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Couch attenuation impacts doseAttenuation by the treatment couch during radiation therapy can reduce target dose. External-beam radiation therapy is performed with the patient lying on a treatment couch. It is gener-ally assumed that this couch is radiotranslucent and, as such, it is not generally accounted for during treatment planning. However, a new study from the MD Anderson Can-cer Center shows that this approach is not strictly valid.

Stephen Kry, assistant professor at MD Anderson’s Radiological Phys-ics Center, described the problem. “Historically, posterior treatment fields were not common, and when patients were treated with poste-rior fields they were treated through minimally attenuating couch mate-rials. Therefore, the couch attenua-tion was generally a less important issue. However, it is now common to treat using a large number of angles around the patient that may inter-sect different parts of the couch, including the highly attenuating rails. Some recent treatment couch tops are also thicker and therefore more attenuating than historical couches.”

Kry also pointed out that data regarding the clinical impact of couch and rail-based attenuation are lacking. To address this issue, the MD Anderson team examined the impact of the Varian Exact Couch on intensity-modulated radiotherapy (IMRT) and RapidArc treatments, using Varian’s Eclipse v8.6 treat-ment planning system to model the couch components (Phys. Med. Biol. 56 7435).

Dose discrepancyThe team planned IMRT (eight-field) and RapidArc (two-arc) treatments for five prostate-cancer patients, initially ignoring treatment couch attenuation (no-couch plans). Dose distributions were then recalculated to include the couch and support rails in three configurations: couch top with rails out; couch top with rails in; and couch top-only, in which the rails are moved to avoid the beam during IMRT delivery.

Comparing the calculated doses (no-couch plans) with measured doses for the various configura-tions revealed disagreement of up to 6.2% . On average, all RapidArc plans and rails-out IMRT plans failed or nearly failed the clinical IMRT quality assurance agreement criterion of ±3%.

The researchers then used dose-volume histograms to evaluate changes in target dose and cover-age. For IMRT, the average dose

loss (from the prescribed 76 Gy) was 4.2% (3.2 Gy) for the rails-out plan, with a maximum loss of 5.1% seen in one patient. With the rails in, approximately 2% (1.5 Gy) was lost. For RapidArc plans, dose losses were 3.2% (2.4 Gy) and 2.9% (2.2 Gy) for the rails-out and rails-in plans, respectively, with a maximum loss of 4% . Kry and colleagues then examined the percentage of the tar-get covered by the prescribed dose. When the couch and rails were included, target coverage dropped to 35% (rails-out) and 84% (rails-in). For RapidArc plans, coverage of the prostate dropped from 99% (no-couch) to 18% (rails-out) and 17% (rails-in).

The long-term impact of these dose losses was explored using tumour control probability (TCP) modelling, revealing an average loss in tumour control of 6.3%. For one IMRT patient, the presence of the couch and rails reduced the TCP by 10.5% to a minimum of 80%.

Less TCP reduction was seen in the RapidArc plans, with inclusion of the couch and rails resulting in a minimum TCP of 78%, 8% less than that predicted by the no-couch sce-nario for that patient. The authors note, however, that for both of the delivery modalities, this reduction

in tumour control necessitates sub-stantial clinical management of the couch and rails.

The way aheadThe researchers concluded that the treatment couch can cause clinically unacceptable loss of dose and tar-get coverage. One possible solution could be to use a less attenuating couch insert, such as the unipanel mesh couch top available with the

Varian Exact couch. A follow-up study revealed that the unipanel mesh does not cause a clinically relevant loss of dose or coverage for IMRT, but still causes an unaccepta-ble loss for RapidArc plans.

Another option would be to use the Eclipse system to account for the couch during planning. While this is a viable approach, extra care is required in positioning the patient with respect to the couch top and rails, as incorrect alignment could introduce even larger dose errors. Furthermore, other planning sys-tems do not offer the ability to add the couch during treatment plan-ning. Manual addition has been attempted using CT images of the couch top; however, it is not feasible to generate CT images of the rails so this remains an incomplete solution.

“Eclipse could solve the issue for IMRT or RapidArc. But including the couch model for other planning systems, to our knowledge, is some-thing that would be very difficult to do,” Kry told medicalphysicsweb. “Hopefully this paper could push the planning system manufacturers to include couch models in future versions of their software.”

Tami Freeman is editor of medicalphysicsweb.

“It is now common to treat using a large number of angles that may intersect different parts of the couch, including the highly attenuating rails.”

Couch and rails: representative dose differences between the no-couch set-up and other configurations. IMRT rails-out (top left), IMRT rails-in (top right), RapidArc rails-out (bottom left) and RapidArc rails-in (bottom right). Dose differences of 1 Gy (orange), 2 Gy (green) and 3 Gy (red) are shown on the images.

Welcome to medicalphysicsweb review, a special supplement brought to you by the editors of medicalphysicsweb.

This issue, distributed exclusively at ESTRO 31 in Barcelona, Spain, brings you a taster of our recent online content. If you like what you see, check out the website to read more in-depth news and research articles. Or why not register for free as a member – simply visit medicalphysicsweb.org or come or see us at booth #6550.Tami FreemanEditor, medicalphysicsweb

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focus on: radiotherapy 3

An in vitro study has demonstrated that DNA repair mechanisms respond more effectively when exposed to low doses of ionizing radiation, compared to high doses. The observations potentially con-tradict the benchmark for radiation-induced cancer risk estimation, the linear-no-threshold (LNT) model, and if so, could have large impli-cations for cancer risk estimation (PNAS 109 443).

In essence, the LNT model pro-vides an estimate of risk of radia-tion-induced cancer for low-dose exposures by linearly extrapolating the risks observed for high doses, based on studies of the survivors of the Nagasaki and Hiroshima atomic bombs. But the new study, led by bio-physicist Sylvain Costes of the Law-rence Berkeley National Laboratory in Berkeley, CA demonstrates a non-linear relationship between dose and DNA repair.

“It is reassuring to see that at least, at the cellular level, cells exposed to low dose may be much less likely to have aberrant response to radiation than at high dose. If we assume the LNT risk model is based theoreti-cally on DNA damage being linear with dose, then the fact that the DNA damage response is not linear casts some doubt on the LNT,” Costes explained.

The findings are important new knowledge in the understanding of how human cells respond to dif-fering levels of ionizing radiation exposure. However at this stage, the precise implications for risk of radi-ation-induced cancer are unclear.

“This is difficult to say. Our work looks at DNA damage from cells in a dish. We are far from a full organism and from cancer endpoints,” com-mented Costes.

Radiation-induced tumourigen-esis is thought to be initiated by gene mutations. These arise from two types of DNA damage. Point mutations occur as a result of iso-lated fractures of the double helix, or single double strand breaks (DSB), while translocations occur when two DSB rejoin incorrectly. Radia-tion-induced foci (RIF) are centres consisting of aggregations of pro-teins where DSB are repaired; their formation is initiated by the presence of DSB.

The researchers used time-lapse imaging of epithelial breast cell cul-tures and mathematical modelling of the cellular response to ionizing radiation to observe the kinetics of DSB formation and DNA repair at RIF.

The researchers’ use of continuous real-time imaging provided a more accurate picture of RIF behaviour, which is transient in nature, than previous studies that used static imaging. They observed that while the number of RIF also increased

with dose, for doses greater than 1 Gy, RIF levels saturated. For exam-ple, the induction of only 15 RIF/Gy was observed for doses greater than 2 Gy, compared to 64 RIF/Gy for doses above 0.1 Gy.

“We hypothesized that as the dose increases, there are multiple DSBs co-localized into single RIF ‘repair centres’. Having multiple DSBs in a common location is an event that is known to increase the risk of trans-locating chromosomes,” Costes explained. “At low doses, it seems that the number of RIF was consist-ent with the expected numbers of DSB, and thus suggests one DSB per RIF, and therefore no risk of trans-location. One can then hypothesize that at low dose, the cell will handle any DSB better, with a much reduced risk of chromosomal aberrations.”

The researchers are now working on new experimental techniques that will allow them to move from the simplified cellular environment used in this study, towards their eventual goal of observing DNA repair mechanisms in tissue.

Jude Dineley is a freelance science writer and former medical physicist based in Sydney, Australia.

Tumour motion is recognised as a major limiting factor in the target-ing accuracy of radiotherapy. Previ-ous research has focused on tumour translation, but tumours also rotate. Incredibly, rotations greater than 45 and 25° have been reported for lung and prostate tumours, respectively. The resulting dosimetric “misses” are in some cases more significant than those due to tumour translation.

To address this problem, an inter-national collaboration has provided proof-of-principle that tumour rota-tion can be detected and corrected in real-time using dynamic multileaf collimator (DMLC) tracking (Int. J. Radiat. Oncol. Biol. Phys. 82 e545).

Lead investigator Paul Keall, pre-viously of Stanford University and now based at the University of Syd-ney in Australia explained: “We are very pleased with the study out-come. We demonstrated that target rotation can be detected and cor-rected in real-time in an integrated radiotherapy system. And we quan-tified that geometric and dosimetric accuracy of treatment delivery can remain high for a rotating target, for both conformal radiotherapy and IMRT delivery.”

Real-time DMLC tracking technol-ogy, incorporated into a Varian IX linac was integrated with a dedicated Calypso 4D localization system. The treatment target – a disc shaped puck – was rotated by rotating the treat-ment couch. Electromagnetic tran-sponders in the target monitored its rotation and translation, providing data to the tracking software, which generated a corrected treatment

aperture. The researchers assessed tracking

accuracy as the discrepancy in angle between the D-shaped MLC aperture and the target, which was embedded with 3 mm diameter tungsten mark-ers for monitoring by continuous electronic portal imaging. The sim-plest case of target rotation in the plane perpendicular to the radiation beam, at a constant angular velocity of 4°/s, was used as proof of princi-ple. Tracking of two types of target rotation was assessed: “fixed” rota-tion, where the target was rotated prior to irradiation with no subse-quent motion, and “active” rotation where target was rotated continu-ously during irradiation.

As anticipated, geometrical accu-racy improved with rotational track-ing. The DMLC successfully tracked fixed target rotation to within 0.3 ± 0.6° and active target rotation to within 0.3 ± 1.3°.

The dosimetric advantages of DMLC tracking over no tracking were demonstrated using the same experimental set up, with a 2D ion chamber array placed underneath the target for dose measurement. Static irradiation of a static target provided a reference standard for comparison with fixed and active target rotation, with and without tracking. Gains in dosimetric accu-racy were marked. Gamma tests with a 3 mm/3% criteria reported failure rates of 9% versus 35%, for tracked versus non-tracked active target rotation, amongst other posi-tive results.

“Our next steps are to study patient tumour rotation and transla-tion to quantify the clinical impact of correcting versus not correcting for tumour rotation,” explained Keall.

Memory impairment is a well docu-mented side-effect of cranial irra-diation, but the underlying cause is ill-defined. One possible hypothesis focuses on a neurogenic stem cell compartment in the hippocampus that is highly sensitive to radiation and potentially central to radiation-induced memory impairment.

To investigate this premise fur-ther, US researchers have conducted a prospective study of adult patients with brain tumours treated with fractionated stereotactic radiother-apy (FSRT). The aim was to correlate hippocampal dose with long-term neurocognitive function impair-ment (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2011.10.021).

“The purpose of this study was to examine the effect of focal brain irradiation, using high-precision radiotherapy, on neu-rocognitive function,” explained Wolfgang Tomé, from the University of Wisconsin-Madison.

“The neurocognitive functions investigated included hearing, vision, language, motor function

and memory, specifically list-learn-ing delayed recall,” said Tomé.

Tomé and colleagues examined 18 adults with benign or low-grade brain tumours. Radiation doses and fraction sizes were chosen accord-ing to current FSRT clinical prac-tice. Four low-grade gliomas, three meningiomas and two pituitary adenomas received a dose of 50.4 or 54 Gy in 1.8 Gy fractions. Nine ves-tibular schwannomas were treated with either 20 Gy in 4 Gy fractions, or 50.4 Gy in 1.8 Gy fractions.

After completion of FSRT, the researchers delineated the bilateral hippocampi, using a contouring pro-tocol that focuses on regions where hippocampal neural progenitor cells associated with memory function are thought to be clustered.

The researchers then generated dose-volume histograms for the left and right hippocampi and for the composite pair. The doses were converted to biologically equiva-lent doses in 2 Gy fractions (EQD2) assuming an α/β ratio of 2 Gy.

All of the participants underwent

a series of cognitive function tests, at baseline and 18 months after under-going FSRT. Six age-matched healthy control individuals also performed the tests at the same interval.

The researchers compared the patients’ retest scores with those predicted on the basis of the control data. These differences were trans-formed into standardized Z-scores: defined as the observed retest score minus the predicted score, divided by the standard error. Cognitive impairment was defined as a nega-tive change in Z-score of at least –1.5.

At the 18-month follow-up, all patients remained free of disease progression. Cognitive impairment

was noted in a varying percentage of patients (up to 33.3%) for the differ-ent cognitive tests.

Statistically significant associa-tions were seen between impairment in delayed verbal memory (meas-ured using Wechsler Memory Scale-III Word Lists) and two dosimetric factors: EQD2 to 40% of the bilateral hippocampi of greater than 7.3 Gy, and EQD2 of above 0.0 Gy to 100% of the bilateral hippocampi. Impair-ment was noted in 66.7% and 80.0% of these cases, respectively.

Tomé noted that the first of these factors was the most clinically rel-evant. “The dose-response relation-ship was also statistically significant,

but the 7.3 Gy threshold is the dose to 40% of the hippocampus beyond which the normal tissue complica-tion probability starts to rise sharply,” he explained. “A patient receiving an EQD2 above 7.3 Gy is 19.3 times more likely to develop a deficit in delayed recall than a patient receiving an EQD2 of less than 7.3 Gy.”

Impairment in visual integration was also significantly associated with two factors: maximum EQD2 of more than 15.0 Gy to the left hip-pocampus, and EQD2 of above 6.2 Gy to 30% of the left hippocampus. None of the other associations were statistically significant.

The researchers conclude that their findings provide an incen-tive for exploring the hypothesis that avoidance of the hippocampus using IMRT may spare patients some of the cognitive sequelae of cranial irradiation.

As such, they are now undertaking a multi-institutional Phase II clini-cal trial of hippocampal avoidance during whole-brain radiotherapy in patients with brain metastases.

Does LNT model overvalue risk?

MLC tracks target shift and rotation

Dosimetry predicts cognitive decline

Keep clear: sparing of the hippocampus (red) using four coplanar arcs.

Low-dose implications: biophysicist Sylvain Costes led the study.

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MPWRSpr12_p03.indd 1 10/04/2012 10:02

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focus on: radiotherapy 5

PET images provide valuable biologi-cal information that is used to help diagnose disease, assess prognosis and delineate radiotherapy targets. PET also has the potential to monitor tumour response to radiotherapy. Researchers at the Peter MacCal-lum Cancer Centre in Melbourne, Australia are investigating the lat-ter, focussing on patients with non-small cell lung cancer (NSCLC).

At the EPI2k12 conference, held in Sydney in March, postdoctoral researcher Sarah Everitt presented her group’s work. The researchers are particularly interested in the information that PET can provide on tumour response when implemented during, rather than following, a patient’s course of radiotherapy.

The researchers’ rationale is that by monitoring tumour response to radiation during therapy, a patient’s treatment course can be biologically adapted to maximize the likelihood of disease control. “We are aiming for personalized medicine,” said Everitt.

For 20 NSCLC patients receiv-ing radiotherapy, Everitt and co-researchers performed a series of

paired PET/CT scans using fluorode-oxyglucose to demonstrate changes in tumour metabolism, and fluoro-thymidine (FLT) to highlight changes in cell proliferation. Scans were per-formed prior to treatment, two and four weeks into the six-week treat-ment course, and at follow up.

In the resulting images, the researchers observed instances of local, regional and distant disease progression in several patients. This information, not normally available to clinicians, guided changes in treat-ment geometry and fractionation, and the abandonment of therapy in a number of patients.

“One of the exciting aspects of this research is to look at the potential of incorporating the findings of these molecular imaging scans into the delivery of biologically guided radio-therapy,” said Everitt. One approach uses FLT to identify particularly proliferative regions within a given tumour and guide the delivery of high-dose boosts to those regions. The researchers are also investigat-ing PET monitoring of normal tissue reactions to radiotherapy.

Radiotherapy of lung cancer is com-plicated by geometric changes in thoracic anatomy during the treat-ment course. Image-guided adaptive radiotherapy provides a means to manage such variations, but the wide range of underlying causes – includ-ing respiration-induced motion, change in baseline lung volume, and tumour growth and regression – ren-ders this a complex task.

To ease this problem, researchers from the Department of Radiation Oncology at Virginia Common-wealth University have developed a method for categorizing the differ-ent sources of geometric variability. This should then enable selection of the appropriate intervention for each type of anatomical change (Phys. Med. Biol. 57 395).

“A rigid shift, for example, may be compensated by shifting the patient or radiation beams, whereas a shrinking target may not be opti-mally addressed by such a shift,” explained senior author Geoffrey Hugo. “Our approach seeks to sepa-rate and measure the underlying basic components of the complex anatomical variability seen in an image of the patient.”

Hugo and colleagues employed principal component analysis (PCA) to classify and separate causes of interfractional changes in gross tumour volume (GTV) for lung cancer patients. They generated a set of dominant eigenmodes that accounted for at least 95% of the observed variability, and classified these according to volume change, position change and temporal trending.

Eigenmodes that demonstrate

small volume change and some posi-tion change represent a rigid shift. Large volume changes imply defor-mation, either anisotropic (when a position change is also seen) or iso-tropic (no position change). Each eigenmode was classified as trend-ing or non-trending depending on whether its contribution to GTV variability included a time trend over the treatment course.

Time trending eigenmodes are most likely due to tumour regression and possibly also progression or res-olution of an associated pathology. Such changes may be best managed via periodic replanning. Non-trend-ing eigenmodes are related to ana-tomical variations, such as breath hold reproducibility, baseline shifts in respiration and setup error, and can be addressed using image-guided position correction.

The researchers tested the clas-sification scheme on 12 lung can-cer patients (13 GTVs) undergoing image-guided radiotherapy. Weekly breath-hold CT scans were used to determine geometric changes, with image registration employed to identify corresponding structures. These shape changes were then used to determine the dominant eigen-modes for each patient.

All patients had between two and four dominant eigenmodes, with at least one trending and one non-trending eigenmode. The team used these data to reconstruct three GTVs for each patient, based on: trending eigenmodes; non-trend-ing eigenmodes; and all dominant eigenmodes.

The trending-only reconstruc-tions were compared to the original semi-automatically delineated GTVs by analysing reconstruction errors in GTV volume and position. The average volume difference from the

original GTV was 4.3% ± 2.4%. GTV volumes reconstructed using all dominant eigenmodes were approx-imately 1% more accurate than GTVs reconstructed with trending-only modes.

On average, the trending-only reconstructions achieved lower vari-ability in centroid position than the original delineated GTVs, reducing the standard deviation from 1.9 ± 1.4 mm to 1.2 ± 0.6 mm. These results demonstrate that the trending-only model reduced the random posi-tional variation of the GTV while preserving GTV volume and shape.

The researchers also compared a prospective model (modelling the first four weekly images and project-ing future weeks) with a retrospec-tive model that used all available data. For most patients, these mod-els were in good agreement, demon-strating the feasibility of clinically implementing such a classification scheme in adaptive radiotherapy. In three cases, the dominant eigen-mode switched between trending and non-trending from the prospec-tive to the retrospective model.

The researchers concluded that the classification scheme appears feasible for separating types of geo-metric variability by time trend. “The next step is to see if we can predict future shapes – or at least, the likely distribution of future shapes – from a partial, prospective model for each patient,” Hugo told medicalphysicsweb.

“For example, if we have only a handful of measurements early in the treatment course, can we predict what the tumour surfaces might look like during later weeks. So far, we are working only with anatomical mod-els, but for radiotherapy, it might be worthwhile to incorporate some radiobiological models others have recently developed.”

Researchers in the US have published what they believe to be the first non-invasive measurements of tumour haemodynamic changes during X-ray radiation delivery. Follow-ing further investigations on a large patient population, the team – from various institutes at the University of Kentucky – hope that its real-time optical measurements will be capa-ble of correlating haemodynamic responses with clinical outcomes (Biomed. Opt. Express 3 259).

“It is our hope that real-time mon-itoring of tumour haemodynamic changes during radiation delivery, integrated with the pre-treatment absolute measurements of tumour blood f low and oxygenation, will provide crucial information for the early prediction of cancer treatment outcomes,” said Guoqiang Yu, direc-tor of the University of Kentucky’s Biomedical Optics Laboratory.”

It is well known that tumour oxygenation plays a vital role in the

success of radiotherapy. Despite this, tumour haemodynamics and metabolism are not routinely meas-ured due to a lack of appropriate instrumentation. The objective of the group’s pilot study was to inves-tigate whether a flow-oximeter based on diffuse correlation spectroscopy (DCS) could offer a portable, fast and low-cost solution to the problem.

“We want to use our DCS f low-oximeter to identify highly hypoxic tumours before treatment so that the patient can be directly referred

for surgery instead of radiotherapy,” explained Yu.

DCS uses near-infrared light to make high temporal resolution measurements of speckle f luctua-tions in tissue to a depth of several centimetres. In non-muscular tissues, such as head-and-neck tumours, the motion of red blood cells is primarily responsible for these fluctuations.

Yu and his colleagues developed a DCS flow-oximeter capable of mak-ing non-invasive measurements of

the relative blood flow (rBF) and the changes of oxygenated and deoxy-genated haemoglobin concentra-tions relative to their baseline values prior to treatment. Their system uses two laser diodes emitting at 785 and 854 nm. Light from these lasers is coupled into two multimode fibres that are attached to the tissue of interest. The scattered light is then collected by an additional sing-lemode fibre and analysed.

The team used its DCS flow-oxi-meter to monitor 23 patients under-going chemo-radiation therapy for head-and-neck tumours. Each patient received a total dose of 70 Gy, delivered in once-daily fractions of 2 Gy. During each radiation delivery, the source and detection fibres were secured to the surface of a cervical tumour node using a pre-moulded mask and the DCS f low-oximeter was controlled remotely from out-side the treatment room.

Although 23 patients were moni-

tored, data from 12 were discarded due to possible contamination. Data from the remaining 11 patients revealed a significant increase in tumour blood f low during the first week of treatment, which the team believes may be a physiologic response to hypoxia created by radi-ation-induced oxygen consumption. Only insignificant changes were found in tumour blood oxygenation.

“This suggests that oxygen utiliza-tions in tumours during the short period of fractional radiation deliv-eries were either minimal or bal-anced by other effects such as blood f low regulation,” commented Yu. “Our results indicate that simulta-neous measurements of both blood f low and oxygenation provide a deeper insight compared to single parameter measurement.”

Jacqueline Hewett is a freelance science and technology journalist based in Bristol, UK.

PET helps personalize treatmentSource of motion directs approach

Blood monitoring predicts efficacy

Optical monitoring: the researchers used non-invasive techniques to monitor neck tumour haemodynamic responses during radiotherapy.

Tailored therapy: PET could guide selective dose-boosting of tumours.

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focus on: particle therapy6

Future prospects for proton therapy“Don’t treat tomorrow’s patients with yesterday’s proton therapy technology.” This was the opening observation from Marco Schippers, speaking at the recent ICTR-PHE meeting in Geneva, Switzerland. Schippers, from the Paul Scher-rer Institute (PSI) in Switzerland, emphasized the necessity of develop-ing novel proton therapy techniques, citing a wish list of “five highs”: higher quality, higher accuracy, higher f lexibility, higher intensity and higher energy. He also listed one low: lower equipment costs – gener-ally achieved via a reduction in the size of the accelerator system.

To increase the quality of dose delivery, Schippers recommended that “in future, everyone should move to pencil-beam scanning”. Currently, this technique – in which a narrow pencil beam is magnetically deflected to paint the dose through-out the target – is only used by PSI and a small number of other sites. Meanwhile, every other proton ther-apy centre in the world still employs passive scattering.

Pencil-beam scanning is more efficient than beam delivery via scat-tering, and also offers the highest flexibility for shaping the dose dis-tribution. However, it is inherently

more sensitive to organ motion during treatment. Interplay effects between the motion of the target and the proton beam can lead to hot and cold spots in the target volume. So how can the accuracy of proton dose delivery be improved?

Schippers detailed several poten-tial approaches: gating, in which the beam is only applied at certain points in the breathing cycle; adaptive scanning, in which the pencil beam is moved to track the organ motion (although this is only in the research stage and not used yet); and fast res-canning, where the target volume is painted multiple times to average out motion effects. This latter approach requires high scanning speeds, which can be achieved by PSI’s state-of-the-art Gantry 2. PSI is also investigating fast 3D scanning, in which the beam intensity is also rapidly modulated during the beam sweep.

One other option for increasing the beam delivery accuracy is integrating MRI guidance with proton therapy – such as is being developed for pho-ton-based treatments. “I think that this is one of the things that we should go for in the future,” Schippers said.

The third item in Schippers’ wish-list was high f lexibility – both in the treatment dynamics and in the

equipment itself, which represents a huge investment that must be future-proof and upgradeable. “A cyclotron is the ideal accelerator for maxi-mum flexibility,” he told delegates, citing benefits including a continu-ous beam, high reliability and rap-idly adjustable beam intensity. The 250 MeV cyclotron at PSI, for exam-ple, can modify beam intensity with 3% accuracy in just 50 μs.

The disadvantage of the cyclotron is that, in contrast to a synchrotron, it produces a beam at a single energy. Altering the beam energy requires external regulation by a degrader. The PSI system can be adjusted between 238–70 MeV, with 1% field changes (or

5 mm change in penetration depth) in 50–80 ms. Increasing the beam inten-sity, meanwhile, to 1–1.5 μA, would enable splitting of the beam between multiple treatment rooms. This would allow more than one gantry to be used at one time, greatly increasing patient throughput.

Schippers went on to discuss the issue of higher proton energy, and why one would actually need this. One key application is proton radiog-raphy, as protons with an energy of 350 MeV will travel straight through the patient. “The best way to measure the range of protons in a patient is by measuring the energy loss of protons in a patient,” he explained.

Increasing the proton energy will also sharpen the edge of the dose distribution, as the beam spreads less, which could prove beneficial in the treatment of very small lesions. PSI is currently working to develop such a high-energy system, by add-ing a linac based on a design of the TERA Foundation (Italy) to the exist-ing beam transport system in order to boost proton energy from 250 to 350 MeV (the ImPulse project).

Finally, Schippers took a look at proton therapy’s inescapable need to lower costs. Ultimately, this will be achieved via the development of

smaller accelerators that can fit into a single treatment room.

The size of a cyclotron can be reduced by increasing the magnetic field. However, at very strong fields, the field weakens towards the cyclo-tron’s outside edge. To mitigate this effect, synchrocyclotron systems in which the frequency of the driving field is adapted with radius are being investigated. This arrangement is exploited in Mevion’s S250 system and IBA’s Proteus ONE, both of whom announced first installations of their systems towards the end of last year. Around this time, installation also commenced of ProTom’s Radiance 330, a compact synchrotron system.

Looking further ahead, there’s the dielectric-wall accelerator, which could be small enough to be mounted on a rotating gantry. And at the very end of Schippers’ usability time scale of “now, up until mañana”, sits the fixed-field alternating gradient accelerator (FFAG), the laser-driven accelerator and the plasma wakefield accelerator.

Schippers ended his presentation with a note of caution. “Smaller is bet-ter; but can we achieve the same qual-ity as we can with the current bigger system?” he asked. “I’m not saying don’t do it, but just be very careful.”

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focus on: particle therapy 7

Intensity-modulated proton therapy (IMPT) – in which a proton beam is magnetically scanned over the tumour volume – offers increased dose conformality compared to pas-sive scattering-based proton deliv-ery. However, due to the steep dose fall-off of individual Bragg peaks, IMPT is highly sensitive to patient set-up errors and range uncertainties.

One way to decrease this sensitiv-ity is to employ robust optimization, which incorporates uncertainty information into the treatment plan-ning. This approach can produce high-quality plans that are accept-able even with errors present, but can be a lengthy process. Now, research-ers from Harvard Medical School and MGH have designed a novel method for including robustness into a multicriteria optimization (MCO) framework for IMPT (Phys. Med. Biol. 57 591).

“MCO is a methodology for explic-itly exploring the feasible plan space, in order to locate the overall optimal plan by considering multiple objec-tives simultaneously,” explained pro-ject leader Wei Chen. “Robustness is among the most important objec-tives, especially for IMPT.”

MCO works by creating a database of plans (the Pareto surface), each emphasizing a different objective. These plans are then used to deter-mine the best compromise between specified criteria. The researchers integrated robustness into MCO by adding robustified objectives and constraints to the problem, which allows the planner to trade-off robustness and plan quality.

The MGH team examined two clinical cases : a base-of-skull tumour and a chordoma. They used the base-of-skull case to compare robust optimization (independent

of MCO) with a margin-based plan. Nine scenarios were modelled – the “nominal” plan without errors, plus eight with errors.

Comparing dose-volume histo-grams (DVHs) for the clinical tar-get volume (CTV)and brainstem revealed that the nominal DVHs were almost equally good for both plan types. In some error scenarios, how-ever, target coverage was far worse in the margin plan than the robust plan.

The researchers then employed MCO to assess the trade-offs between brainstem sparing and target cover-age for the chordoma case. Here, 29 error scenarios were examined. First, they used MCO to trade-off target coverage and brainstem sparing for a nominal, non-robust case. A three-proton-beam treatment plan repre-senting a good balance between the two objectives could be created. However, evaluating this plan for the 29 error scenarios revealed insuf-ficient plan quality for several cases.

Next, the researchers calculated a set of Pareto plans incorporating robustified objectives for brainstem maximum dose and CTV underdose. Use of the ART3+O algorithm ena-bled individual Pareto optimal plan optimization in less than 5 min-utes on a standard computer. This optimization process improved the robustness of the treatment plan, with DVHs for the CTV and brain-stem demonstrating improved robustness for the 29 error scenarios.

The researchers note that the trade-off between brainstem sparing and CTV coverage becomes harder upon inclusion of robustness, i.e. worse target coverage has to be accepted to maintain a given level of brain-stem sparing. The next step will be to implement this work on Astroid, MGH’s IMPT planning system.

Tumour hypoxia can limit the effi-cacy of radiation therapy. One means suggested for reducing hypoxia-induced radioresistance is to irra-diate the tumour with high-linear energy transfer (LET) radiation, such as carbon ions. At the recent ICTR-PHE meeting in Geneva, Swit-zerland, Armin Lühr from Aarhus University Hospital in Denmark examined the use of LET-optimized treatment planning as a strategy for overcoming hypoxia.

High-LET irradiation is associated with a lowered oxygen enhancement ratio (OER), a measure of cellular sensitivity to the presence or absence of oxygen. However, simply irradiat-ing a target with high-LET radiation will also result in increased damage to healthy tissue. The highest-LET of a particle beam occurs at the very end of its Bragg peak, and for the spread-out Bragg peaks used to create treat-ment plans, this leads to an uneven LET distribution throughout the

tumour. Often, the resulting dose-average LET in the target volume is too low to effectively reduce the

OER, while high-LET areas occur at the tumour edges, risking damage to nearby organs at risk.

What’s needed, said Lühr, is a way to shift the high-LET region into the target volume or into smaller hypoxic tumour sub-volumes. It’s also imper-ative to have an effective method for measuring the spatial distribution of oxygen within the tumour (such as PET imaging) in order to identify and contour hypoxic structures. “The idea is to keep the dose to the target homogenous, but redistribute the LET in the target to create high LET in hypoxic regions and reduce the OER,” Lühr explained.

Lühr and colleagues used the treatment planning system TRiP98, together with PyTRiP, to determine the best way to perform this LET painting. Applying two opposed flat carbon-ion fields resulted in two LET peaks along the beam axis outside the target volume – not the desired distri-bution. Instead, using two opposed ramp fields led to a flattened high-LET region inside the target. Such ramps can be used to shape and move

the LET distribution as required.It’s also advantageous to combine

high-LET irradiation with low-LET photon or proton irradiation, in order to achieve LET painting with the desired homogenous target dose. Lühr presented the example of a hypothetical H-shaped target containing three small “hypoxic” target sub-volumes. He showed that ramped carbon-ion fields applied from two directions could shift the high-LET regions into these three target spheres. Superposing proton irradiation from four opposed fields resulted in a relatively constant dose throughout the entire target.

Lühr emphasised that, unlike the case for dose painting, LET can’t be scaled. But using ramp fields, it can be redistributed. The next step in this work will be to examine the clinical relevance of LET painting via studies of tumour control probability (TCP) and normal tissue complication probability (NTCP).

Robust MCO aids IMPT planning

Can LET painting overcome hypoxia?

LET control: dose and LET distributions using LET painting (left) and two flat fields (right). The left column shows regions with elevated LET.

Proton model eases beam QAAn analytical expression that accu-rately models Bragg curves gener-ated by a scanning proton pencil beam has the potential to signifi-cantly increase patient throughput in busy proton therapy centres (Phys. Med. Biol. 56 7725).

The measurement of Bragg curves, which demonstrate the variation in radiation dose with depth in tissue, is a key task in the commission-ing of a treatment planning system (TPS) prior to clinical use. Such measurements are also one way of performing patient-specific quality assurance (QA) prior to treatment. But while they are vital, such meas-urements can also be onerous and time-consuming for the medical physicist.

The analytical expression, devel-oped by physicists at the MD Ander-son Cancer Centre, has the potential to be incorporated into proton TPS dose calculation algorithms. Impor-tantly, it could also substantially reduce the number of measurements required for TPS commissioning, by enabling interpolation and extrapo-lation from a reduced set of meas-ured Bragg curves.

“We would gain an estimated time saving of at least 100 hours of meas-urement by reducing the need to measure all 94 energies in the com-missioning of our TPS,” explained co-author X Ronald Zhu. Dose calcu-lation using the expression could also reduce the number of patient-specific QA measurements that are required, presenting the opportunity for fur-ther time savings in the clinic.

“Improving the efficiency of patient-specific QA is the key to increasing the throughput of patients in a busy proton therapy

centre,” said Zhu. “We hope our cur-rent and future research can reduce the long learning curve for other proton centres, and make the most advanced radiotherapy delivery technique widely available for our cancer patients.”

The researchers’ starting point was the original analytic expression for Bragg curves, devised by Thomas Bortfeld some 14 years ago. They adapted this expression by adding a third-order polynomial term. This corrected for the use of an oversim-plified dose deposition model in the original expression, which otherwise produces a systematic discrepancy between the modelled and measured data proximal to the Bragg peak. A simultaneous optimization algo-rithm was then used to obtain “best fit” values for the polynomial coef-ficients, based upon a set of seven measured Bragg curves which ranged in energy from 126 to 212 MeV.

The accuracy of the newly adapted and optimized expression was assessed with the calculation of Bragg curves for three energies (121, 169 and 212 MeV), which were compared with reference measured data. The researchers found good agreement, observing a maximum discrepancy between the calculated and measured data of 2%.

The team then took their study

one step further, testing the ability of their expression to provide a suf-ficiently accurate set of Bragg curves for TPS commissioning. If success-ful, the expression would provide an alternative approach to that used when the TPS was originally accept-ance tested and commissioned, which required the time-consum-ing measurement of up to 94 Bragg curves for the MD Anderson scan-ning-beam delivery system.

After inputting the calculated Bragg curves as commissioning data, the newly commissioned dose model was used to calculate two spread-out Bragg peaks (SOBPs), composed of 18 and 29 energy layers respectively. Again, the calculated data were com-pared with reference measured data and good agreement was found, with an observed maximum discrepancy between calculated and meawsured data of 2%.

What next for the group? “We are extending the simultaneous opti-mization method to provide the analytical form of the proton pen-cil spot lateral dose profile,” author Xiaodong Zhang told medicalphys-icsweb. “Again, this work will save many hours of measurements. The analytical form of the Bragg peaks together with the lateral dose profile will provide a complete picture of the proton pencil beam.”

MD Anderson team: Wei Liu, Xiaoqiang Li, Michelle Quan, Xiaodong Zhang, Radhe Mohan, Michael Gillin, X Ronald Zhu and Yupeng Li.

MPWRSpr12_p07.indd 1 10/04/2012 10:07

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focus on: nuclear medicine 9

The Endo-TOFPET-US project has an ambitious aim: to create a bimodal imaging probe that combines a min-iaturized time-of-flight PET detector head with an ultrasonic endoscope. What’s more, the PET section must deliver high sensitivity, a timing resolution of 200 ps and millimetre spatial resolution.

The longer-term goal of Endo-TOFPET-US, which is now one year into its four-year duration, is to use the probe as a tool to develop new biomarkers for pancreatic and pros-tate cancer. At the recent ICTR-PHE meeting in Geneva, Switzerland, CERN senior physicist Paul Lecoq told delegates about the latest pro-gress in this international project.

The proposed probe design is based around a split PET configuration, in which one PET detector remains external to the body while the other resides on the endoscope tip.

To achieve the targeted millimetre spatial resolution, the internal PET detector head requires high granu-larity. To achieve this, the researchers created a matrix of scintillating crys-tal fibres, with each crystal measur-ing just 0.75 × 0.75 × 10 mm. The crystals are made from LYSO or cerium-calcium co-doped LSO.

The photodetector, meanwhile, comprises a silicon photomultiplier (SiPM) with a single-photon ava-lanche diode (SPAD) readout. This fully digital light detector enables single photon counting, thus maxi-mizing the timing resolution. SiPM readout is performed using a low noise, front-end amplifier based on CERN’s NINO chip. Lastly, a 500 µm thick diffractive optics film cou-

pled between the crystal matrix and the photodetector maximizes the amount of light collected.

The internal PET detector is cou-pled to a commercial ultrasound biopsy endoscope. The researchers designed separate detector heads for use in the prostate and pancreas, the latter of which comes with more stringent anatomical constraints.

The external PET plate measures 20.5 × 20.5 cm and comprises a matrix of larger LYSO crystals (each measuring 3 × 3 × 15 mm) sand-wiched between two SPAD matri-ces. During imaging, this plate will be placed on the patient’s stomach. The system determines the relative position of the internal and external PET detectors using electromagnetic tracking sensors.

In initial tests of crystal perfor-mance, an array of 16 of the smaller crystals exhibited a light yield of 10300 photons/MeV and an energy resolution of 17%. The larger crys-tals produced similar results. “But the real innovation is the photode-tector, we want to go to fully digital,” said Lecoq. “Using our very low noise NINO amplifier we have already achieved better than 188 ps on the bench, with crystals of similar size and still analogue SiPM.”

The use of ultralow-dose CT scans for attenuation correction and res-piratory gating of PET scans is feasi-ble. That’s the conclusion of a recent study, in which doses an order of magnitude lower than existing low-dose CT protocols on PET/CT scan-ners were achieved (Phys. Med. Biol. 57 309).

“The methods we have developed will directly benefit patients receiv-ing extended-duration CT scans as part of a PET/CT acquisition pro-tocol, most likely those with lung and abdominal cancers, where res-piratory motion is the greatest,” explained medical physicist and senior author Paul Kinahan, from the University of Washington.

The value of quantitative analysis of 18F-FDG PET images in oncology, using parameters such as standard uptake value (SUV), is increasingly of interest. Such parameters are poten-tial indicators of prognosis early on in a patient’s treatment course. How-ever, variation in photon attenuation with tissue depth and the blurring

effects of breathing motion intro-duce inaccuracies that must be cor-rected for if such information is to be exploited fully.

CT-based attenuation correction and respiratory gating are popular solutions to the problems. Respira-tory-gated CT is phase-matched to correct for attenuation in gated PET data, which in turn is used to sepa-

rate photons from different respira-tory phases. However, this process involves extended, continuous CT data acquisition over several breath-ing cycles, which can result in high effective doses to the patient.

The researchers set out to identify whether ultralow-dose CT scans could be used to perform attenuation correction and respiratory gating in

PET data. Ultralow-dose CT would enable the extended CT acquisitions necessary for gating, while minimiz-ing dose to the patient. Such scans, while exhibiting inferior image qual-ity compared to diagnostic scans, are nevertheless adequate for attenuation correction and respiratory gating.

“A key enabler was the recognition that if a diagnostic-quality CT image is not needed, we can significantly reduce the CT radiation dose without degrading the accuracy of the PET image,” explained Kinahan. “This led to a fun part of this project: dis-cussions with CT experts in industry and academia to convince them that we can relax the requirements for CT image quality in some conditions. At first they were sceptical, quite reasonably, but once convinced they became very enthusiastic about the concept.”

The researchers explored several dose reduction strategies, such as optimization of scanning param-eters, using simulations and phan-tom measurements. They also used

indirect approaches to compensate for the lower signal-to-noise ratios associated with ultralow-dose CT.

Simple alteration of CT acquisition parameters was enough to achieve ultralow-dose CT, while at the same time producing attenuation cor-rections of acceptable accuracy in accompanying PET scans. For exam-ple, scanning with a tube voltage of 140 kVp and 1 mm of copper filtra-tion to increase photon penetration resulted in a CT absorbed dose of 0.14 mGy at the central slice of the scan. This was a three-fold reduction compared to scanning with 80 kVp and no filtration.

Furthermore, sinogram smooth-ing was found to reduce CT noise in ultralow-dose scans, enhancing the capacity of the CT data to correct for attenuation in accompanying PET data. The combined effects of these methods indicated the effective dose from the CT component of the PET/CT scan could be reduced from 16 mSv to less than 3 mSv without degrading PET image quality.

Novel design for mini PET probe

Ultralow-dose CT enables PET correction

University of Washington team: Adam Alessio, Ting Xia and Paul Kinahan.

Split configuration: one PET plate is external to the body, the other is within the endoscopic probe.

Highly conformal radiation treat-ments, such as IMRT and stereotac-tic radiosurgery, necessitate precise determination of the target tumour volume. PET with 18F-FDG, widely used for cancer diagnosis and stag-ing, is now also being employed for such target volume delineation. Con-ventional whole-body PET scanners based on bismuth germanate (BGO) scintillators, however, offer rela-tively low spatial resolution, mak-ing it difficult to determine tumour boundaries.

This situation may be improved with the use of a new brain PET scanner based on cadmium telluride (CdTe) semiconductor detectors that directly convert gamma-rays with-out scintillator material. The CdTe detectors exhibit a spatial resolution of 2.3 mm, compared with 4–7 mm for a whole-body BGO scanner, as well as superior energy resolution.

“High-resolution PET with less partial volume effect can offer bet-ter identification of active tumour volume than MRI or CT,” explained Norio Katoh, assistant professor in the Department of Radiation Medi-cine at Hokkaido University Gradu-ate School of Medicine. “The CdTe detector has good energy resolu-tion characteristics for use at room temperature.”

Previous phantom studies showed that the contrast obtained with the new brain PET scanner was 27% higher than that achieved using the whole-body BGO scanner. Studies of patients demonstrated that the brain PET system exhibited more detailed images with sharper tumour edges. The Hokkaido team has now exam-

ined the impact of the new scanner on radiotherapy planning (Int. J. Radiat. Oncol. Biol. Phys. 82 e671).

The researchers examined 12 nasopharyngeal carcinoma patients, all of whom underwent FDG-PET scans using both the brain PET scan-ner and a conventional whole-body PET system. The two scans were per-formed on the same day, in random order, followed by CT imaging. Gross tumour volumes for the two scan types (GTVNEW and GTVCONV) were visually delineated using just the PET images.

The team then created radiother-apy treatment plans for all of the GTVs, using a prescribed dose to 95% of the planning target volume (PTV) of 2000 cGy in four fractions. They then calculated dose-volume histograms (DVHs) for the PTV, cer-ebrum, cerebellum and brain stem.

The average absolute volume of GTVNEW was 15.7 ml, compared to 34.0 ml for GTVCONV. Regardless of the order in which the scans were conducted, the GTV NEW volumes were smaller than the GTVCONV vol-umes for all 12 patients. Maximum and mean doses to the PTV were

similar for the two regimes.In the simulated treatment plans,

this reduction in target volume resulted in a significant decrease in radiation dose to organs-at-risk. In the plan based on GTVNEW, the average maximum doses to the cerebrum/cerebellum and to the brain stem were 2001 and 1475 cGy, respectively. For the plan based on the conventional scan, these values were 2233 and 1816 cGy.

The authors suggest several causes for the smaller GTV of the brain PET system. One major factor is that its higher spatial resolution yielded shaper tumour edges. Other possi-ble reasons include the lower scatter fraction and higher contrast.

The team is now working to real-ize clinical use of their scanner. “The next prototype PET system with a wide scan range, up to the lower neck level, is already in operation,” said Katoh. “We are now investigat-ing this second machine with semi-conductor detectors using a hypoxic tracer, 18F-f luoromisonidazole (F-MISO), for radiotherapy plan-ning in patients with head-and-neck cancers.”

Brain scanner eases planning

PET team: the researchers, including Norio Katoh (left group, front row, right) and co-authors, radiation oncologists and Hitachi engineers.

MPWRSpr12_p09.indd 1 10/04/2012 10:09

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Quantitative PET imaging relies on accurate attenuation correction of the recorded tracer distribution. This is usually performed by estimating the tissues’ attenuation coeffi cients from CT scan data. But in some cases – such as PET/MR imaging, for exam-ple – CT data are not available.

Previous attempts to estimate attenuation correction factors using only PET emission data have had limited success. Now, researchers in Belgium have demonstrated that for time-of-fl ight (TOF) PET scanners, it is possible to estimate this attenua-tion, except for a constant, using just the TOF emission data.

“Measurement of time-of-f light provides additional information on the spatial distribution of the injected radioactive tracer,” explained Michel Defrise, from Vrije Universiteit Brus-sel. “Specifi cally, it yields an approx-imate localization of each decaying positron along the line of response linking the two detectors. This additional information turns out to be suffi cient to determine both the attenuation image and the emission image.”

Defrise and colleagues have devel-oped a simple analytic method for estimating the attenuation sinogram and demonstrated the feasibility of their approach on a software phan-tom (Phys. Med. Biol. 57 885).

The attenuation sinogram is basi-cally a map of the probability of attenuation for each photon path through the tissues that comprise the scanned object. It is used to correct the PET sinogram, without which, the reconstructed PET image will be quantitatively inaccurate.

The researchers begin by prov-ing the theorem that for TOF PET, “the emission data determine the ϕ and s derivatives of the attenuation sinogram, for all ϕ and s values in the region containing activity” (where ϕ and s are the transaxial sinogram coordinates). They then develop an

analytical algorithm to estimate the gradient of the attenuation sinogram from 2D TOF emission data, fol-lowing the logic of the proof of this theorem.

To assess the viability of this method, the team performed a 2D TOF simulation using a software phantom comprising regions of tis-sue, bone, lung and air, with known attenuation coefficients. TOF-PET data were generated by sampling the phantom’s activity and attenuation images and using forward projection to obtain PET sinograms.

The researchers used the above-mentioned analytical algorithm to estimate the gradient of the attenu-ation sinogram, and then employed the iterative Landweber algorithm to estimate the attenuation sinogram from its gradient.

The final step in this method involves determining the arbitrary offset associated with this estimated attenuation sinogram. This con-stant can be estimated if the initial PET image can be segmented, and attenuation coefficients are avail-able in at least some of the segmented regions. For the phantom example, the researchers employed simple thresholding to obtain a region con-taining mostly tissue and bone, and used the known attenuation coeffi -cient of tissue.

This process enabled calculation of the final estimated attenuation sinogram. “If the offset is known and the data is noise free, the match is accurate to a few per cent for the specifi c case study in the paper,” said Defrise. “The accuracy, of course, degrades with increasing noise.”

“We are now working on iterative methods for solving this problem, which take into account the Poisson nature of the measurement noise,” Defrise told medicalphysicsweb. “We are also working towards extending the analytical results presented in this paper to three dimensions.”

PET imaging exploits the rapid decay of positron emitting isotopes, most commonly fl uorine-18 (18F), embed-ded in biologically active tracer molecules. Many potentially use-ful 18F-labelled probe molecules are currently unavailable for imaging because the 110-minute half-life of 18F requires rapid syntheses.

Now, researchers at Harvard University have developed a new chemical process that simplifi es the creation of PET tracer molecules

(Science 334 639).The process begins by chemi-

cally altering f luoride to create a palladium-based electrophilic f luorination reagent. This is used to synthesize aromatic 18F-labelled molecules via late-stage fl uorination, in which fl uorination takes place at the end of a compound’s synthesis and eliminates concerns regarding the isotope’s short half-life.

This development enables the synthesis of conventionally unavail-able PET tracers for applications in pharmaceutical development, as well as pre-clinical and clinical PET imaging.

TOF data quantify PET emission

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Attenuation sinograms: (left to right) true, and estimated sinograms for simulations without noise, with moderate noise and with high noise.

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focus on: technology transfer 11

CERN, the European Organization for Nuclear Research, is renowned for its pioneering research in funda-mental physics: investigating the ori-gins of the universe and how it works. Yet many of the tools employed in this illustrious endeavour, such as particle accelerators and advanced detectors, also play an invaluable role in diagnostic and therapeutic medicine.

In an attempt to exploit this con-nection and foster relationships between physicists and the medical community, two years ago, CERN established the Physics for Health (PHE) workshop. “I think that the fi rst thing we have to do is to under-stand each other, to know what is needed, what is available and what is possible,” explained Rolf-Dieter Heuer, Director General of CERN.

The outcome of that initial meeting was a CERN Position Paper detailing three initiatives covering biomedi-cal research, accelerator design and radioisotope development. Earlier this month, the second PHE confer-ence took place in Geneva, Switzer-land, this time in collaboration with the established International Con-ference on Translational Research in Radiation Oncology (ICTR).

The conference saw more than 500 attendees come together to share ideas, strengthen links and further explore CERN’s role in advancing medical technology. “For medi-cal applications, CERN can bring its experience with accelerators and particle detection, as well as in large-scale computing,” said Heuer. “Personalized cancer treatment, for example, generates a tremendous amount of data that must be dealt with effi ciently, and CERN can help.”

Perhaps even more signifi cantly, CERN also brings to the table its vast experience in managing inter-national projects and bringing communities together. “One thing CERN does very well is catalyse col-laboration,” explained Manjit Dos-anjh, co-chair of the 2012 ICTR-PHE conference. “This has been demon-strated for physics, and we want to bring this strength to these multidis-ciplinary efforts where collabora-tions are not simple.”

Work in progressWork on the three initiatives is now underway, and this year’s conference saw researchers share updates on these projects. Daniel Abler, from CERN and the University of Oxford, told ICTR-PHE delegates about pre-liminary studies into the feasibility of using CERN’s LEIR accelerator to provide ion-beams for biomedical experiments.

LEIR, the Low Energy Ion Ring, is used to accelerate heavy ions for injection into the Large Hadron Col-lider (LHC). But it only does this for six or seven weeks per year. Add in the fact that the accelerator’s energy

range is comparable to energies used for hadron therapy, and this makes it an attractive proposition for setting up a new cost-effective biomedical research facility. The facility would provide particle beams of different types and energies for use by the international scientifi c community.

One obvious application of such a resource is radiobiological stud-ies related to particle therapy, such as investigations of the relative bio-logical effectiveness (RBE) of differ-ent ion beams, for example. Beam requirements for such experiments, said Abler, include delivery of pro-tons, carbon ions and other light ions up to oxygen, with energies of up to 400 MeV/n.

Space radiat ion protect ion research could also benefi t from this type of facility. Potential projects could include investigating RBE for low fl uences of high-energy, high-Z particles, to better estimate the excess risks to crew from high-Z radiation. Here, beam requirements also include provision of ions up to iron, with energies up to 10 GeV/n.

Fur ther non-radiobiological experiments are also foreseen, such as physics studies of ions beams, and development and testing of detectors and instrumentation for dosimetry.

So how does LEIR match up to these requirements? While the cur-rent ion source can, in principal, generate any ion, light ions are dif-fi cult to accelerate at present. Install-ing a second ion source and possibly a new pre-acceleration structure optimized for light ions would allow operation during LHC fillings and fast switching between species.

Currently, the beam energy is lim-ited by the main power converter. New power supplies could enable beams of up to about 400 MeV/n for a wide range of ions. Other upgrades required include the implementation of a new slow extraction system, as well as installation of beam trans-port lines to the experimental end-

stations. “LEIR can provide ions in the energy range used for treatment, however upgrades are required and new extraction needs to be imple-mented,” Abler concluded.

Advancing acceleratorsAnother of the projects instigated by the initial PHE workshop involves setting up and coordinating an inter-national collaboration to devise a medical accelerator complex. This will include development of a com-pact, reliable accelerator with low capital and running costs, as well as design of the transfer lines and

gantries.The project, PIMMS2, follows on

from CERN’s PIMMS (Proton-Ion Medical Machine Study) initiative, which developed a synchrotron opti-mized for treating moving targets with proton and carbon ion beams.

A call has been sent out for Euro-pean institutes and laboratories to submit proposals and requirements for the PIMMS2 accelerator design, and a review committee has been set up to evaluate proposals and choose the one to pursue. “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,” explained Steve Myers, CERN’s Director for Accelera-tors and Technology.

Myers also presented details of the third initiative: the creation of

a European user facility for produc-tion of innovative radioisotopes. The aim here is to identify radionuclides with clear medical utility, but which are not generally available. The pro-ject will defi ne standard production methods and specifi cations for these radionuclides, and create a commu-nity of laboratories that can produce them for use in preclinical and clini-cal research studies.

“The fi rst Physics for Heath work-shop was two years ago, with CERN trying to be the catalyser to bring people together. This year we are ICTR-PHE, and to my knowledge it’s the fi rst workshop of this kind,” Heuer told medicalphysicsweb. “We are just at the start. One should not expect immediate results from these discussions, but I think you can expect results in the near future. I see this as a seed for the next project.”

CERN expertise strengthens medicine

Science and innovation: CERN can offer expertise in particle detectors, accelerators and large-scale computing, as well as vast experience in managing international projects and bringing communities together.

Low Energy Ion Ring: the possibility of using CERN’s LEIR ring as a new cost-effective biomedical research facility is under investigation.

MPWRSpr12_p11.indd 1 10/04/2012 10:11

focus on: optical imaging12

Easing fluorescence image reconstructionFluorescence molecular tomogra-phy is a promising, low-cost imaging modality that exploits the specificity of fluorescent biomarkers to visual-ize molecular targets in small ani-mals. The goal is to compute the three-dimensional distribution of f luorescent probes from the pho-ton density detected on the surface. The high degree of absorption and scattering of light through tissue, however, makes the inverse problem of determining probe distribution inherently ill-posed.

To address this issue, a US research team has developed an image recon-struction scheme based on regu-larization, which involves adding a penalty function to encourage certain properties in the solution. The researchers validated their pro-cedure using simulated and experi-mental data from a mouse-shaped phantom (Phys. Med. Biol. 57 1459).

The most common regulariza-tion method for handling ill-posed inverse problems includes the L2

norm penalty. This penalty gener-ates the minimum energy solution, which tends to be spread out in space. Fluorescent probes, on the other hand, typically localize within particular regions, such as tumours.

“The idea of regularization is to alleviate the ill-posedness by mak-ing use of additional a priori knowl-

edge,” explained Joyita Dutta, from the University of Southern Califor-nia, currently a postdoctoral fellow at Massachusetts General Hospi-tal. “Fluorescent probes are often designed to accumulate within spe-cific areas of interest, resulting in a spatial distribution that is sparse overall and smooth locally.”

Based on this knowledge, Dutta and colleagues designed a regulariza-tion technique that includes a combi-nation of L1 and total variation (TV) norm penalties. The L2 norm penalty

suppresses spurious background sig-nals and enforces sparsity, while the TV penalty preserves local smooth-ness in the reconstructed images.

Solving the problemNext, the researchers developed an optimization method to solve the resulting reconstruction problem. They first used the preconditioned conjugate gradient (PCG) algorithm to minimize the L1 and TV penalties. While this algorithm is straightfor-ward to implement, the computa-

tional time per iteration is large. So they also examined a method based on the separable paraboloidal surro-gates (SPS) algorithm, using ordered subsets to accelerate this approach.

Comparing the convergence speeds of the SPS algorithm with ordered subsets (OSSPS) and the PCG algorithm revealed that, for starting points far from the true solution, the OSSPS approach was much faster than PCG, while PCG was significantly faster near the solu-tion. Thus the researchers employed a compound approach using 10 OSSPS iterations to initialize the optimization problem, followed by PCG to determine the final solution.

Dutta and co-workers validated their optimization method using simulated and experimental data from a mouse-shaped phantom con-taining two embedded fluorescent line sources. Surface f luorescence data were collected at an emission wavelength of 720 nm, using a 3D f luorescence molecular tomogra-phy set-up with a 650 nm excitation source.

Using the simulated data, the team reconstructed the embedded line sources using the L2 , L1, TV and joint L1-TV penalties. They compared these four regularization schemes using a range of performance metrics.

Simulation results showed that

the L1, TV and jointL1-TV penalties generated lower mean squared error (MSE) values, stronger ROI mean signal levels, and higher signal-to-background ratio values than theL2

regularizer. The joint L1-TV approach generated a smooth solution with a sparse background. This scheme had the lowest MSE value, the least mean background signal level, and a lower background standard deviation than the L1 and TV penalties individually.

Next, the researchers recon-structed the experimental data using the four penalties. Overlaying the L1-TV reconstructed image against a CT image of the phantom revealed “a reasonable degree of overlap between the reconstructed fluores-cence molecular tomography image and the ground truth revealed by the CT image”.

The researchers concluded that L1 or TV regularization, used in combination or separately, leads to improvements in localizing fluores-cent sources. Qualitatively, the joint L1-TV images had the most natural appearance in the simulation and phantom studies, but the quantita-tive studies did not identify a clear winner. In terms of computational demand, the joint L1-TV regulariza-tion penalty is more demanding than the L2 norm, but comparable to indi-vidual L1 and TV norm penalties.

Simulated phantom: coronal sections of the mouse phantom showing (a) the two simulated line sources, and reconstructions for (b) the L2 penalty, (c) the L1 penalty, (d) the TV penalty, and (e) L1–TV penalties.

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13focus on: optical imaging

Photoacoustic device offers early diagnosisEarly detection of melanoma is criti-cal, as once this aggressive skin can-cer spreads throughout the body, prognosis is extremely poor. But even after diagnosis and excision of a melanoma lesion, it can be hard to detect the presence of metastases until the cells have already formed a millimetre-sized tumour.

Now, researchers at the Univer-sity of Missouri have developed a photoacoustic device that can detect individual metastasized melanoma cells in the blood, far sooner than can be seen using imaging equip-ment and before the cells take root in organs and form into tumours. The system can also capture any detected cancer cells for further analysis.

“This is a blood test that melanoma patients will have, after removal of the primary lesion, in order to detect and track metastatic disease,” explained the device’s inventor John Viator, associate professor in the University’s Bond Life Sciences Center. “It will provide evidence of metastasis months or even years prior to evidence in a conventional CT, MRI or PET scan.”

The first step in the test is separa-tion of the patient’s blood sample into white and red blood cells. Any circu-lating tumour cells (CTCs) cells will remain mixed with the white blood

cells. This mixture is then f lowed through a glass detection chamber. Rather than a continuous f low of cells, the system uses a two-phase flow, in which microlitre droplets of blood cell suspension are separated by similar sized bubbles of air.

Once a droplet enters the detection chamber, it is irradiated by a short pulse of high-intensity laser light. Any cells containing pigment (i.e. the melanoma cells) will absorb the light, heat up and expand, resulting

in the emission of a high-frequency acoustic wave. Droplets that emit such signals are diverted for collec-tion and analysis, while those that do not are discarded.

“Of course, positive droplets will contain many normal blood cells, so if purification is necessary, the drop-let will be diluted and run through the system again,” explained Viator. “One or more passes will result in a purified droplet containing only the CTC and saline.”

Captured cells can be individually tested to identify the form of cancer and help choose the best treatment approach for that particular mela-noma type. The photoacoustic blood test can also be used to monitor a patient’s response to a treatment, tracking whether CTCs increase or decrease over time.

Viator has recently signed a license to commercialize his device for research applications, via a newly formed company, Viator Technolo-gies. The research team is also pre-paring studies for FDA approval, a process that is expected to take two to three years. “Clinical trials will commence after validation and pilot work being conducted this year,” Via-tor told medicalphysicsweb.

“We are attempting to provide a faster and cheaper screening method, which is ultimately better for the patient and the physician,” said Viator. “There are several mela-noma drugs on the horizon. Com-bined with the new photoacoustic detection method, physicians will be able to use targeted therapies and personalized treatments, changing the medical management of this aggressive cancer. Plus, if the test is as accurate as we believe it will be, our device could be used as a standard screening in targeted populations.”

Early detection: inventor John Viator says that the photoacoustic device and method will provide an earlier diagnosis for aggressive melanomas.

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Scientists from the Scripps Research Institute have demonstrated an advanced blood test for detecting and analysing circulating tumour cells (CTCs) in cancer patients. The technique could help predict and understand cancer progres-sion and metastasis. The test, called HD-CTC, labels cells in a blood sample with fluorescent dyes con-taining antibodies that target spe-cific proteins expressed by CTCs. High-resolution digital images of the cells are analysed by an image- processing algorithm that isolates suspect cells with morphologies unlike those of healthy cells. Images of suspected CTCs can then be exam-ined by a pathologist to eliminate false positives (Phys. Biol. 9 016003).

The researchers examined 83 advanced cancer patients using HD-CTC to document the test’s sensitiv-ity and accuracy for different cancer types. The test detected five or more CTCs per millilitre of blood in 80% of patients with prostate cancer, 70% of breast cancer patients, 50% of patients with pancreatic cancer, and in no healthy controls. The current gold-standard CTC test, CellSearch, was less sensitive in detecting tumour cells in these samples. This paper is the first of a series of five studies published by the team.

Blood test finds metastatic cells

MPWRSpr12_p13.indd 7 10/04/2012 09:56

14 focus on: nanomedicine

medicalphysicsweb review Spring 2012 Sign up as a member at medicalphysicsweb.org

Gold nanoparticles are promising molecular imaging agents; and con-jugating such particles with cancer-seeking antibodies enables their direct targeting to tumours. The ability to quantitatively and nonin-vasively detect targeted nanoparti-cles in vivo could provide a promising cancer diagnostic tool.

With this aim, researchers at the Engineering Faculty of Bar Ilan University in Israel are developing tumour detection techniques based on diffusion refl ectance (DR) meas-urements of injected gold nanorods (GNRs). In their latest work, they use DR – an inexpensive and easy-to-use method for analysing tissue optical parameters – to quantitatively meas-ure the in vivo concentration of GNRs ( J. Biophotonics 5 263).

“We have performed DR measure-ments of squamous cell carcinoma containing GNRs. The nanorods were antibody-conjugated to EGFR [epidermal growth factor receptor], which is highly presented by squa-mous cell carcinoma cells,” explained study author Dror Fixler. “The EGFR concentration directly correlates with the carcinoma amount. And since the higher the EGFR amount in the cells, the larger the GNR concen-tration, the GNR concentration can indicate tumour size.”

The DR technique involves meas-uring the refl ected light intensity pro-fi le of an irradiated tissue at a range of source-detector distances. This profi le can then be used to estimate the tissue’s absorption and reduced scattering coeffi cients – the former of which will be influenced by the presence of highly absorbing GNRs.

To calculate these coefficients, Fixler and colleagues employ a diffusion-theory-based light propa-gation model. They validated this model by performing Monte Carlo simulations of photon migration through irradiated tissues. Simula-tions revealed that a higher absorp-tion coefficient leads to a sharper decay of the refl ected light intensity profi le (a linear decay, achieved by plotting the logarithm of “distance squared, multiplied by refl ectance” versus distance).

Even when the absorption coef-ficients only differed slightly, the curves exhibited distinctly different slopes. A linear relationship between the square of this slope and the absorption coeffi cient was observed – confirming that it’s possible to extract the tissues’ optical properties

from the measured refl ectance data.The team next measured the

refl ected light intensities from eight tissue-like phantoms with a known scattering coefficient and different absorption coeffi cients. The DR meas-urement set-up comprised a 650 nm laser diode excitation source and a 1 mm-diameter photodiode detector.

Plots of the refl ected light inten-sity profi le (as described above) con-fi rmed analytical predictions that a higher absorption coeffi cient results in a sharper slope. “The phantoms enabled creation of a medium with known absorption and scattering properties. Therefore, they were used to calibrate the DR profile dependence,” Fixler explained.

DR measurements were also per-formed on six phantoms contain-ing various concentrations of GNR. For each phantom, the researchers calculated the total absorption coef-fi cient due to the phantom plus the GNRs. In all cases, calculated values correlated well with those deter-mined from DR data.

In the fi nal stage of this study, the researchers examined the refl ected light intensity from tumour-bear-ing mice injected with antibody-conjugated PEG-coated GNRs. DR measurements of the tumour were performed before injection, and 15 minutes, fi ve hours and 10 hours post-injection.

Reflected light intensity profiles before the GNR injection exhibited no negative slope (when presented as the logarithm of distance squared, multiplied by refl ectance), implying low absorption and scattering prop-erties. Following injection, increas-ing accumulation of GNRs in the tumour was clearly detected by the DR profile, with a small negative slope seen after 15 minutes. After fi ve hours, this slope was steep enough to calculate the GNR absorption coef-fi cient – as 0.0096 mm–1.

Ten hours after injection, the GNR absorption coefficient was 0.015 mm–1. This corresponds to a GNR concentration in the tumour of 0.015 mg/ml.

The researchers concluded that their results prove that DR measure-ments can be used to calculate GNR concentration in a tumour. Such a molecular detection tool could facili-tate early detection of superficial tumours, such as head-and-neck can-cers, breast cancer and melanoma. It could also fi nd application in image-guided therapy of such tumours.

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Bar Ilan University researchers: Dror Fixler (top right), Menachem Motiei (top left), Rinat Ankri (lower right), Hamootal Duadi (lower left).

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