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Applications of magnetic resonance spectroscopy in radiotherapy treatment planning
G S Payne, DPhil and M O Leach, PhD, FInstP, FMedSci
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Cancer Research UK Clinical Magnetic Resonance Research Group, Institute of Cancer Research and
Royal Marsden NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
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Following advances in conformal radiotherapy, a key problem now facing radiation oncologists is target
definition. While MRI and CT provide images of excellent spatial resolution, they do not always provide
sufficient contrast to identify tumour extent or to identify regions of high cellular activity that might be
targeted with boost doses. Magnetic resonance spectroscopy (MRS) is an alternative approach that holds
great promise for aiding target definition for radiotherapy treatment planning, and for evaluation of
response and recurrence. MRS is able to detect signals from low molecular weight metabolites such as
choline and creatine that are present at concentrations of a few mM in tissue. Spectra may be acquired
from single voxels, or from a 2D or 3D array of voxels using spectroscopic imaging. The current state of
the art achieves a spatial resolution of 6–10 mm in a scan time of about 10–15 min. Co-registered MR
images are acquired in the same examination. The method is currently under evaluation, in particular in
brain (where MRS has been shown to differentiate between many tumour types and grades) and in
prostate (where cancer may be distinguished from normal tissue and benign prostatic hypertrophy). The
contrast achieved with MRS, based on tissue biochemistry, therefore provides a promising alternative for
identifying tumour extent and regions of high metabolic activity. It is anticipated that MRS will become an
essential tool for treatment planning where other modalities lack the necessary contrast.
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Encouraged by positive responses to our reviews of 2004 and 2005, the Editors again offer a selection of
papers which they feel have made a mark during 2006. These have been chosen for the immediate impact
they have had on individual Editors, rather than by any formal assessment or comparison, and we hope
that they will remind readers of some key radiological issues of 2006, or at least alert them to what they
might otherwise have missed.
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Since the introduction of online submission, the British Journal of Radiology continues to receive an
increased flow of papers, with 2006 exceeding all previous records. Submissions were received from 53
countries, with just over one quarter from the UK. Encouraged by this, the Editorial Board has explored
several ways in which the overall quality of published papers may be enhanced and we look forward to
implementing these during 2007. Although we may view the Journal Impact Factor with some
scepticism, we are conscious of its standing, particularly in the UK, and most of our proposals for raising
standards will, we hope, be reflected in an increased Impact Factor in future years.
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A mention of these initiatives gives us the opportunity to express our appreciation and thanks to Dr
Philip Dendy, Honorary Scientific Editor and a driving force for improved quality, who retired from his
position in September 2006, after many years of invaluable service to the British Journal of Radiology,
including the last eight as Deputy, and then Honorary Scientific Editor.
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One of the many highlights of the year, the annual British Institute of Radiology President's conference,
reflects the interests of the incumbent President, and the year opened with an overview of the 2005
Conference "Technology in Imaging and Radiotherapy – towards improved workflow and
productivity". The wide ranging nature of the subject matter, from the status of CT to IMRT (intensitymodulated radiation therapy), and with tributes to Sir Godfrey Hounsfield, is typical of the British
Institute of Radiology's multidisciplinary ethos and was summarized by Dendy [1]. The CT papers, in
particular, offer an insight into the development of CT and illustrate the unpredictability (at least to
those not intimately involved) of the development of this technology. After the initial surge in
development in the 1970s, immediately following the announcement of the invention, the pace
slackened in the 1980s, only to gather renewed momentum in the following decade with the emergence
of spiral CT and multidetector arrays.
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One can speculate about the future development cycles of other less well established technologies, one
such being particle radiotherapy, also covered in the President's Conference. Jones [2] pointed out the
recent disappointments of rejected bids for UK particle therapy centres in contrast with similar facilities
abroad, and suggests that 5000–12 000 patients might need therapy abroad if no UK centres are
forthcoming.
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Diagnostic radiology
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The broad range of topics that are met on a day-to-day basis by clinical and academic radiologists has
again been reflected in last year's published diagnostic papers. The majority of papers have focused on
the ever increasing armamentarium of diagnostic and therapeutic techniques available and have, as one
would expect, demonstrated that modern technology is of benefit, but this may be at a cost.
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The paper by Taylor et al [3] on CT colonography reflects the trend away from conventional barium
examinations in the investigation of bowel disease, and confirmation that this trend is justified is
increasingly seen in the published literature and in clinical practice. Their paper suggests that CT
colonography is both more accurate than barium enema in the detection of polyps greater than 6 mm in
size, and importantly may also be reported with a high degree of confidence by experienced observers.
Interestingly, two of five colonic cancers in the study group were only detected by the CT examination.
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The additional value or otherwise of CT colonography, namely the ability to detect extracolonic
abnormalities, has been less well studied. The paper by Xiong et al [4] reviews the additional financial
cost of detecting disease warranting investigation and suggests that the additional findings may result in
a doubling of the examination cost, and also result in potentially significant morbidity and possibly even
mortality. This is unsurprising given the high prevalence of additional unrelated abnormalities, 116 of
225 patients investigated in their report, and is not dissimilar to reports on additional abnormalities
discovered in patients in lung cancer screening programmes [5]. Perhaps such examinations may only be
regarded or reported as normal in the future, if an additional and clinically irrelevant abnormality is
detected!
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Riddell et al [6] reported on the utilization of magnetic resonance imaging (MRI) in the investigation of
oesophageal disease in a similar manner to its use in the investigation of rectal cancer. They are to be
congratulated on their meticulous application and assessment of different scanning parameters,
including cardiac gating, and this paper is a lesson to us all in the careful investigation and application of
new technologies in disease investigation.
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PET/CT is becoming more widely available. Its value in colorectal cancer is well recognized, but two
papers showing novel use of the technique in investigating gastrointestinal disease are worthy of
mention. Goshen et al [7] described the use of PET/CT to detect abdominal wall and port site
metastases. They concluded that the technique seems to be a sensitive tool for the diagnosis of
abdominal wall recurrence with accurate localization enabling functional aspects of PET supplemented
by the anatomical features of CT to help such recurrences to be resected with curative results. The same
technique was also described by Zissin et al [8] who utilized it for diagnosing mesenteric panniculitis.
The technique allows differentiation between mesenteric panniculitis and mesenteric tumoural
involvement, an almost impossible task using CT alone.
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It is always interesting to read of a technique which has the potential to replace a more invasive one.
Hollingsworth et al [9] described the technique of rapid non-invasive MR assessment of hepatic lipid
content. They used it in assessing the liver of those on low carbohydrate diets, using 10 volunteers. They
showed a strong correlation between the initial fat content and the percentage of fat content reduction
in the first 3 days of the diet. Weight loss was not correlated however with hepatic fat loss after 3 days
or 10 days of dieting. The technique is very promising for hepatic fat quantification in longitudinal
studies and may reduce the need for liver biopsies in some cases.
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With the increasing use of interventional radiology, it was instructive to read the paper by Vaño et al
[10] on occupational radiation doses in interventional cardiology spanning a 15 year period. It was
perhaps gratifying to note that a 14% reduction has been achieved in the doses under and over the lead
apron from 1989 to 1992. The most effective action in reducing operator dose has been patient dose
reduction and the systematic use of radiation protection measures, particularly the use of ceiling
suspended protective screens.
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Hiorns et al [11] reminded us that it may well be possible to keep radiation doses below a national
standard. They reviewed current local dose–area product (DAP) levels in a paediatric setting and
reported marked reductions, by a factor of between 5 and 25 below the current national reference
doses, over a 21 month period. They make the point that with appropriate education, national
recommendations can sometimes be bettered.
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All radiologists believe that they are good at detecting pulmonary nodules. Manning et al [12] studied
this with volunteers consisting of radiologists, experienced radiographers and novices. Observers' eye
movements were tracked and correlated. True negative decisions from all observers were associated
with shorter fixation times than falsenegative decisions. No correct negative decisions were made after
fixations exceeding 3 s. True negative decisions were made more quickly than false ones. Perhaps rapid
reporting has some advantages!
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An increasing number of papers reporting in vitro or animal studies are submitted to the British Journal
of Radiology, and these often provide an insight to future studies in man. The report by Lee et al [13] on
the investigation of different radiofrequency electrodes for ablating disease in lungs will inform future
investigators when, as is increasingly the case, this technique is used to ablate both primary and
metastatic disease in the lungs. Meticulous attention to detail is necessary to inform us of best practice,
and this report provides an example of just such methodology. An interesting report of the
characteristics of gold nanoparticles as a new X-ray contrast agent in mice [14] noted a threefold
improvement in contrast relative to iodine at 100 keV, coupled with, amongst other characteristics, a
greater tumour retention and lower muscle accumulation. This suggests the possibility of enhanced
tumour detection, and the extension from mouse to human studies is awaited.
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Diffusion-weighted MRI
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One of the aims of new and improved imaging techniques is to differentiate between malignant and
non-malignant tissues at all stages in a patient's care. A cluster of papers in the August 2006 issue
looked at this aspect of some recent advances in the functional imaging technique of diffusion-weighted
MRI (DWI).
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A commentary by Koh and Padhani [15] gives a good overview. At a fundamental level, DWI provides
information on the random motion of water molecules in tissues and this will manifest itself as a
standard deviation about some mean position over a period of time characterized by a diffusion
coefficient. In tissues, diffusion is primarily in the extracellular space, but is modified by interactions
with hydrophobic cellular membranes and macromolecules. The resulting effect is sometimes referred
to as "apparent diffusion" and differences in apparent diffusion can be a means of tissue differentiation.
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Images are acquired with various b values (derived from the amplitudes, lengths and intervals between
diffusion gradients) and the data are processed to obtain "apparent diffusion coefficients" (ADC). It is
important to note that tumour shows as a cold area on a functional ADC map (indicating a low diffusion
rate) but as a hot area on original images obtained at high b values.
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Vandecaveye et al [16] examined the value of DWI for differentiation of persistent or recurrent tumour
from post-radiotherapeutic sequelae or complications for four patients with laryngeal squamous cell
carcinoma. The two true positive patients demonstrated the appearance of recurrent tumour tissue on
the DWI images. The lesions were hyperintense on the b 1000 map (b = 1000 s mm–2) and
hypointense on the ADC map, in contrast to the surrounding tissue. In the two true negatives, the
diffuse ADC value and the absence of any focal restrictive signal on the b 1000 images were consistent
with diffuse laryngeal necrosis and absence of tumour recurrence.
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In the same issue Fan et al [17] evaluated the usefulness of DWI and the related technique of perfusionweighted MRI (PWI) for predicting tumour grading of supratentorial brain gliomas. Some 15–45% of
supratentorial gliomas which show no enhancement on conventional contrast-enhanced T1 weighted
MRI images were subsequently found to be malignant. 22 patients with such non-enhancing tumours
were enlisted as the cohort for this study. Histologically, 14 tumours were low grade gliomas (WHO
Grade I and II) and 8 tumours were anaplastic. Low ADC values were found in the solid portions of the
anaplastic gliomas but not in low grade tumours. On the other hand, ADC values in the peritumoural
regions, although lower than in the contra-lateral normal white matter, were a poor discriminator,
showing no significant difference between anaplastic and low grade gliomas.
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Unlike conventional contrast-enhanced imaging, perfusion imaging may be used to obtain information
on tumour angiogenesis with or without the destruction of the blood–brain barrier. Fan et al [17]
expressed perfusion data in terms of relative cerebral blood volume ratios, and these were raised in
both solid portions and peritumoural regions of anaplastic gliomas, but not in low grade gliomas.
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In the simplified diffusion theory normally applied in DWI, it is assumed, to a first approximation, that
diffusion is isotropic. However, in highly structured parts of the body this assumption may not be
justified and a more complete mathematical treatment of diffusion is required resulting in MR diffusion
tensor imaging (MRDTI), where the diffusion coefficient is resolved along the three principal axes.
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The standard methodology is to compute the mean diffusion rate and the fractional or relative
anisotropy. In the February 2006 issue, Peña et al [18] proposed an alternative approach in which the
diffusion tensor is decomposed into its isotropic (p) and anisotropic (q) components. The method was
tested on a healthy volunteer, a sequential study on a patient with a recent stroke, a patient with
hydrocephalus and a patient with an intracranial tumour. Distinctive p:q patterns were recorded for the
four cases, but further work will be required to determine if a particular pattern is sufficiently unique to
be of diagnostic value.
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Fan et al [17] conclude that DWI and PWI should be integrated in the diagnostic work-up of nonenhancing gliomas in order to better predict grading and, taken as an ensemble, the papers reviewed
here suggest that these forms of functional imaging will make an important contribution to tumour
evaluation. However, in respect of DWI, Koh and Padhani [15] draw attention to some outstanding
challenges, including (a) overlap in ADC values between malignant and non-malignant tissues, (b)
averaged ADC values from selected regions of interest may not adequately characterize tumour
heterogeneity. The work of Peña et al [18] shows that in MRDTI there remains a wealth of data to be
uncovered, but unfortunately we still do not know which tensor scalar measure or measures best
describe brain tissue and its pathological changes.
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Radiotherapy and oncology
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One clear message that emerges from reviewing the British Journal of Radiology in 2006 is the increasing
importance of imaging in the day-to-day practice of radiation oncology. We are a long way from 20 years
ago, when a few plain films and a pair of orthogonal films on the simulator were all that it took to get a
patient from diagnosis through to the completion of treatment. It is not just the emergence of the new
technologies, CT, MRI, PET and online portal imaging that have influenced practice, it is also the way in
which these technologies are integrated into departmental protocols and management plans for
individual patients. There is usually the assumption that more is better, and the result is that work
expands to fill the technology available. There are consequences from all of this and several papers in
the British Journal of Radiology in 2006 either deliberately or inadvertently point to some of the
difficulties and questions that may arise. A special issue in September 2006 was devoted to issues
concerning imaging in radiotherapy treatment planning and delivery. There were important
contributions on functional imaging [19, 20] and on how to fuse and manage images acquired using
different technologies [21]. But this was not all: there were two substantial publications on the role of
imaging in improving the planning of radiotherapy for head and neck cancer [22, 23], and other
important contributions on functional imaging [24, 25]. Two papers [26, 27] attempted to provide a
clinical context for the use of imaging. Both suggested that, for follow-up at least, excessive imaging of
asymptomatic patients is unlikely to be helpful.
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So, what are the issues raised by the papers published in 2006 on imaging and radiotherapy? The first
issue is that we need to know far more about whether the investment of time and effort in better
localization and definition of target volumes is worthwhile. The images are of good quality, registration
is perfect throughout treatment, but is the patient any better off? If there are better outcomes, what
has the cost been and are the results so much better that extra costs are justified? We also need to
address the issue of opportunity cost: imaging capacity is finite, we already have waiting lists for
diagnostic imaging procedures. A scanner that is being used for target localization in radiotherapy is a
scanner that cannot be used for diagnostic or staging scans. We need to be explicit about the trade-offs
we make when we introduce unproven technologies. Nowhere in radiation oncology is this problem so
acute as it is in the introduction of new image-based technology into the processes of planning and
delivering radiotherapy treatment. Another key issue concerns resources – not just machines, but
people and expertise. Who is going to interpret the images and integrate these interpretations into the
clinical context: what is the appropriate PTV (planning target volume) for this particular patient with this
particular tumour at this particular time? As a journal, the British Journal of Radiology is healthily
positioned to facilitate and co-ordinate debates on these issues. By looking back on what we published
in 2006 we can easily define the framework for the discussions. Looking forward to 2007, perhaps we
will be able to publish more in the way of analysis and less that is simply hopeful expectation, analysis
that will inform the important debates that we need to have if we are to ensure that the introduction of
these new techniques is to be handled sensibly. It is not just about what we can do, it is also about what
we should be doing.
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Radiobiology
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A strong recurring theme amongst the radiobiology papers this year was the perennial concept of
hypoxic radioresistance in radiotherapy. While the importance of this issue has been recognized for
decades, new evidence continues to accumulate, reinforcing its importance. We were reminded of the
history of the topic, inextricably linked to the work of LH Gray and his colleagues, in a commentary by
Dendy and Wardman [28]. It described contributions to an international meeting marking the centenary
of the birth of LH Gray and celebrating his contributions to science.
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More specifically, the role of hypoxia in determining outcome in head and neck cancer was reviewed in
the October 2006 issue [29]. Potential markers for hypoxia in the clinical setting were discussed,
together with strategies to reduce levels of hypoxia or to target hypoxic cells with hypoxia-specific
cytotoxins. A combination of these approaches could lead to individualized therapy based on hypoxic
status of tumours.
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The impact of hypoxia on the effectiveness of radiotherapy in prostate cancer was the subject of a
modelling study [30]. These authors used measurements of relative hypoxia in prostate tumours to
calculate the additional dose that would be needed in the clinical setting to compensate for hypoxia.
This "clinical oxygen enhancement ratio" was in the range 1.2–1.5, depending on the exact modelling
parameters used, emphasising the importance of hypoxia in this disease.
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Radiation protection
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The UK Radiological Congress debate in 2004 on low doses and risks [31] seems to have helped to keep
alive the controversies surrounding the risks of low dose radiation. Wall et al, in a comprehensive review
article on this subject [32], discuss the current consensus of the linear no-threshold (LNT) model and its
challenges from those who argue for a non-linear relationship between dose and risk at low doses, due
to possible adaptive responses. For practical patient protection in radiology, the emergence of adaptive
response hypotheses, interesting though they are, are overshadowed by the need for practical advice.
For these purposes, Wall et al argued that the LNT model provides sufficiently reliable risk estimates for
patient protection and give four risk bands into which all radiological examinations may be divided.
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The implications of the dose–risk relationship at low doses comes into sharp focus when applied to
mammography. Heyes et al [33] considered the implications for mammography screening programmes
of enhanced relative biological effectiveness (RBE) for mammography X-rays of between 1 and 6, and on
this basis advised caution in programmes involving early regular screening in women with a family
history of breast cancer. This view was challenged by Law et al [34] and Redpath and Mitchel [35] and
defended by Heyes et al [36] in subsequent letters. In the field of low dose risk, controversy is almost
guaranteed because of the paucity of hard data and the numerous variables involved (such as in vivo vs
in vitro data, non-linear hypotheses, extrapolation from high doses and photon energy dependence).
Law and Faulker [37] also discuss radiation benefit and risk at the assessment stage of the UK breast
screening programme.
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In contrast to today's low dose issues, an historical perspective on patient and staff doses in radiology
was given by Kotre and Little [38] who estimated the doses received by radiographic staff between 1899
and 1902 in Newcastle by simulating the X-ray characteristics of a cold cathode X-ray tube and applying
the results to radiographic examinations recorded in a log book of the period. The radiographer who
carried out these examinations suffered severe radiation injuries and his effective dose was estimated
as 940 mSv per year. The median entrance surface dose for posteroanterior views of the chest was 68
mGy, nearly 500 times greater than expected today.
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