissue invasion in 17 patients with advanced buccal SCC. No DW MRI was available. Results were correlated with pathology. The sensitivity and speciﬁcity of PET/MRI software fusion

were the highest among the four modalities (90%/91% for PET/MRI, 80%/84% for PET/CT, 80%/80% for MRI and 55%/ 82% for CT, respectively). As the level of diagnostic confidence was also highest for PET/MRI software fusion, Huang et al98 concluded that, in advanced buccal SCC, PET/MRI is more reliable than PET/CT, MRI or CT for the assessment of local invasion and for the delineation of tumour size. Kanda et al99 evaluated the clinical value of retrospective image fusion of MRI and FDG PET from PET/CT in 30 patients with oral cavity and hypopharyngeal SCC. The authors compared the performance of PET/MRI, PET/CT and MRI with histopathology regarding the T and N stage and found that the accuracy for T stage for fused PET/MRI and MRI was similar but superior to PET/CT (87% and 90% vs 67%, p 5 0.04). Regarding N stage, the sensitivity and specificity for the detection of nodal metastasis on a level-per-level basis were 77%/96% for both PET/ MRI and PET/CT, compared with 49%/99% for MRI, respectively. The differences in sensitivity (p 5 0.0026) were significant.99

Figure 3. Positron emission tomography (PET)/MRI and PET/CT obtained for primary staging of squamous cell carcinoma of the hypopharynx. (a) Axial PET/CT image shows a hypermetabolic tumour located in the posterior hypopharyngeal wall (arrow). (b) Corresponding hybrid PET/MRI (fused PET and T2) shows poor data fusion due to patient motion. Note anterior displacement of the PET image in comparison with T2, suggesting hypermetabolic base of the tongue–vallecula tumour (dashed arrow). True location of the tumour in the hypopharynx (arrow).

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Diagnostic challenges Despite the above-mentioned encouraging results, interpreting hybrid PET/MRI studies in clinical routine constitutes a diagnostic challenge. Ideally, one would assume that the diagnostic information provided by morphological MRI, DW MRI and PET would be complementary, thereby resulting in a diagnostic gain. Assuming that artefacts have been correctly identified, false-positive and false-negative evaluations with morphological MRI, DW MRI or PET may still occur. How should one deal with discrepant findings between morphological MRI, DW MRI and PET (Figures 4 and 5)? Should one rather “rely on” morphology, DW MRI, perfusion or PET? How can one prospectively identify false-positive and false-negative evaluations with multimodality imaging? False-negative interpretations may have catastrophic consequences for the patient, whereas false positives will result in unnecessary medical procedures and high cost. Only future studies including larger patient series can answer these questions. Although the issue of discrepant PET, MRI and DW MRI findings is not new, hybrid PET/MRI has certainly brought it to the forefront. In our own institution, we are conducting a prospective clinical study to evaluate the performance of PET/MRI in head and neck oncology patients. Based on our preliminary experience, whenever all data are concordant (morphology, DW MRI and PET), the diagnosis is correct (either true positive or true negative) (Figure 6). However, in cases with discordant findings on morphological MRI, DW MRI and PET, we currently recommend endoscopic biopsy, image-guided biopsy or close imaging follow-up depending on the clinical situation. Combined SUV, ADC and perfusion measurements, in particular for lesions interpreted as indeterminate, possibly positive or possibly negative, may facilitate interpretation of findings in the future; multiparametric quantification could ideally be complemented by a decisional algorithm. However, for the time being, no such data exist.

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Figure 4. Hybrid positron emission tomography (PET)/MRI obtained 6 months after radiotherapy of laryngeal squamous cell carcinoma. Clinically, recurrence was suspected. (a) Axial fat-saturated T2 shows diffuse oedema with posterior commissure involvement (arrow). No evidence of recurrence. (b) Fused T2 and b 1000 illustrate absent restriction of diffusivity (arrow). Normal high signal of the spinal cord and nerve roots on b 1000. No major geometric distortion. (c) Fused PET and gadolinium-enhanced T1 show increased 18-fludeoxyglucose uptake (mean standardized uptake value 5 3.8; maximum standardized uptake value 5 5.2) in the posterior commissure (arrow) suggesting recurrence. Surgical biopsy and follow-up revealed scar tissue.

One of the major potential disadvantages of PET/MRI over PET/ CT in head and neck cancer patients is due to the fact that MRI is less sensitive than CT for the detection of pulmonary nodules.100 Appenzeller et al100 prospectively evaluated whether the performance of PET/MRI using the body coil is sufficient from a diagnostic point of view when compared with standard low-dose non-contrast-enhanced PET/CT regarding the overall diagnostic accuracy, lesion detectability, size and lesion conspicuity. The authors used an axial Dixon-based T1 weighted 3D gradient echo sequence with a slice thickness of 6.8 mm. Comparison of PET/ MRI with PET/CT in 63 patients referred for a variety of malignant tumours revealed a statistically significant superiority of PET/CT over PET/MRI for the conspicuity of pulmonary lesions (p50.016).100 The authors suggested that, for this reason, an additional chest CT will probably still remain necessary for most patients in the near future. Nevertheless recent data suggest that PET/MRI may perform somewhat better in this respect.82 Results from our institution have shown that in head and neck cancer patients PET/MRI may perform as well as PET/CT regarding lung nodule detection provided that a high-resolution Dixon sequence (voxel size 0.85 3 0.85 3 3 mm) is obtained.82 Nevertheless, the reported data are based on a small number of patients with a low prevalence of lung lesions; further studies in head and neck cancer patients are therefore required to confirm

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Figure 5. Hybrid positron emission tomography (PET)/MRI obtained 6 months after proton therapy and chemotherapy for undifferentiated sinonasal carcinoma. Recurrence in the nasopharynx was suspected clinically. (a) Axial fat-saturated gadoliniumenhanced T1 shows a large nasopharyngeal mass (asterisk) with extensive destruction of the clivus (arrow) and central skull base, suggesting recurrence vs radiation-induced inflammation. (b) Apparent diffusion coefficient (ADC) map reveals restricted diffusivity (ADCmean 5 0.98) suggesting recurrence (asterisks). (c) Corresponding fused PET and gadolinium-enhanced fat-saturated T1 reveal absent 18-fludeoxyglucose uptake (asterisk) suggesting inflammation. Surgical biopsy and follow-up revealed inflammatory tissue.

these ﬁndings. Our preliminary results in a larger patient series (unpublished data) also show that although the conspicuity of the lung lesions may be less good on PET/MRI than on PET/CT, FDG avid lung nodules are equally well detected with both modalities (Figure 7). ONGOING RESEARCH AND POTENTIAL FUTURE CLINICAL APPLICATIONS Ongoing research regarding future clinical applications of PET/ MRI in head and neck oncology focuses on the evaluation of the

added value of this technique in comparison with the already widely available panoply of diagnostic procedures. In particular, future research involving larger patient series will show whether PET/MRI outperforms PET/CT, MRI, DW MRI or the combination thereof for the detection of metastatic lymph nodes and recurrent disease and for the assessment of treatment response. In addition, combining quantitative parameters from DW MRI, PET and perfusion may add diagnostic certainty and may also prove beneﬁcial for an optimized and individualized treatment plan. A particular challenge for future research consists in developing

Figure 6. Images obtained from the same hybrid positron emission tomography (PET)/MRI examination as shown in Figure 5. (a) Fused b 1000 and gadolinium-enhanced water-only Dixon image show restricted diffusivity in the C2 vertebral body (arrow). (b) Fused PET and gadolinium-enhanced water-only Dixon image illustrate increased 18-fludeoxyglucose uptake (mean standardized uptake value 5 4.4; maximum standardized uptake value 5 6) in the C2 vertebral body (arrow). Similar findings were present in the vertebral bodies of C3–C6 (not shown). The vertebral bodies had been included in the radiation portal. Nevertheless, bone metastases were suspected. (c) Sagittal maximum enhancement perfusion map obtained by dynamic gadolinium-enhanced MRI shows increased vascularization in the vertebral bodies of C2–C6 (in red) supporting the diagnosis of bone metastases. Bone biopsy and follow-up confirmed metastases.

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Figure 7. This patient was a follow-up case of a squamous cell carcinoma of the oropharynx. (a) Axial positron emission tomography (PET)/CT shows metastatic mediastinal lymph nodes (dashed arrows) and metastatic lung nodules (arrows). (b) Corresponding hybrid PET/MRI (fused PET and gadoliniumenhanced water-only Dixon image and slice thickness of 2 mm) shows similar findings. Metastatic mediastinal nodes (dashed arrows). Lung metastases (arrows). Note that lung nodule conspicuity is slightly better on PET/CT than on PET/MRI.

sequences with minor geometric distortion, faster high-resolution MRI sequences and, last but not least, economic aspects. SUMMARY Although the integration of PET and MRI remains technically complex, this new hybrid imaging modality holds promise because it can combine morphological, functional and molecular information at the same time. We have discussed some of the potential areas where PET/MRI may add diagnostic value to the existing imaging modalities. However, further research is needed to assess the true impact of this technique in HNSCC. Switching clinical workflows to PET/MRI introduces a number of image registration challenges, which were not of major concern with conventional PET/CT scanners. These are linked to the additional artefacts within MRI, the range and number of additional MRI sequences and the range of fields-of-view and orientations of the acquired images. Despite remarkable technical progress in imaging modalities, one must keep in mind that diagnostic interpretation of imaging studies in the context of head and neck tumours remains a challenging task. It demands a great amount of experience and a profound knowledge of the anatomical and functional local changes that may be observed before and after treatment. Because multiple non-invasive imaging studies may sometimes provide contradictory or confusing information, sound clinical judgement is needed to indicate when biopsy may remain the only guide towards correct treatment. FUNDING The figures and the preliminary data presented in this review are part of an ongoing clinical study supported by the Swiss National Science Foundation under grants SNF 320030_135728/1 and 31003A_149957.

diagnostic and therapeutic decisional algorithms based on multiparametric qualitative and quantitative information. The success of ongoing clinical studies will also depend on technical issues, in particular the development of improved quantiﬁcation algorithms, motion and respiratory compensation software, robust DW MRI

ACKNOWLEDGMENTS The authors would like to thank B´en´edicte M.A. Delattre, Arthur Varoquaux, Olivier Rager, Osman Ratib, Christoph D. Becker, Pavel Dulguerov, Nicolas Dulguerov, Karim Burkhardt, Angeliki Ailianou, Vincent Lenoir and the entire technical team for their contributions to the Geneva PET/MRI project.

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BJR Received: 26 September 2013

Accepted: 5 December 2013

doi: 10.1259/bjr.20130617

Cite this article as: Onal C, Sonmez S, Erbay G, Guler OC, Arslan G. Simultaneous integrated boost to intraprostatic lesions using different energy levels of intensity-modulated radiotherapy and volumetric-arc therapy. Br J Radiol 2014;87:20130617.

FULL PAPER

Simultaneous integrated boost to intraprostatic lesions using different energy levels of intensity-modulated radiotherapy and volumetric-arc therapy 1

C ONAL, MD, 1S SONMEZ, MSci, 2G ERBAY, MD, 1O C GULER, MD and 1G ARSLAN, MSci

Department of Radiation Oncology, Baskent University Faculty of Medicine, Adana, Turkey Department of Radiology, Baskent University Faculty of Medicine, Ankara, Turkey

Address correspondence to: Mr Cem Onal E-mail: hcemonal@hotmail.com

Objective: This study compared the dosimetry of volumetric-arc therapy (VMAT) and intensity-modulated radiotherapy (IMRT) with a dynamic multileaf collimator using the Monte Carlo algorithm in the treatment of prostate cancer with and without simultaneous integrated boost (SIB) at different energy levels. Methods: The data of 15 biopsy-proven prostate cancer patients were evaluated. The prescribed dose was 78 Gy to the planning target volume (PTV78) including the prostate and seminal vesicles and 86 Gy (PTV86) in 39 fractions to the intraprostatic lesion, which was delineated by MRI or MR-spectroscopy. Results: PTV dose homogeneity was better for IMRT than VMAT at all energy levels for both PTV78 and PTV86. Lower rectum doses (V30–V50) were significantly higher with SIB compared with PTV78 plans in both

IMRT and VMAT plans at all energy levels. The bladder doses at high dose level (V60–V80) were significantly higher in IMRT plans with SIB at all energy levels compared with PTV78 plans, but no significant difference was observed in VMAT plans. VMAT plans resulted in a significant decrease in the mean monitor units (MUs) for 6, 10, and 15 MV energy levels both in plans with and those without SIB. Conclusion: Dose escalation to intraprostatic lesions with 86 Gy is safe without causing serious increase in organs at risk (OARs) doses. VMAT is advantageous in sparing OARs and requiring less MU than IMRT. Advances in knowledge: VMAT with SIB to intraprostatic lesion is a feasible method in treating prostate cancer. Additionally, no dosimetric advantage of higher energy is observed.

Randomized trials have shown a gain in biochemical relapse-free survival using dose escalation for prostate cancer.1 However, isolated local failure is still reported in nearly one-third of patients, even with higher radiotherapy (RT) doses.1 Local recurrence is of clinical importance because a relationship has been suggested between local control, distant metastasis and survival.2 It has also been demonstrated that intraprostatic failure mainly originates at the initial tumour location as a result of intrinsic resistance of a fraction of the tumour clones, which implies that selective dose escalation to the dominant intraprostatic lesion using simultaneous integrated boost (SIB) might be beneﬁcial.3

SIB is rare. In these studies, target volume and organs at risk (OARs) doses may vary with different treatment planning systems. Another aspect not often addressed in these planning studies is the photon energy level.4,8,9,11 Although higher energy photons have the potential advantage of reduced attenuation with depth, this may in turn increase the risk of secondary malignancies because of the presence of neutrons generated in the accelerator head at treatment energies .8 MV.12

With new RT techniques, such as intensity-modulated RT (IMRT) and volumetric-arc therapy (VMAT), SIB could be delivered without increasing acute toxicity.4–7 Several recent studies have performed dosimetric comparison of IMRT and VMAT plans in prostate cancer;8–10 however, dosimetric evaluation of IMRT and VMAT plans delivering

Functional imaging techniques can clearly demonstrate tumour within the prostate. MRI, MR spectroscopy (MRS) and positron emission tomography are capable of demonstrating intraprostatic lesions (IPLs).13 The advent of combined MRI with MRS or dynamic contrast enhanced (DCE)-MRI improves the detection rate of tumours within the prostate.13–15 The aim of the present study was to make dosimetric comparisons of VMAT and 7-ﬁeld IMRT with dynamic

BJR

C Onal et al

multileaf collimators (MLCs) using the Monte Carlo algorithm with XVMC code in the treatment of prostate cancer with or without SIB, which can provide improved dose calculation accuracy and has been implemented successfully in the clinical setting.16,17 Additionally, the impact of three photon energies on target volumes, OARs and normal tissue was evaluated in IMRT and VMAT plans. METHODS AND MATERIALS The CT and MRI/MRS data of 15 consecutive intermediate risk prostate cancer patients were selected for the present study. The inclusion criterion was the presence of an MRI or MRS detected IPL, which was defined as an MRI- and/or MRS-detected prostate tumour with characteristics suggesting a high probability of malignancy according to the criteria of Cruz et al18 for MRI and Villeirs et al13 for MRS. CT and MRI All patients had undergone 2.5-mm slice thickness CT with a comfortably full bladder and empty rectum.19 MRI scans were acquired with the same conditions as CT. Because of the negative effects of androgen deprivation on the metabolism of prostate cancer cells, MRS examinations were performed in the absence of or before hormone therapy.20 The MRI scans used for image fusion and treatment planning were acquired on a 1.5 T Siemens Avanto® MRI System (Siemens Healthcare, Erlangen, Germany). T2 weighted (T2W) diffusion weighted images and DCE-MRI examinations were performed using an eight-element phased array coil during the scans without an endorectal coil. T1, T2, MRS, apparent diffusion coefficient (ADC) and DCE images of the prostate were reviewed by an experienced radiologist (GE). The IPLs identified on T2, ADC, DCE images or MRS were used for SIB planning.21 The CT and MRI data were digitally transferred to an Eclipse™ (Varian Medical Systems, Palo Alto, CA) workstation and coregistered to delineate the regions of interest. The CT and MRI fusion was done by automated computerized fusion and then checked manually, as described in other IPL boost studies.14,21,22 Clinical target volume (CTV) included the prostate and the entire seminal vesicles. The planning target volume for 78 Gy (PTV78) was defined as CTV with a margin of 5 mm posterior and 8 mm in other directions.19,23 The delineation of IPL was done together with a radiologist (Figure 1). The PTV for 86 Gy (PTV86) was created using a three-dimensional, isotropic, 4-mm margin around the IPL.6 The OARs included the rectum, sigmoid, bladder and femoral heads. The rectum was delineated

from the anal verge to the recto-sigmoid junction.24 The femoral heads were contoured to the level of ischial tuberosities. Treatment plans The treatment plans were generated using IMRT and VMAT techniques. The IMRT plans consisted of seven coplanar fields, at gantry angles of 0°, 37°, 75°, 135°, 225°, 285° and 327°. The plans were calculated with Monaco treatment planning system (CMS; Elekta, Crawley, UK) using the Monte Carlo algorithm and a sliding window MLC delivery technique. The VMAT plans consisted of a single 360° arc. Gantry speed, MLC leaf position and dose rate varied continuously during VMAT delivery.25 For each patient, three different plans with 6, 10, and 15 MV energies were generated for both IMRT and VMAT techniques. Additionally, the same plans were made with SIB. All plans were created for delivery on an Elekta linear accelerator (Elekta) equipped with an MLC and designed for dynamic IMRT and VMAT. The leaf width of the Elekta accelerator used in the present study was 0.4 cm, and the leaves did not interdigitate. Dose prescription Two plans were generated and each plan was normalized to deliver 99% of CTV and 95% of PTV78 and PTV86 receiving at least 78 and 86 Gy, respectively. All treatments were planned to be delivered in 39 fractions. Dose constraints for the rectum and bladder were based on Radiation Therapy Oncology Group recommendations,26 where V50 and V70 for the rectum were 50% and 20% and V55 and V70 for the bladder were 50% and 30%, respectively. Normal tissue complication probability values for rectum and bladder were ,10% and #5%, respectively.27,28 The femoral heads were limited to receive a maximum of 50 Gy. Plan evaluation We evaluated the treatment plans by comparing the planning results with the planning and physical indices (Table 1). D2 and D98 were used as surrogates for maximum and minimum doses for target volumes, respectively. Target dose homogeneity index (TDI) was calculated as: TDI 5 [(D2 – D98)/D50], where D50 is the minimal dose to 50% of target volume. Additionally, the heterogeneity index (HI) was defined as HI 5 D1/D95, where D1 and D95 are minimal dose to 1% and 95% of target volume, respectively. For the rectum, D2cc was defined as the minimum dose value in the 2-cc volume receiving the highest dose. To quantify the dose to normal tissues, relative volumes of the 50% isodose (V50%) was determined. Dose verification Dose verification for the treatment plan was performed using a two-dimensional (2D) ion chamber array detector (IMRT

Figure 1. Representative image demonstrating intraprostatic lesion (a) in diffusion weighted MR scan and (b) coregistered MR and CT scans. (c) PTV86 and PTV78 are generated with given margins to intraprostatic lesion and prostate.

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Br J Radiol;87:20130617

BJR Received: 6 June 2013

Accepted: 16 September 2013

doi: 10.1259/bjr.20130334

Cite this article as: Milgrom SA, Alberto Vargas H, Sala E, Frankel Kelvin J, Hricak H, Goodman KA. Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI. Br J Radiol 2013;86:20130334.

FULL PAPER

Acute effects of pelvic irradiation on the adult uterus revealed by dynamic contrast-enhanced MRI 1

S A MILGROM, MD, 2H ALBERTO VARGAS, MD, 2E SALA, MD, 3J FRANKEL KELVIN, RN, MSN, 1H HRICAK, MD and K A GOODMAN, MD

1 1

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY 3 Survivorship Center, Memorial Sloan-Kettering Cancer Center, New York, NY 2

Address correspondence to: Dr Karyn A Goodman E-mail: goodmank@mskcc.org

Objective: Pelvic radiation therapy (RT) can influence fertility in female rectal cancer survivors. Data regarding its effects on the adult uterus are scant. This study aims to evaluate the uterus before and after RT, using dynamic contrast-enhanced MRI. Methods: Eligible patients (n510) received RT for rectal cancer, had an intact uterus and underwent dynamic contrast-enhanced MRI before and after RT. Seven patients were pre-menopausal. Results: Patients received pelvic RT (median, 50.2 Gy) with concurrent 5-fluorouracil. Five patients were treated with intensity modulated RT (IMRT) and five with a three-field technique. The median D95 of the uterus was 30 Gy; D05 was 48 Gy; and V95 was 97%. The median cervical D95 was 45 Gy; D05, 50 Gy; and V95, 100%. Cervical dose was higher with IMRT than with three-field plans (p#0.038).

On T2 MRI, the junctional zone was visible in nine patients before and in one after RT (p50.001). Median cervical length (2.3 vs 3.0 cm) and endometrial thickness (2.6 vs 5.9 mm) were reduced after RT (p#0.008). In pre-menopausal patients, the volume transfer constant, Ktrans, (0.069 vs 0.195, p50.006) and the extracellular extravascular volume fraction, Ve, (0.217 vs 0.520, p50.053) decreased. Conclusion: Pelvic RT significantly affected uterine anatomy and perfusion. Cervical dose was higher with IMRT than three-field plans, but no attempt was made to constrain the dose. Advances in knowledge: Pelvic RT significantly affects the adult uterus. These findings are crucial to understand the potential consequences of RT on fertility, and they lay the groundwork for further prospective studies.

As the cure rate in locally advanced rectal cancer continues to improve, understanding the long-term sequelae of therapy is gaining importance. Research has shown that young cancer survivors are concerned about treatmentrelated effects on fertility, pregnancy and neonatal outcomes [1,2]. Previously, pelvic irradiation, standard in the management of locally advanced rectal cancer, invariably caused sterility in females as a result of acute ovarian failure. Currently, however, the risk of ovarian dysfunction may be greatly reduced by transposing the ovaries to the paracolic gutters before radiation therapy (RT) [3]. Additionally, an increasing number of females undergo embryo or oocyte cryopreservation before receiving RT [4]. These advances prompt the question: if a young female has undergone pelvic RT, can she carry a pregnancy to term?

paediatric cancer survivors suggest that pelvic RT alters uterine volume, distensibility and vasculature, with patients who are younger at the time of RT being the most vulnerable to these effects [5–7]. Additionally, population-based studies of paediatric cancer survivors have demonstrated an association between abdominal and/or pelvic RT and adverse pregnancy and neonatal outcomes, including placental abnormalities, pre-term delivery, low birth weight infants and perinatal mortality [8–11]. However, only sparse data exist regarding the effects of pelvic RT on the adult uterus, which may be more radioresistant.

Answering this question requires an understanding of the effects of the pelvic RT on the uterus. Ultrasounds of

The aim of this study was to use dynamic contrast-enhanced (DCE) MRI to assess the acute effects of RT on the uterus in females treated for locally advanced rectal cancer. A second aim was to compare dosimetric parameters of conventional three-ﬁeld RT and intensity modulated RT (IMRT) treatment plans.

BJR

S A Milgrom, H Alberto Vargas, E Sala et al

METHODS AND MATERIALS Study design After obtaining a waiver of authorisation from the institutional review board, females who received pelvic RT for rectal cancer at a single institution between January 2008 and December 2012 were identified retrospectively. Eligibility criteria included the presence of an intact uterus and evaluation by DCE MRI, using the same acquisition protocol, before and during the 12 weeks after the completion of pelvic RT. 10 patients were eligible for analysis. Treatment information Pelvic RT with concurrent 5-fluorouracil was recommended. RT was provided using either a conventional three-field technique or IMRT, according to the institutional practice. The three-field treatments used posteroanterior and opposed lateral fields to treat the whole pelvis to 45 Gy, followed by a 5.4 Gy boost to the rectal tumour, to give a total dose of 50.4 Gy at 1.8 Gy per fraction. With IMRT, the pelvis was treated to 45 Gy at 1.8 Gy per fraction, and the rectal tumour was treated to 50 Gy at 2 Gy per fraction using an integrated boost (Figure 1). Contouring was performed according to the Radiation Therapy Oncology Group consensus guidelines [12]. The uterus and cervix were contoured by a single person to ensure consistency. Treatment plans for both IMRT and conventional three-field RT were generated using an in-house treatment-planning system (Memorial Sloan-Kettering Radiation Treatment Planning System; New York, NY). Dosimetric data were extracted, and the dose to the uterus and the cervix with IMRT vs the three-field treatment plans was compared using the mean and the maximum dose to the organ, the volume of the organ receiving at least 95% of the prescription dose (V95) and 5% of the prescription dose (V05) and the dose to 95% of the organ (D95) and 5% of the organ (D05). The prescription dose was defined as the dose to the pelvis (45 Gy).

obtained on 1.5- or 3-T MRI systems (Signa HDx; GE Healthcare Technologies, Waukesha, WI) using a multichannel phased-array pelvic coil. Axial, sagittal and coronal two-dimensional fastrecovery fast spin echo T2 weighted images were obtained with the following parameters: repetition time/echo time, 4000–6000 ms/102–120 ms; echo-train length, 24; flip angle, 90°; bandwidth, 32 MHz; field of view, 18–36 cm; section thickness, 3-mm and 1-mm intersection gap; matrix, 192–2243320. DCE MRIs were acquired after intravenous injection of 0.1 mmol kg21 body weight gadolinium-diethylene triamine pentaacetic acid (Magnevist®; Berlex Laboratories, Montville, NJ) at a rate of 2 ml s21 with an automatic injector (MEDRAD, Warrendale, PA), using a transverse three-dimensional T1 weighted spoilt gradientecho sequence (repetition time/echo time, 3.3–4.1 ms/1.2–1.4 ms; section thickness, 4–6 mm; field of view, 24 cm; matrix, 2563128–2563160). Temporal resolution was 5–8 s. All studies were evaluated in consensus by two fellowshiptrained genitourinary radiologists. The following parameters were recorded at each MRI examination: uterine volume [(anteroposterior3transverse3craniocaudal dimensions)/2], cervical length, myometrial thickness and endometrial thickness. A region of interest of approximately 10 mm2 was marked over a homogeneous-appearing area of the myometrium, cervical stroma and glutaeus maximus muscle on T2 weighted images, and the corresponding signal intensity (SI) in each region of interest was recorded. The SI of the myometrium and cervical stroma normalised to muscle was calculated according to the following formulae: SImyometrium 2 SImuscle 3 100 SImuscle and

MRI evaluation Patients underwent pelvic MRI examination, including DCE MRI, before and during the 12 weeks after RT. All images were

ðSIcervix 2 SImuscle Þ 3 100: SImuscle

Figure 1. Intensity modulated radiation therapy (IMRT) and three-field radiation therapy (RT) treatment plans. Axial slices from treatment plans of two patients, one treated with IMRT (a) and another with conventional three-field RT (b). Dotted lines represent the central axis of each beam. Triangles represent wedges. The cervix is shown as the central oval shape in each image. The isodose lines represent the dose measured in Gray.

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Br J Radiol;86:20130334

BJR Received: 2 August 2013

Accepted: 3 October 2013

doi: 10.1259/bjr.20130481

Cite this article as: Kim SM, Choi J-H, Chang S-A, Choe YH. Detection of ischaemic myocardial lesions with coronary CT angiography and adenosine-stress dynamic perfusion imaging using a 128-slice dual-source CT: diagnostic performance in comparison with cardiac MRI. Br J Radiol 2013;86: 20130481.

FULL PAPER

S M KIM, MD,

2,3

J-H CHOI, MD,

2,3

S-A CHANG, MD and

1,2

Y H CHOE, MD

Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea 2 Cardiovascular Imaging Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Republic of Korea 3 Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea Address correspondence to: Dr Yeon Hyeon Choe E-mail: yhchoe@skku.edu

Objective: We assessed the diagnostic performance of adenosine-stress dynamic CT perfusion (ASDCTP) imaging and coronary CT angiography (CCTA) for the detection of ischaemic myocardial lesions using 128-slice dual-source CT compared with that of 1.5 T cardiac MRI. Methods: This prospective study included 33 patients (6168 years, 82% male) with suspected coronary artery diseases who underwent ASDCTP imaging and adenosine-stress cardiac MRI. Two investigators independently evaluated ASDCTP images in correlation with significant coronary stenosis on CCTA using two different thresholds of 50% and 70% diameter stenosis. Hypoattenuated myocardial lesions on ASDCTP associated with significant coronary stenoses on CCTA were regarded as true perfusion defects. All estimates of diagnostic performance were calculated and compared with those of cardiac MRI.

Results: With use of a threshold of 50% diameter stenosis on CCTA, the diagnostic estimates per-myocardial segment were as follows: sensitivity, 81% [95% confidence interval (CI): 70–92%]; specificity, 94% (95% CI: 92–96%); and accuracy 93% (95% CI: 91–95%). With use of a threshold of 70%, the diagnostic estimates were as follows: sensitivity, 48% (95% CI: 34–62%); specificity, 99% (95% CI: 98–100%); and accuracy, 94% (95% CI: 92–96%). Conclusion: Dynamic CTP using 128-slice dual-source CT enables the assessment of the physiological significance of coronary artery lesions with high diagnostic accuracy in patients with clinically suspected coronary artery disease. Advances in knowledge: Combined CCTA and ASDCTP yielded high accuracy in the detection of perfusion defects regardless of the threshold of significant coronary stenosis.

It is important to evaluate not only anatomical information about coronary arteries but also physiological information about myocardial perfusion for the precise assessment of coronary artery disease (CAD) [1]. Myocardial perfusion imaging (MPI) can provide haemodynamic information during exercise-induced or pharmacological stress. Singlephoton emission tomography (SPECT), cardiac MRI or positron emission tomography (PET) has been extensively used for MPI [2,3]. Moreover, a normal MPI determined using these techniques carries an excellent prognosis with a low rate of cardiac events [4–6].

not only anatomical structure, including coronary artery morphology, but also myocardial perfusion status. Although radiation dose associated with CT perfusion (CTP) is a concern, recent studies have shown that exposure to radiation can be reduced using different techniques, such as high-pitch helical scan of static CTP, half-scan duration of dynamic CTP and anatomical tube current modulation [7,8]. SPECT is more frequently used than MRI as a reference standard for evaluating the diagnostic accuracy of CTP. However, Jaarsma et al [9] reported that both cardiac MRI and PET showed a signiﬁcantly higher diagnostic accuracy than SPECT for detection of obstructive CAD. Among several techniques of CTP, adenosine-stress dynamic CTP (ASDCTP) using 128slice dual-source CT (DSCT) has the advantages of quantitative analysis of myocardial blood ﬂow (MBF) and the use of

SPECT and PET are limited in their ability to evaluate coronary artery morphology and cardiac structures. By contrast, CT MPI with coronary CTangiography (CCTA) can evaluate

BJR

S M Kim, J-H Choi, S-A Chang and Y H Choe

dynamic data sets [10–14]. There have been 2 previous studies of dynamic CTP using stress perfusion MRI as the reference standard [13,15], but these reports enrolled only 10 patients in the study arm evaluating dynamic CTP. The purpose of this study was to evaluate the diagnostic performance of ASDCTP using a 128-slice DSCT for the detection of myocardial perfusion defects compared with adenosine-stress cardiac MRI. METHODS AND MATERIALS Patients Our institutional review board approved this prospective study, and written informed consent was obtained from each patient. 33 patients with clinically suspected CAD were enrolled. They were referred to our unit for MPI using ASDCTP and cardiac MRI. The study included males and non-pregnant females who were older than 50 years and able to hold their breath during CTor MRI scan. The nature of the chest pain was evaluated with regard to three characteristics: (1) substernal pain, (2) whether the symptoms were precipitated by physical exertion or emotion and (3) whether prompt relief occurred within 10 min with rest or nitroglycerin. Typical angina was defined as presence of all of these characteristics. Atypical angina pectoris was defined as presence of two of the three characteristics. Non-anginal chest pain was characterised as presence of one or absence of the described features. The pre-test probability for obstructive CAD was estimated using the Duke Clinical Score, which included age, gender and character of chest discomfort [16,17]. Patients were categorised into low (1–30%), intermediate (31–70%) or high (71–99%) estimated pre-test probability. Exclusion criteria included poor renal function (serum creatinine .1.5 mg dl21), coronary artery bypass graft placement and haemodynamic and clinical instability (angina during rest, malignant arrhythmia). Patients were screened for contraindications to adenosine administration. Contraindications included second- or third-degree atrioventricular block without a functioning pacemaker, a history of asthma or severe obstructive lung disease, systolic blood pressure ,90 mmHg, acute myocardial infarction or unstable coronary syndrome within 24 h after symptom onset, hypersensitivity to adenosine and intake of caffeine- or xanthine-containing compounds within the last 12 h. Metformin was discontinued at the time of CT imaging and was subsequently withheld for a minimum of 48 h in patients with an estimated glomerular filtration rate of ,60 ml min21 1.73 m22. Beta-blockers and nitrates were discontinued prior to the CT examination. CT protocol All patients underwent cardiac CT using a DSCT system (SOMATOM Definition Flash; Siemens Medical Solutions, Forchheim, Germany) with 236430.6 mm detector collimation and the z-axis flying focal spot technique, resulting in 23128 sections. Adenosine was infused in the left arm and contrast was injected in the right arm using bilateral antecubital intravenous catheters. Electrocardiography (ECG) leads were placed on the patient’s chest, and a blood pressure cuff was placed on the patient’s lower extremity. A detailed explanation of the CT examination with instructions for breath-holds was also included in patient preparation.

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For calcium scoring, single-heartbeat CT scans were acquired with the following parameters: 280 ms gantry rotation time, 120 kV tube potential and 80 reference mAs per rotation tube current time product with the automatic tube current modulation technique (CARE Dose 4D; Siemens Medical Solutions). Adenosine (0.14 mg kg21 min21) infusion was then started for stress CTP, with monitoring of the patient’s vital signs. Iodine contrast was also injected at 2 min and 54 s after the start of adenosine infusion with 40–50 ml of iomeprol 350 mg I ml21, followed by 40–50 ml of saline injected at 4–5 ml s21. The CTP scan was initiated at 3 min after the start of adenosine infusion and was performed in dynamic acquisition mode for 30 s, while maintaining adenosine infusion. Dynamic CTP was performed by shuttling the table between the two alternating table positions with ECG-triggered mode for every other R–R interval. The anatomical coverage of this imaging technique was 73 mm with a 10% overlap between both acquisition ranges for a given detector width of 38 mm. 100 kV tube voltage and automatic tube current modulation technique (CARE Dose 4D) with 350 reference mAs per rotation were used for dynamic stress scan. After the ASDCTP scan, the adenosine infusion was discontinued immediately. This was followed by an interval of 5–10 min with monitoring of the patient’s heart rate. When the patient’s heart rate returned to baseline, CCTA was performed 1 min after sublingual administration of 0.4 mg of nitroglycerin. Beta-blockers were not administered before CCTA to reduce the time interval between stress CTP and rest CCTA. In our institute, oral betablockers are only available for use to patients undergoing CCTA. However, it takes at least 1 h to be effective. Retrospective ECGgated helical mode scan was performed with the full radiation dose window set at 68–78% of the R–R interval in patients with heart rates #70 bpm or 200–400 ms after the R peak in patients with a heart rate of .70 bpm. The minimum tube current with 4% of the full radiation dose (MinDose®; Siemens Medical Solutions, Forchheim, Germany) was applied to the remainder of the R–R interval to minimise radiation dose. The typical contrast dose for CCTA was 70–80 ml of iomeprol 350 followed by 40 ml of saline at 4–5 ml s21. The CT scan was initiated 9 s after the bolustracking trigger was activated in the ascending aorta with a trigger threshold of 100 Hounsﬁeld units. The acquisition parameters were 236430.6 mm detector collimation, resulting in 2312830.6 mm sections, 280 ms gantry rotation time and 100 kV tube potential and 330 mAs per rotation tube current time product. The scan range was from above the origin of the coronary arteries to below the dome of the diaphragm in the craniocaudal direction. Cardiac MRI Cardiac MRI was performed using a 1.5 T unit (MAGNETOM Avanto; Siemens Medical Solutions, Erlangen, Germany). For stress MR perfusion imaging, adenosine was injected intravenously at 0.14 mg kg21 min21) for 3 min before perfusion MRI and continued during perfusion MRI. Four short-axis slices (one each in the basal and apical levels, two in mid-ventricular levels) were obtained. Sequences were acquired immediately after the injection of gadobutrol (Gadovist®; Bayer Healthcare, Berlin, Germany) at 0.1 mmol per kilogram of body weight at an

Br J Radiol;86:20130481

BJR Received: 3 August 2013

Accepted: 20 November 2013

doi: 10.1259/bjr.20130484

Cite this article as: Zhang J-M, Zhao X-M, Wang S-J, Ren X-C, Wang N, Han J-Y, et al. Evaluation of molecular imaging. Br J Radiol 2014;87:20130484.

99m

Tc-peptide-ZHER2:342 Affibody® molecule for in vivo

FULL PAPER

Evaluation of 99mTc-peptide-ZHER2:342 Affibody® molecule for in vivo molecular imaging 1

J-M ZHANG, MD, PhD, 1X-M ZHAO, MD, PhD, 2S-J WANG, MD, 1X-C REN, MD, 1N WANG, MD, 1J-Y HAN, MD and 1L-Z JIA, MD

Department of Nuclear Medicine, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China Department of Tumor Imaging, the Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, China

Address correspondence to: Dr Shi-Jie Wang E-mail: shijiewang100@163.com

Shi-Jie Wang and Xin-Ming Zhao both contributed equally to this article.

Objective: The aim of this study was to develop an improved method for labelling ZHER2:342 with Technetium99m (99mTc) using Gly-(D) Ala-Gly-Gly as a chelator and to evaluate the feasibility of its use for visualization of HER2 expression in vivo. Methods: The Affibody® molecule ZHER2:342 was synthesized by Fmoc/tBu solid phase synthesis. The chelator, Gly-(D) Ala-Gly-Gly, was introduced by manual synthesis as the N-terminal extensions of ZHER2:342. ZHER2:342 was labelled with 99mTc. The labelling efficiency, radiochemical purity and in vitro stability of the labelled molecular probe were analysed by reversed-phase high performance liquid chromatography. Biodistribution and molecular imaging using 99mTc-peptide-ZHER2:342 were performed. Results: The molecular probe was successfully synthesized and labelled with 99mTc with the labelling efficiency of 98.10 6 1.73% (n 5 5). The radiolabelled molecular

probe remained highly stable in vitro. The molecular imaging showed high uptake in HER2-expressing SKOV3 xenografts, whereas the MDA-MB-231 xenografts with low HER2 expression were not clearly imaged at any time after the injection of 99mTc-peptide-ZHER2:342. The predominant clearance pathway for 99mTc-peptideZHER2:342 was through the kidneys. Conculsion: 99mTc-peptide-ZHER2:342 using Gly-(D) AlaGly-Gly as a chelator is a promising tracer agent with favourable biodistribution and imaging properties that may be developed as a radiopharmaceutical for the detection of HER2-positive malignant tumours. Advances in knowledge: The 99mTc-peptide-ZHER2:342 molecular probe is a promising tracer agent, and the results in this study provide a foundation for future development of protocols for earlier visual detection of cancer in the clinical setting.

The human epidermal growth factor receptor Type 2 (ErbB2), also known as HER2 or p185, is a transmembrane tyrosine kinase receptor. HER2 overexpression has been detected in a number of malignant tumours, such as carcinomas of the breast, ovary and prostate.1 Blocking of HER2 signalling using the monoclonal antibody trastuzumab (Herceptin) can improve the survival of patients with HER2-positive cancer.2 As not all tumours express HER2, an accurate method for detection of this marker is required to select patients who can beneﬁt from trastuzumab therapy.

the primary tumour and metastases. Moreover, it is not possible to biopsy tumours at all sites. Targeted radionuclide imaging may help to avoid such issues by visualizing HER2 expression in both primary tumours and metastases. Meanwhile, compared with traditional imaging techniques, such as MRI, CT and ultrasound imaging, radionuclide imaging is attractive because it speciﬁcally detects expression of tumour markers such as HER2 rather than gross anatomical changes.

Currently, the most widely used methods for evaluating receptor expression on tumours and metastases are immunohistochemical staining and fluorescent in situ hybridization of biopsy samples.3 However, the deficiencies in using biopsies are false-negative findings due to sampling errors and discordance in HER2 expression between

Monoclonal antibodies have often been used to target HER2 for radionuclide imaging, but slow uptake in tumours and slow blood clearance are well-recognized problems of these agents.4–6 Reduction of tracer molecular size is considered a promising way to improve imaging contrast by increasing the rates of tumour localization and clearance from blood and healthy tissues.7 The Afﬁbody® molecule ZHER2:342 is a 58-amino acid 3-helix bundle protein that originates from

BJR

J-M Zhang et al

the B-domain of the staphylococcal protein with a low molecular weight of about 7 kDa. ZHER2:342 has been reported to bind to the extracellular domain of HER2 with an affinity of 22 pM.8 ZHER2:342, labelled with 125I and 111In, can target HER2-expressing xenografts with high specificity.9,10 The labelling of this protein with 68Ga has also provided high-quality imaging of HER2expressing tumours in patients.11 In addition, radionuclides such as 18F, 186Re, 177Lu and Technetium-99m (99mTc) have been used to label Affibody molecules.12–14 Of note, HER2-binding Affibody molecules have been successfully developed and studied in conjunction with various radiolabels for diagnostic imaging applications. However, an optimal radiotracer is still not available. The aim of the study was to develop an improved method for labelling ZHER2:342 with 99mTc using Gly-(D) Ala-Gly-Gly as a chelator and to evaluate the feasibility of its use in the visualizing of HER2 expression in vivo. METHODS AND MATERIALS Peptide synthesis and characterization The Affibody molecule ZHER2:342 (VENKFNKEMRNAYWEIALL PNLNNQQKRAFIRSLYDDPSQSANLLAEAKKLNDAQAPK) was synthesized by Shanghai Science Peptide Biological Technology Co., Ltd, Shanghai, China. Fmoc/tBu solid phase synthesis was used on a peptide synthesizer with a substitution of 0.67% mmol g21. 10 molar equivalents of Fmoc-protected amino acids, 1hydroxybenzotriazole (HOBt) and 2-(1H-benzotriazol-1-yl)1,1,3,3-tetramethyluronium hexafluorophosphate, were used to activate equal molar equivalents of Fmoc-protected amino acid, and acetic anhydride was used to terminate peptides where acylation was incomplete. The Tc-chelating moieties were introduced to the N-terminal extensions of ZHER2:342 by manual synthesis. The N-terminal Fmoc protecting group was removed by incubation with 20% piperidine-N-methylpyrrolidone for 20 min. Peptides were released from solid support and deprotected by a 2-h incubation in trifluoroacetic acid (TFA):ethanedithiol:H2O:triisopropylsilane (94.0:2.5:2.5:1.0) followed by extraction with tert-butyl methyl ether:H2O (50:50) three times before filtration and lyophilization. At the N-terminus of the ZHER2:342 sequence, four amino acids (Gly-(D) Ala-Gly-Gly), forming an N4 configuration were used as a linker for coupling ZHER2:342 and 99mTc.15 In addition, one g-aminobutyric acid (g-Aba) was introduced as a barrier to prevent steric hindrance,

and then ZHER2:342 was labelled with 99mTc by the ligand exchange method as shown in Figure 1. To verify the identity of the peptide, reversed-phase high performance liquid chromatography (RP-HPLC) was performed. In addition, mass spectrometric analysis was carried out on a mass spectrometer (LCMS-2011; Shimadzu Corp., Kyoto, Japan) with an electrospray ionization source to confirm the protein mass. Radiolabelling with 99mTc To obtain 99mTc-pertechnetate, the 99Mo-99Tc generator (Beijing Atom HighTech Co., Ltd., Beijing, China) was eluted with sterile 0.9% sodium chloride. Before labelling, freeze-dried ZHER2:342 was dissolved in distilled water and stored at 220 °C. For labelling, 20 ml of ZHER2:342 (1 mg ml21) was mixed with 20 ml of 0.15 M NaOH to obtain the final pH of about 11. Thereafter, 35 ml of a solution of SnCl2·2H2O in 0.01 M HCl (1 mg ml21) was added, followed by 600 mL (370 MBq) of fresh 99mTc-pertechnetate solution. The mixture was lightly vortexed and incubated for 60 min at room temperature. The labelling efficiency and radiochemical purity of the labelled conjugate were analysed using RP-HPLC (Alltech 305, Deerfield, IL) using a 4.6 3 250 mm C18 column with a particle size of 5 mm, a 30-min gradient of 5–70% A (A: 0.1% TFA-CH3CN; B: 0.1% TFA-H2O) and a flow rate of 1 ml min21. In vitro stability analysis To assess the stability of the radiotracer in vitro, 99mTc-peptideZHER2:342 was incubated in saline or fresh human serum at 37 °C, and the stability of the radiotracer in vitro was evaluated at 1, 2, 4, 6 and 24 h by RP-HPLC using the same conditions as those for testing labelling efficiency above. Cell culture The HER2-expressing ovarian carcinoma cell line, SKOV-3 (displaying approximately 1.2 3 106 HER2 receptors per cell),16 and human breast carcinoma cell line, MDA-MB-231 with low HER2 expression (4 3 104 HER2 receptors per cell),17 were purchased from the Institute of Cell Biology of the Chinese Academy of Sciences (Shanghai, China). All cells were cultivated in Roswell Park Memorial Institute 1640 (RPMI 1640) medium supplemented with 10% foetal bovine serum (Invitrogen, Carlsbad, CA) under standard conditions (37 °C, humidified atmosphere containing 5% CO2). Cell growth was

Figure 1. Radiolabelling of peptide-ZHER2:342 with Technetium-99m (99mTc).

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Br J Radiol;87:20130484

BJR Received: 29 November 2013

Accepted: 23 January 2014

doi: 10.1259/bjr.20130781

Cite this article as: Hyland WB, McMahon SJ, Butterworth KT, Cole AJ, King RB, Redmond KM, et al. Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy. Br J Radiol 2014;87:20130781.

FULL PAPER

Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy 1

W B HYLAND, PhD, 2S J MCMAHON, PhD, 2K T BUTTERWORTH, PhD, 2,3A J COLE, MB BCh, MRCP, 1R B KING, PhD, K M REDMOND, PhD, 2K M PRISE, PhD, 1,2A R HOUNSELL, PhD and 1,2C K MCGARRY, PhD

2 1

Radiotherapy Physics, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, UK Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK 3 Clinical Oncology, Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, UK 2

Address correspondence to: Dr Wendy Bridget Hyland E-mail: wendy.hyland@belfasttrust.hscni.net

Objective: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, the incorporation of this dose at the planning stage of treatment has been suggested. Methods: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay of irradiated DU-145 prostate cancer, H460 non-small-cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging-to-treatment times of 7.5 and 15 min were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea–Catcheside dose protraction factor model.

Results: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact on cell survival. These findings were in close agreement with theoretical results. Conclusion: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy. Advances in knowledge: There is a paucity of data in the literature on imaging effects in radiotherapy. This article presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to-treatment times. The data provide a firm foundation for further study into this highly relevant area of research.

Radiotherapy is in a period of rapid scientific and clinical development. With the introduction of adaptive radiotherapy1 and the increasing use of high-precision techniques,2 there has been an increased requirement for verification imaging. Verification imaging can be carried out using megavoltage portal beams, kilovoltage planar fields or cone beam CT (CBCT) using kilovoltage or megavoltage beams. Dependent on the imaging technique employed, the dose required to acquire an image of adequate quality can vary significantly. Whilst doses ranging from a few centigrays to 10 cGy are required for megavoltage portal imaging and CBCT, doses in the order of megagrays are typically required to obtain an image of adequate quality using kilovoltage planar imaging.3 The choice of imaging modality is dictated by the available technology, with megavoltage portal imaging being the most established imaging option. However, with the addition of on-board kilovoltage imaging systems, kilovoltage

imaging options are becoming much more widespread both for their improved image contrast and reduced patient dose.4 Associated with this increasing imaging dose burden are concerns regarding the increased risk of deterministic and stochastic effects due to increased radiation exposure.3,5–7 Whilst it is important to quantitatively determine the longterm effects of increased concomitant exposures, it is equally important to determine any potential changes to the effectiveness of the therapeutic dose.5,8–10 Low-dose biological phenomena such as adaptive responses11–13 and bystander signalling14–17 hold the potential to significantly alter the response of cells to radiation and thus treatment efficacy. However, since these effects tend to occur over a period of hours, it is unlikely that they will have any significant impact with regard to imaging in the

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WB Hyland et al

Table 1. Average imaging-to-treatment times (tI–T) and overall treatment times (OTT) determined from a clinical audit of 30 prostate and pelvic node intensity-modulated radiotherapy (IMRT) patients and 30 prostate three-dimensional conformal radiotherapy (3DCRT) patients

tI–T 6 SD (min)

Upper 95% CI (tI–T)

OTT 6 SD (min)

Upper 95% CI (OTT)

IMRT

8.56 6 3.62

15.67

14.93 6 4.4

23.55

3DCRT

8.18 6 5.25

18.48

11.48 6 5.62

22.48

Treatment type

CI, confidence interval; SD, standard deviation associated with the calculated values.

treatment room.18 By contrast, sublethal damage repair that can occur over a period of minutes may be of signiﬁcance in radiotherapy when the dose delivered from imaging beams is incorporated with the prescribed therapeutic dose at the treatment planning stage.9,10,19–22

The effect of imaging dose incorporation was previously reported in a preliminary study by Yang et al.10 In particular, they showed an unexpected 12.6% increase in cell survival when H460 cells were exposed to a pre-treatment imaging dose of 5 cGy followed by a therapeutic dose of 200 cGy, they attributed

Figure 1. (a) An image of the irradiation set-up. (b) A schematic representation of the experimental set-up. The cells were irradiated at 4.8 cm deep in a custom-made polymethyl methacrylate phantom, with 5 cm of backscatter. (Inset) the dose profile across the three flasks at the cell level, acquired using a two-dimensional matrix ion chamber array at an effective depth of 5 cm.

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Br J Radiol;87:20130781

BJR Received: 29 May 2013

Accepted: 31 July 2013

doi: 10.1259/bjr.20130310

Cite this article as: ¨ tterer JJ, van Strijen MJL, Hoogeveen YL, de Lange F, et al. Cone beam CT guidance provides superior accuracy for Busser WMH, Braak SJ, Fu complex needle paths compared with CT guidance. Br J Radiol 2013;86:20130310.

FULL PAPER

Cone beam CT guidance provides superior accuracy for complex needle paths compared with CT guidance ¨ W M H BUSSER, MSc, 2S J BRAAK, MD, 1J J FUTTERER, MD, PhD, 2M J L VAN STRIJEN, MD, PhD, 1Y L HOOGEVEEN, PhD, F DE LANGE, PhD and 1L J SCHULTZE KOOL, MD, PhD

1 1 1

Department of Radiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands Department of Radiology, St. Antonius Hospital Nieuwegein, Nieuwegein, Netherlands

Address correspondence to: Ms Wendy M H Busser E-mail: w.busser@rad.umcn.nl

Objective: To determine the accuracy of cone beam CT (CBCT) guidance and CT guidance in reaching small targets in relation to needle path complexity in a phantom. Methods: CBCT guidance combines three-dimensional CBCT imaging with fluoroscopy overlay and needle planning software to provide real-time needle guidance. The accuracy of needle positioning, quantified as deviation from a target, was assessed for inplane, angulated and double angulated needle paths. Four interventional radiologists reached four targets along the three paths using CBCT and CT guidance. Accuracies were compared between CBCT and CT for each needle path and between the three approaches within both modalities. The effect of user experience in CBCT guidance was also assessed. Results: Accuracies for CBCT were significantly better than CT for the double angulated needle path (2.2 vs 6.7 mm, p,0.001) for all radiologists. CBCT guidance showed no significant differences between the three

approaches. For CT, deviations increased with increasing needle path complexity from 3.3 mm for the inplane placements to 4.4 mm (p50.007) and 6.7 mm (p,0.001) for the angulated and double angulated CT-guided needle placements, respectively. For double angulated needle paths, experienced CBCT users showed consistently higher accuracies than trained users [1.8 mm (range 1.2–2.2) vs 3.3 mm (range 2.1–7.2) deviation from target, respectively; p50.003]. Conclusion: In terms of accuracy, CBCT is the preferred modality, irrespective of the level of user experience, for more difficult guidance procedures requiring double angulated needle paths as in oncological interventions. Advances in knowledge: Accuracy of CBCT guidance has not been discussed before. CBCT guidance allows accurate needle placement irrespective of needle path complexity. For angulated and double-angulated needle paths, CBCT is more accurate than CT guidance.

Needle guidance for puncture or other minimally invasive procedures is increasing in standard interventional radiology practice. In local therapy procedures, such as percutaneous ablations, accurate placement of one or more needles is important in order to provide effective treatment [1]. This is especially the case in treatment or biopsy procedures of small lesions, in which the tip of the needle needs to be placed within a range of millimetres of the target point. Therefore, image guidance plays a signiﬁcant role in accurate percutaneous needle placement [2].

radiation dose to the patient and operator [4]. Acquiring CT ﬂuoroscopy images to check needle position takes approximately 1 s, time in which the needle cannot be progressed.

Currently, most needle placement procedures are performed using CT guidance, ﬂuoroscopy or ultrasound [3]. CT images provide good visualisation of the target and surrounding tissues. For needle guidance, however, CT has limitations mainly because it does not allow real-time feedback on needle progression. For semi-real-time imaging within the CT scanner, CT-ﬂuoroscopy can be used at the expense of a higher

Fluoroscopy in the angiography suite, however, provides optimal patient accessibility and real-time imaging of needle progression but is limited to two-dimensional visualisation. A radiation-free technique that also provides real-time imaging is ultrasound. However, the accuracy is operator dependent and, owing to ultrasound’s low penetration depth, the area of use is restricted to superﬁcial targets and moderate-sized patients [3]. New techniques combining cone beam CT (CBCT) and ﬂuoroscopy with dedicated needle guidance software within an angiography C-arm system aim to overcome the disadvantages of CT and allow real-time three-dimensional needle guidance in the interventional suite [5].

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W M H Busser, S J Braak, J J F¨ utterer et al

Several authors described the use of this CBCT with navigational tools in various types of procedures [6–19]. Braak et al [8] described the effective patient dose of CBCT guidance procedures to be reduced by 13–42% compared with CT guidance for abdominal and thoracic procedures. Other authors reported diagnostic accuracies of CBCT guidance to be comparable to or higher than other guidance modalities [14–16, 20–22]. However, until now, the accuracy of CBCT guidance for reaching small (millimetre-sized) targets has not been addressed speciﬁcally.

Figure 1. Outline of the interventional three-dimensional abdominal phantom showing an internal target (black dot) and three corresponding needle paths: dotted/dashed line, inplane path; dashed line, angulated path; and solid line, double angulated path. Grey spots represent the corresponding skin entry points. The axes indicate the right (R), head (H) and anterior (A) sides of the phantom.

In clinical practice, the used needle path is determined based on the location of the target tissue and its surrounding structures. A safe needle path avoids puncturing critical structures such as large vessels or nerves. For CT imaging ease, an inplane needle path is often used. However, this might not always be the safest path. In those cases, a more complex needle path would be more suitable, complicating accurate needle placement. The purpose of our phantom study was to determine and compare the accuracy of CBCT and CT guidance in reaching small targets by paths with different levels of complexity under standardised conditions. MATERIALS AND METHODS Phantom To analyse accuracy, a modified model 057 Interventional 3D Abdominal Phantom (CIRS Inc., Norfolk, VA) was used for simulating abdominal needle placements in a standardised setting. The phantom represents a small adult abdomen (range T9/ T10–L2/L3) and consists of materials mimicking tissues in CT imaging. Four 2.3 mm spheres (CT spots #119; Beekley, Bristol, UK) acting as targets were randomly spread in the phantom. The targets were spread roughly in the centre of the phantom at depths of 84, 98, 117 and 125 mm from the anterior phantom side. This represents a wide range of clinical targets in the abdomen, such as liver or kidney lesions. Needle placement procedure The procedures were performed using CBCT guidance (XperGuide; Allura Xper FD-20 Angio system, Philips Medical Systems, Best, Netherlands) and CT guidance (Siemens SOMATOM® Sensation 16 CT scanner; Siemens, Erlangen, Germany). Each of the four targets was reached with an 18G, 20 cm long Trocar EchoTip Needle (COOK Medical, Bloomington, IN) following three paths with different degrees of difficulty (Figure 1). First was an inplane path in which the skin entry point and the target were in the same axial plane and on a vertical line (direction of A-axis, Figure 1). The second path followed an angulated line in one axial plane (R/A plane in Figure 1). For the third and most difficult needle path, the skin entry point and target were located on a double angulated line, which means an angulated needle path crossing several axial scanning slices. Four experienced interventional radiologists (JJF, SJB, MJLVS, LJSK) were asked to reach all four targets along the three paths, as with a clinical procedure, on both modalities. They were allowed to redirect the needle towards the target but without pulling back, as this is not desirable in clinical practice owing to resulting trauma to tissue. All radiologists are experienced users of CT guidance (SJB, JJF, .5 years; MJLVS, LJSK, .10 years). All four had

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received hands-on training using the CBCT guidance software by a representative of the company and were given the opportunity to practice. There were, however, differences in the level of clinical experience with the guidance software. Two radiologists had performed only a few clinical guidance procedures (i.e. JJF, LJSK, ,10), whereas two (SJB, MJLVS) had performed over 200. A slightly different path was chosen for each puncture to avoid placing the needle in a previously followed path possibly still present in the phantom material. The precise angle of the needle path does not influence or determine the difficulty of the needle placement; however, the direction of the angulation does (inplane angulated vs angulated through several axial planes). The inplane needle paths had a mean length of 106 mm (range 84–125 mm) and no angulation in the axial plane. The angulated needle paths had a mean length of 142 mm (range 106–167) and angulations in the axial plane of 30°, 50°, 60° or 70° for the different targets. The double angulated needle paths had a mean length of 145 mm (range 128–184 mm) and angulations of 30°, 40° or 50° in the axial plane and 15°, 20° or 25° in the sagittal plane. Cone beam CT The CBCT guidance procedure commenced with acquisition of a CBCT scan (312 projections over 240°) and reconstruction of a three-dimensional (3D) data set. In this 3D data set, both target and skin entry point were defined by the interventional radiologist so as to create a safe needle path. The 3D data set with planned needle path was subsequently overlaid with the real-time fluoroscopy images and the projection followed the movements of the C-arm [5,6]. This allowed real-time visualisation of needle position and progression towards the target point.

Br J Radiol;86:20130310

BJR Received: 30 July 2013

Accepted: 22 January 2014

doi: 10.1259/bjr.20130472

Cite this article as: Abdul Rashid SN, Mohamad Saini SB, Abdul Hamid S, Muhammad SJ, Mahmud R, Thali MJ, et al. Walking on thin ice! Identifying methamphetamine “drug mules” on digital plain radiography. Br J Radiol 2014;87:20130472.

FORENSIC RADIOLOGY SPECIAL FEATURE: FULL PAPER

Walking on thin ice! Identifying methamphetamine “drug mules” on digital plain radiography 1,2

S N ABDUL RASHID, MD, 1S B MOHAMAD SAINI, MD, 1S ABDUL HAMID, MD, 3S J MUHAMMAD, MD, 1R MAHMUD, MD, M J THALI, MD and 4,5P M FLACH, MD

4 1

Department of Radiology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor, Malaysia Institute of Forensic Medicine, Kuala Lumpur Hospital, Kuala Lumpur, Malaysia 3 Department of Radiology, Hospital Serdang, Selangor, Malaysia 4 Institute of Forensic Medicine, University of Zurich, Winterthurerstrasse, Zurich, Switzerland 5 Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, Zurich, Switzerland 2

Address correspondence to: Dr Patricia M. Flach E-mail: patricia.flach@irm.uzh.ch

Objective: The purpose of this study was to retrospectively evaluate the sensitivity, specificity and accuracy of identifying methamphetamine (MA) internal payloads in “drug mules” by plain abdominal digital radiography (DR). Methods: The study consisted of 35 individuals suspected of internal MA drug containers. A total of 59 supine digital radiographs were collected. An overall calculation regarding the diagnostic accuracy for all “drug mules” and a specific evaluation concerning the radiological appearance of drug packs as well as the rate of clearance and complications in correlation with the reader’s experience were performed. The gold standard was the presence of secured drug packs in the faeces. Results: There were 16 true-positive “drug mules” identified. DR of all drug carriers for Group 1 (forensic imaging experienced readers, n 5 2) exhibited a sensitivity of 100%, a mean specificity of 76.3%, positive predictive value (PPV) of 78.5%, negative predictive value (NPV) of 100% and

a mean accuracy 87.2%. Group 2 (inexperienced readers, n 5 3) showed a lower sensitivity (93.7%), a mean specificity of 86%, a PPV of 86.5%, an NPV of 94.1% and a mean accuracy of 89.5%. The interrater agreement within Group 1 was 0.72 and within Group 2 averaged to 0.79, indicating a fair to very good agreement. Conclusion: DR is a valuable screening tool in cases of MA body packers with huge internal payloads being associated with a high diagnostic insecurity. Diagnostic insecurity on plain films may be overcome by low-dose CT as a cross-sectional imaging modality and addressed by improved radiological education in reporting drug carriers on imaging. Advances in knowledge: Diagnostic signs (double-condom and halo signs) on digital plain radiography are specific in MA “drug mules”, although DR is associated with high diagnostic insecurity and underreports the total internal payload.

For the past decade, signiﬁcant worldwide manufacturing of amphetamine-type stimulants has been reported to the United Nations Ofﬁce on Drugs and Crime, Vienna, Austria, with a predominance of methamphetamine (MA) and its derivatives, which are also known as “syabu” or “ice”, throughout East and South East Asia.1 In this region, the use of this synthetic drug is more prevalent than that of cocaine or heroin, which are more common in relatively developed areas, such as Europe and the USA.2 During the course of this development, an increase in the number of drug carriers being intercepted by law enforcement at the borders of Malaysia has been observed. Drug carriers or “drug mules” are generally referred to as a human harbouring internal illicit drug packet(s). Internal body concealment of illegal drugs is one of the methods used to smuggle this illicit drug across the border.3,4 “Drug mules”

are generally known as body packers.5,6 However, for correct terminology, one should differentiate between the terms body packer, body pusher and body stuffer. A body packer swallows a large amount of specially prepared drug packets to smuggle the packets in their gastrointestinal tract across a national border.5,6 A body pusher hides a few containers in easily accessible body cavities, such as the rectum or vagina. Body stuffers, including trafﬁckers and users, ingest intentionally small amounts of loosely wrapped drug pellets (typically initially hidden in the mouth), usually immediately before an unexpected encounter with law enforcement.5–10 The generally accepted radiological examination is a plain abdominal radiograph in the supine projection.4–6 This technique is widely available at a low cost and is a simple

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method of detecting drug-filled packets within the alimentary tract. Radiation exposure to the patient is relatively moderate. In the literature, the detection rate for drug-filled packets is highly variable, and sensitivities from 58.3% to 90% have been reported.4,5,11 Hence, plain abdominal radiography is a flawed screening method for identifying “drug mules”. Examining the bowel for foreign bodies, such as drug containers with variable sizes and radiodensities, is problematic, even for an experienced radiologist because the drug-filled packets may have an appearance similar to that of stool and gas and may be superimposed. Specific appearances described in the literature, such as the “double-condom”, “halo” and “rosette” signs, may be diagnostic for drug packages but are not necessarily so.4–6,11–13 Other modalities employed worldwide for the identification of body packers include CT, ultrasound, MRI and low-dose linear slit digital radiography (LSDR or LODOX®; Lodox Systems, Johannesburg, South Africa).4,5,14–18 Recent research has mainly concentrated on cocaine and heroin drug trafficking, which occurs predominantly in Western

SN Abdul Rashid et al

countries.3,4,6,7,11,14,19 There is little research on the accuracy of plain abdominal radiography in MA drug carriers, although there has been a significant increase of MA in Asia, accompanied by draconian legal measures in cases of drug trafficking.1,2 The purpose of this study was to retrospectively evaluate the sensitivity, specificity and accuracy of plain abdominal digital radiography (DRL) for identifying the internal payloads of MA in “drug mules”. METHODS AND MATERIALS Approval was obtained from the ethics committee and the institutional review board. A retrospective evaluation of the radiology information system database of all acquired images in cases of alleged drug packing between August 2009 and October 2010 yielded 35 suspects. The inclusion criteria were adult suspected drug carriers with internal MA who were brought to the emergency department by the police. Exclusion criteria were incomplete documentation, internal illicit drugs other than MA, discharge to another centre, imaging positioning other than supine and paediatric cases.

Figure 1. Flow diagram for a comprehensive overview of the study population, regarding the obtained images. DR, digital radiography.

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Br J Radiol;87:20130472

BJR Received: 26 March 2013

doi: 10.1259/bjr.20130176 Revised: 22 May 2013

Accepted: 29 May 2013

© 2013 The Authors. Published by the British Institute of Radiology under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported License http://creativecommons.org/licenses/by-nc/3.0/, which permits unrestricted noncommercial reuse, provided the original author and source are credited.

Cite this article as: Wang X, Zhang X, Li X, Amos RA, Shaitelman SF, Hoffman K, et al. Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? Br J Radiol 2013;86:20130176.

FULL PAPER

Accelerated partial-breast irradiation using intensity-modulated proton radiotherapy: do uncertainties outweigh potential benefits? 1

X WANG, PhD, 1X ZHANG, PhD, 1X LI, BS, 1R A AMOS, MSc, 2S F SHAITELMAN, MD, 2K HOFFMAN, MD, 1R HOWELL, PhD, M SALEHPOUR, PhD, 1S X ZHANG, PhD, 1T L SUN, MS, 2B SMITH, MD, 2W TEREFFE, MD, 2G H PERKINS, MD, 2 T A BUCHHOLZ, MD, 2E A STROM, MD and 2W A WOODWARD, MD, PhD 1

Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Address correspondence to: Dr Wendy A. Woodward E-mail: wwoodward@mdanderson.org

Objective: Passive scattering proton beam (PSPB) radiotherapy for accelerated partial-breast irradiation (APBI) provides superior dosimetry for APBI three-dimensional conformal photon radiotherapy (3DCRT). Here we examine the potential incremental benefit of intensity-modulated proton radiotherapy (IMPT) for APBI and compare its dosimetry with PSPB and 3DCRT. Methods: Two theoretical IMPT plans, TANGENT_PAIR and TANGENT_ENFACE, were created for 11 patients previously treated with 3DCRT APBI and were compared with PSPB and 3DCRT plans for the same CT data sets. The impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields of IMPT plans was evaluated. Results: IMPT plans for APBI were significantly better regarding breast skin sparing (p,0.005) and other normal tissue sparing than 3DCRT plans (p,0.01) with

comparable target coverage (p5ns). IMPT plans were statistically better than PSPB plans regarding breast skin (p,0.002) and non-target breast (p,0.007) in higher dose regions but worse or comparable in lower dose regions. IMPT plans using TANGENT_ENFACE were superior to that using TANGENT_PAIR in terms of target coverage (p,0.003) and normal tissue sparing (p,0.05) in low-dose regions. IMPT uncertainties were demonstrated for multiple causes. Qualitative comparison of dose– volume histogram confidence intervals for IMPT suggests that numeric gains may be offset by IMPT uncertainties. Conclusion: Using current clinical dosimetry, PSPB provides excellent dosimetry compared with 3DCRT with fewer uncertainties compared with IMPT. Advances in knowledge: As currently delivered in the clinic, PSPB planning for APBI provides as good or better dosimetry than IMPT with less uncertainty.

Accelerated partial-breast irradiation (APBI) limits the radiation target to the volume surrounding the surgical cavity and reduces the treatment time from 3–7 weeks to 1 week or less. APBI is considered to be an appropriate alternative to whole-breast irradiation for early stage breast cancer in selected patients [1], although recent studies have highlighted the potential risks of ﬁrst generation catheter-based therapies and photon-based external beam approaches [2,3]. To date, APBI therapy has been reported using multiple catheter-based approaches, using external beam conformal therapy with photons or protons and using interstitial brachytherapy techniques [4–10].

which the proton beam is typically spread out laterally via a double scattering system and longitudinally along the beam axis via a rotating modulator wheel [17]. Although PSPB has been shown to significantly reduce the radiation dose delivered to normal breast tissue, lungs and heart compared with photon three-dimensional conformal radiotherapy (3DCRT) [11–16], it has the potential disadvantage of delivering close to 100% of the prescribed dose to the skin for each beam. Indeed, higher rates of skin toxicity were reported in the literature with PSPB APBI [13], although dose, planning and delivery factors may have influenced this. Using deliberate multibeam configuration arrangements and planning, PSPB plans can render skin-sparing in highdose regions comparable with 3DCRT plans [11,13,16] and have low reported skin toxicity [11]. This affords

Several researchers have investigated APBI using passive scattering proton beam (PSPB) radiotherapy [11–16] in

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a highly conformal non-invasive APBI treatment that achieves comparable normal tissue sparing expected from catheterbased approaches with the homogeneity of photon-based approaches. Although 100% skin doses using PSPB may be clinically acceptable, given a report of significant skin toxicity with this approach with a slightly different dose per fractionation than has been typically used for bid 3DCRT with photons [4 Gy (relative biological effectiveness; RBE) per fraction vs 3.85 Gy in 10 fractions], we investigated the potential benefit for reducing skin dose using APBI delivered with intensity-modulated proton radiotherapy (IMPT). IMPT is delivered via a scanning proton pencil beam, which paints the treatment target spot-by-spot, using scanning magnets to control lateral spot location and varying initial proton energy to control spot depth [18]. The scanning proton beam permits greater proximal conformity than PSPB if the target is deep enough, thereby permitting additional skin sparing compared with PSPB. In addition, the intensities and energies of all pencil beams can be optimised simultaneously in IMPT plans according to user-defined objectives that take into account target and normal-tissue constraints. As such, the dose distribution of IMPT plans can be shaped to potentially achieve higher conformity than PSPB and thereby better spare normal tissue. However, studies of clinical use of IMPT are limited and significant uncertainties must be considered and weighed against the potential benefits. To our knowledge, no investigations of IMPT for APBI have been reported thus far. In this paper, we compare IMPT with both PSPB and 3DCRT for APBI and evaluate the impact of range, motion and set-up uncertainties as well as scanned spot mismatching between fields for IMPT plans with two different beam configurations. METHODS AND MATERIALS CT scanning, treatment planning and dose distribution The CT data sets for 11 patients who underwent APBI at our institution—10 who received photon 3DCRT as per the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/ Radiation Therapy Oncology Group (RTOG) 0413 trial [19] and 1 who received photon and electron (not permitted on NSABP B-39/RTOG 0413) 3DCRT off protocol—were retrospectively selected and replanned using PSPB [16] and IMPT. The CT images were obtained at 2.5-mm slice thickness through the region of interest. All patients were in the supine position with the ipsilateral upper extremity abducted and head rotated slightly towards the contralateral side. The definition of clinical target volume (CTV) followed NSABP B-39/RTOG 0413 guidelines, i.e. uniformly expanding lumpectomy 1.5 cm but no shallower than breast skin and no deeper than the anterior chest wall and pectoralis muscles. In addition to all normal structures defined in the NSABP B-39/RTOG 0413 trial, the breast skin and ipsilateral normal (non-target) breast tissue were contoured for each patient. The “breast skin” in this analysis was defined as a rind of tissue from the ipsilateral breast surface outlined to a depth of 5 mm. The “ipsilateral normal breast” was defined as the ipsilateral breast volume (i.e. breast glandular tissue included in standard whole-breast irradiation fields) excluding the CTV to highlight the dose to the non-target breast.

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X Wang, X Zhang, X Li et al

The 3DCRT plans were designed using the Pinnacle (Philips Medical System, Mipitas, CA) treatment planning system (TPS). The three to five coplanar and non-coplanar beams using 6 MV and 18 MV photons were generated based on patient-specific anatomy and target location. A multileaf collimator was used to manually optimise the plan to maximise the target coverage and minimise normal tissue doses. For the mixed-modality plan, multiphoton beams were designed with an en face electron beam. The target dose and the specified normal tissue constraint followed NSABP B-39/RTOG 0413 protocol. All 3DCRT plans were reviewed and approved by seven breast cancer radiation oncologists in a routine clinical quality assurance conference and used for patient treatment. The proton plans were designed using the Eclipse™ (Eclipse Proton, Varian Medical Systems Inc., Palo Alto, CA) TPS and proton beam lines of the Hitachi PROBEAT™ (proton beam therapy system; Hitachi Ltd, Tokyo, Japan) at our institution. To equalise dose and planning across modalities for the sake of comparison, the prescription dose was 38.5 Gy (RBE) for 10 fractions for all planning studies [in practice PSPB patients treated on a Phase II protocol at our institution are prescribed 34 Gy (RBE) in 10 fractions]. Three to four beams were used for plans using PSPB. Each beam entrance was designed to have minimal overlap on the patient surface to reduce the skin dose when feasible. The proximal and distal margins along each beam axis were designed using Moyer’s formula [20], although less may be feasible in clinical practice for breast given the tissue homogeneity and similarity to unit density. Radial margins were designed to cover 1 cm expansion of CTV (i.e. accounts for the lateral set-up uncertainties of breast irradiation using protons, followed the definition in NSABP B-39/RTOG 0413 for planning target volume (PTV)_eval for consistency). Two IMPT plans with different beam configurations were designed for each patient. One plan used two tangential beams (TANGENT_PAIR), and the other plan used one tangential beam and one en face beam (TANGENT_ENFACE). Although the correct PTV concept for proton planning is beam specific, it is technically impossible to design a single volume a priori in which to place spots that accounts for range uncertainties for multidirectional beams. As such, an approximation spot grid volume was used. The maximum and minimum energies for each beam were determined using distal and proximal margins of the 1 cm expansion of CTV. The radial margin was set to 1.0 cm. The determination of distal, proximal and radial margin of the beam followed the definition in NSABP B-39/ RTOG 0413 for PTV_eval. This creates a comparable volume with the 3DCRT plans but skews the results in favour of 3DCRT as this is undoubtedly larger than needed distally for a shallow target. A 6.7-cm range shifter, as used with the Hitachi PROBEAT delivery system, was included in each beam path to ensure target coverage on the proximal edge. An inverse planning technique and a simultaneous spot optimisation algorithm was used to generate all IMPT plans. To further level the comparison between planning modalities, all plans were normalised for comparable coverage of the PTV_eval. In practice, prescribing to a PTV_eval would be inappropriate. PSPB coverage should be evaluated beam-bybeam, radially, distally and proximally. IMPT plans at this

Br J Radiol;86:20130176

About the journal

We hope you enjoyed reading this collection of influential articles from recent issues of BJR. BJR is an international, multidisciplinary journal covering the clinical and technical aspects of medical imaging, radiotherapy, oncology, medical physics, radiobiology and the underpinning sciences.

READ The full archive of BJR articles are available at birpublications.org/bjr. BJR articles more than 12 months old, back to 2009, are freely available. The Digital Journal Archive (1896â&#x20AC;&#x201C;2008) is available to purchase on pay per view if you do not have access through BIR membership or an institutional subscription. BIR members should access BJR through the members area on bir.org.uk.

CITE The correct Index Medicus abbreviation for BJR is: Br J Radiol

SUBMIT Like the sound of BJR? Submit your next paper to us. Instructions for authors: birpublications.org/page/ifa/bjr Submit your paper online: editorialmanager.com/bjr

CONTACT General publications@bir.org.uk

Editorial For enquiries related to BJR manuscript submissions and peer review: bjroffice@bir.org.uk

Production For enquiries related to BJR manuscripts accepted for publication: bjrproduction@bir.org.uk

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You’ve probably heard of the British Institute of Radiology (BIR); after all, we’re the oldest radiological society in the world. What you may not know is that we are a thriving and developing membership organisation for every member of your team. Whether you are a radiologist, medical physicist, oncologist, radiographer, sonographer or medical technologist, there is a place for you at the BIR. Some of our members tell us they join because they can learn and network with other disciplines. Others join for free online access to BJR. Many of our members benefit from CPD opportunities; we have a fantastic range of educational events, from regional events to our Annual Congress. You don’t have to travel to take advantage of our education portfolio as we now offer videos of our key event lectures and webinars via our website, www.bir.org.uk. We pride ourselves on our active special interest groups, which reflect the interests of our members, including specialties such as clinical imaging, radiotherapy oncology and radiation protection. Members can get involved in these groups and add to the multidisciplinary discussion forum that supports the BIR’s educational, publishing, communications and membership output. The BIR has a rich and interesting history and we are committed to providing high-quality benefits for our diverse and multidisciplinary audience, with new membership benefits such as access to the recently launched BJR archive, and e-learning, BIR diplomas and more coming soon. There’s never been a better time to join the BIR! Jacqueline Fowler CEO | The British Institute of Radiology

Impact of BIR accredited radiation protection course in Kitale Hospital Radiographer Jeanette Snowden talks about the impact of delivering a BIR accredited radiation protection course to peers in Kitale Hospital, Kenya.

“In April 2013 I was approached by EGHO (Exploring Global Health Opportunities), who wanted an imaging service delivered to theatres in Kitale District Hospital, West Kenya. The hospital required an image intensifier (II) and an educational package, and the trip was planned for November 2013…. …. Engaging the local radiographers and the theatre staff in the safe use of the II and radiation protection (RP) was essential to the delivery of the project, and I believed a certified course, accredited by the BIR, would be the key to its success. …. I wrote an RP course, to include a practical session for the radiographers, an exam, safety signage and the all-important certificates. Rather brilliantly, the BIR accredited it. (Once there) I delivered the RP practical training over a few days… the Powerpoint presentation was attentively received by 23 candidates (3 radiographers, 15 doctors and all of the theatre staff), all crammed into a tiny staff room at 8.30am. I tested their prior and post-course knowledge, and am happy to report that all candidates significantly improved their RP knowledge. …. Kitale District Hospital now has an imaging service in theatre, delivered by local professionals who have completely engaged in education accredited by the BIR.”

48–50 St John Street, London, EC1M 4DG T: +44 (0)20 3668 2220 E: admin@bir.org.uk Registered charity number: 215869

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/britishinstituteofradiology The British Institute of Radiology

BIR/Philips Student Bursary award winner tells her story Dr Katharine Kenny, winner of the 2013 BIR/Philips Student Bursary award, fills us in on using her bursary for a placement in the Orkneys. “I applied for the BIR/Philips Student Travel Bursary to provide financial help towards my planned placement in the Orkney Islands. I was delighted to be awarded the bursary, which was a great help in enabling me to travel to the islands in August and September 2013. Having only worked in large city trusts, my aim was to see how radiology services are adapted to suit the particular challenges and opportunities of a small population and a remote and island-based topography. Some of the differences in terrain were obvious from the outset: on my first day, a combination of sea fog and industrial action prevented one of the sonography team from getting to work! Other differences became clearer as my placement progressed: for example, the highly efficient and well-thought-through communication system.

Winners of the BJR 2014 cover competition announced!

The patient transport system is also very impressive, for both emergency and non-emergency patients. Ferry services, scheduled flights and air ambulances, both fixed wing and helicopter, are all taken into account and included in the way Orcadian radiography is run. I would like to thank the Balfour Hospital Radiography team for their kindness and welcome.“ You can find our more about our BIR/Philips Student Travel Bursary and our other awards such as the BIR/Philips Excellence Award at www.bir.org.uk/professional-resources.

We were overwhelmed by the quality of responses to the BJR 2014 cover competition, and could not pick just one winning entry.

Here’s one of our winning entries, featuring the image submitted by Celi Andrade "Corpus callosum tractrography". Watch this space to see the other winning entries, and for information about the BJR 2015 cover competition!

BIR hosts X-ray artist reception at OXO Gallery BIR members, corporate subscribers and colleagues from our sister societies gathered to enjoy an exhibition by BIR Artist in Residence Hugh Turvey. As the BIR “Artist in Residence”, Hugh brings art and science together and promotes the aesthetic of medical images through exhibitions, workshops, talks and BIR partnerships, as well as exploring their potential for improving the patient experience. Hugh Turvey is an artist with an international reputation, and his work is held in public and private collections throughout the world. 48–50 St John Street, London, EC1M 4DG T: +44 (0)20 3668 2220 E: admin@bir.org.uk Registered charity number: 215869

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/britishinstituteofradiology The British Institute of Radiology

Do you have a passion for radiology, radiation oncology and the underlying sciences? The British Institute of Radiology is the multidisciplinary membership organisation ology. for people working in imaging science and radiation technology. Our members come from all disciplines and include radiographers, medical physicists, radiologists, oncologists, nurses, sonographers, doctors, clinical and medical technologists, students and trainees.

Ove 88% o r memb f our ers wo recomm ul end th d e BIR to colleag ues

Why join?

Membership categories

• Education

Consultant All other medical and scientiﬁc staff

• Free access to BJR • Discounts on events and publications

Reduced rates for

• Special interest groups (SIGs)

• retired members • international members • trainee members

• Networking opportunities

FREE for full-time students

• Information and online resources

Join online www.bir.org/join-us 48–50 St John Street, London, EC1M 4DG T: +44 (0)20 3668 2220 E: admin@bir.org.uk Registered charity number: 215869

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/britishinstituteofradiology The British Institute of Radiology

EDUCATION AND EVENTS Opportunities to enhance your CPD portfolio The BIR offers a wide range of engaging educational events aboutt radiation science pertaining to health and disease.

ts even r u O PD are C ed dit accre

Our educational programme challenges and engages attendees through interactive workshops, hands-on training courses, proffered presentations, monthly webinars, as well as the traditional lecture format. We believe in the importance of research and education, and we promote collaboration and the sharing of knowledge and understanding.

Take a look at our online education portal BIR SPECT/CT symposium Dr Neeraj Purohit, trainee radiologist at University Hospital, Southampton “As someone with little nuclear medicine experience, I found the day extremely interesting and it was pitched just at the right level. This course would appeal to radiologists, nuclear medicine physicians, technicians, radiographers and trainees. The day very much had a clinical ﬂavour. There was enough physics and information on the technical aspects of SPECT/CT to cater for the diverse audience that attended. Topics such as malignant bone disease, infection and orthopaedics were covered. Tips on reporting MSK CT and MRI for SPECT/CT reporters were provided in several comprehensive talks. I was sat besides a nuclear medicine technician and a student medical physicist, both of whom found the day very interesting. The day consisted of 13 talks given by a great mix of published eminent presenters from UK and Europe who spoke passionately about their ﬁeld. I was provided with clear indications from experienced practitioners over the course of the day as to how SPECT/CT can best be utilised in conjunction with other imaging modalities. All of the speakers I approached during the breaks were very receptive to my questions and even offered advice regarding training in nuclear medicine.”

Browse our forthcoming events www.bir.org.uk/education-and-events 48–50 St John Street, London, EC1M 4DG T: +44 (0)20 3668 2220 E: admin@bir.org.uk Registered charity number: 215869

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www.bir.org.uk

/britishinstituteofradiology The British Institute of Radiology

BEST OF

BJR

BEST OF

AN INTERNATIONAL JOURNAL OF RADIOLOGY, RADIATION ONCOLOGY AND ALL RELATED SCIENCES

The oldest radiology journal in the world Acceptance to publication 4 weeks Open access option

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BJR

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