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Paediatric protons: key challenges Treating children with proton therapy comes with a unique set of challenges and constraints.

Proton therapy is an ideal fit for pae-diatric patients, delivering high dose conformality while minimizing the dose to non-target tissues. But treat-ing children comes with a unique set of challenges and constraints, as Anita Mahajan explained at the PTCOG 52 meeting held earlier this year in Essen, Germany.

“Children are not just little adults,” said Mahajan, medical director for the University of Texas MD Ander-son Proton Therapy Center. “The proportions of their body are dif-ferent, both on the outside and the inside.” Brain development, for example, occurs rapidly during a child’s first three years, and the increased radiosensitivity of the brain – and other maturing organs and tissues – must be accounted for when planning proton treatments.

Paediatric patients can present with a large variety of tumours, with varying radiosensitivity and location. Another issue is that the tumour size must be considered relative to the patient size, with a 5 cm mass, for example, represent-ing a large proportional volume in a small child. The same goes for any planned margins: “A 1 cm margin may not be a big deal in an adult, but it could well be in a baby,” explained Mahajan, who has been treating paediatric patients with protons at the MD Anderson Proton Therapy Center since it opened in 2006.

Minimizing uncertaintiesThe conformality of proton ther-apy comes hand-in-hand with the requirement for highly accurate tumour delineation, patient set-up and beam delivery. Treatment plans must pay particular attention to reducing dose to normal tissue, and any normal structures observed on imaging should be delineated for avoidance. For example, it’s possi-ble to map functional areas in the brain using functional MRI and then design a beam arrangement to avoid these areas. If possible, information regarding the different susceptibil-ity of tissue at different development should also be incorporated into the treatment plan.

A key part of the set-up process for paediatric patients relates to reduc-ing anxiety. This requires a dedi-cated therapy team and close liaison

with anaesthetists and other spe-cialists. At MD Anderson, around 60% of paediatric patients are under 10, with half of these five years or less. While anaesthesia is gener-ally required for all under the age of five, reduced anxiety may remove the need for sedation in some older children. Mahajan also pointed out that most external immobilization equipment is designed to fit adults, and that children under the age of five cannot use a bite block. It’s important, therefore, to have access to masks and other body immobi-lization kit that can accommodate smaller patients.

The MD Anderson team uses daily kV imaging to increase the accuracy of patient set-up. Mahajan empha-sises the importance of using appro-priate structures – whether bones or fiducials – for alignment.

Another option would be to use volumetric imaging for patient set-up. As such, Mahajan is hoping to install a diagnostic quality CT scan-ner in the treatment room. While

daily CT can reduce the size of the planned target volume (PTV) mar-gins, she emphasized that this must be weighed up against the increased dose delivered, as well as the addi-tional set-up time and patient anxi-ety. It’s important to use the lowest dose and smallest field size possi-ble. Ultimately, it may be feasible to employ alternative, non-ionizing methods for image-guidance, such as surface mapping or MRI.

4D and 5D issuesAs well as accurate daily set-up, intra-fractional movement arising from respiration, bladder filling, bowel gas and other organ motion must also be addressed. Motion management options reflect those under develop-ment for proton therapy in general and include the use of internal target volumes (ITV), gating and tracking. Mahajan pointed out that it’s diffi-cult to develop large programmes to evaluate such techniques in children. “I’m going to see how they do this for adults, and copy and adapt it for use in children,” she said.

Currently, Mahajan treats most paediatric patients using passive scattering, but she is starting to use scanned proton beams for some cases. She explained that the pen-cil beam on MD Anderson’s proton therapy system currently doesn’t have a penumbra trimmer, so while it delivers more conformal target dose, the out-of-field dose may be a little higher in many cases. To address this, the physics team is developing an aperture that will be incorporated into the scanning beam. Once this is installed, many more children will receive scanned pencil beam treatments.

Finally, said Mahajan, one must consider changes that occur within the tumour or patient between frac-tions – the so-called 5th dimension. She noted that paediatric tumours can develop particularly rapidly, resulting in tight time constraints for starting treatment. Once ther-apy has begun, tumours may well shrink and the patient may lose or gain weight. Monitoring such changes and performing adaptive re-planning can help reduce dose to normal structures.

The number of paediatric proton cases is growing year-on-year. The proportion of extracranial treat-ment sites is also increasing, with more treatments in motion-prone areas such as the thorax, abdomen and pelvis. To maximize the poten-tial benefits of particle therapy for paediatric patients, we need to incorporate lessons from both the photon and the adult proton worlds, Mahajan concluded.

Tami Freeman is editor of medicalphysicsweb.

“Children are not just little adults. The proportions of their body are different, both on the outside and the inside.”

Tailored approach: the MD Anderson Proton Therapy Center has been treating paediatric patients with proton therapy since September 2006.

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

This issue, distributed at ASTRO’s 55th Annual Meeting in Atlanta, GA, brings you a taster of our recent online content. If you like what you see, why not register for free as a member – simply go to medicalphysicsweb.org or visit us at booth #418.Tami FreemanEditor, medicalphysicsweb

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Radiation oncology special editionM

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focus on: proton therapy 3

Mevion Medical Systems has secured $55 m to accelerate the deployment of its MEVION S250 single-room proton therapy system. The funds were raised from existing equity investors, including Caxton Heath Life Sciences, ProQuest Investments, Venrock, and CHL Medical Partners, as well as from debt financing pro-vided by Life Sciences Alternative Funding.

While protons have the intrinsic ability to deliver a more highly tar-geted treatment compared to tradi-tional X-ray radiotherapy, proton therapy has been limited to only a select few institutions because of the high cost, large space require-ments and operational complexities of legacy proton systems. According to Mevion, its MEVION S250 deliv-ers the same precise, non-invasive treatment capabilities associated with conventional systems but with a significantly reduced size – a foot-print similar to a modern X-ray radia-tion therapy device – as well as lower implementation cost.

“Mevion was founded to provide cancer centres and patients around the world with cutting-edge proton therapy technology on a scale, size and cost that is accessible and practi-cal for today’s healthcare landscape,”

said Joseph Jachinowski, Mevion’s chief executive officer “These addi-tional funds will support the growth of our business operations in the US and internationally.”

“Providing growth capital to commercial-stage life sciences com-panies is our primary focus, and we are very excited to help fund Mevi-on’s continued leadership in state-of-the-art proton therapy systems,” stated Steve DeNelsky, president of Life Sciences Alternative Fund-ing (LASF). “We believe Mevion provides the most technologically advanced cancer treatment modal-ity at a price point that, for the first time, is making proton therapy broadly accessible to hospitals and patients. LSAF is pleased to provide the capital to allow Mevion to accel-erate its growth.”

The MEVION S250 proton therapy system is the only single-room pro-ton therapy system that is cleared by the US Food and Drug Admin-istration for clinical use. The first MEVION S250 is installed at the S. Lee Kling Center for Proton Ther-apy at Barnes Jewish Hospital at Washington University Medical Center in St. Louis, Missouri and is currently undergoing clinical acceptance and commissioning in preparation for patient treatment later this year. Five centres are under installation and construction and more than a dozen under planning.

Despite a growing volume of studies looking to determine the true pro-ton range in patients, investigations focusing on verifying proton range in the liver in vivo have been limited, due to poor contrast between irradi-ated and non-irradiated liver tissue. Now, however, using functional MRI and a hepatocyte-specific contrast agent, researchers in the US have developed a verification method that offers high soft-tissue contrast and high spatial resolution (Radio-ther. Oncol. 106 378).

“Our method provides a tool to approve the correct delivery of treatment or to detect deviations between the planned and delivered dose distribution retrospectively,” said Yading Yuan, from Harvard Medical School. “Considering that some liver patients need to come back for re-treatment after one year, our technique could also provide physicians with the exact deposited dose in the patients when prescrib-ing their new treatment plans.”

The method developed by Yuan and colleagues relies on the contrast agent Gd-EOB-DTPA. The beauty of the technique lies in the fact that the uptake of Gd-EOB-DTPA is directly related to the liver function loss due to irradiation. So when studying MR

images following administration of Gd-EOB-DTPA, a high MR signal intensity shows areas of functioning liver tissue, whereas reduced signal intensity corresponds to an area with reduced liver function.

“This method has many advan-tages,” commented Yuan. “First and foremost, functional MRI with Gd-EOB-DTPA provides high soft-tissue contrast and high spatial reso-lution. Also, no additional radiation is induced into the normal liver tis-sue during MRI scans and the use of routine follow-up MRI scans makes this an economical method for pro-ton range verification.”

The team studied the routine follow-up MR scans of five patients with metastatic liver cancer treated with 3D conformal proton stereo-tactic body radiotherapy with two cross-fired fields. The time interval between the end of treatment and the MR scans ranged from 11 to 25 weeks, and in all cases the MR images were obtained 20 minutes after an intravenous injection of Gd-EOB-DTPA.

In order to verify proton range, the researchers determined the relation-ship between radiation dose and the resulting MR signal intensity. Then, by applying this dose-signal inten-sity correlation, they were able to explore any differences between the prescribed dose range and the MRI-estimated dose range along each

beam direction.“Our results showed that beam

over- and under-shoot were gener-ally on the order of a few millime-tres, which is within our proton treatment margin,” commented Yuan. “Undershoot was detected for the majority of sampled voxels. For AP/PA beams, the mean differ-ence was –2.18±4.89 mm. For lateral beams, the mean difference was –3.90±5.87 mm.”

Following the success of this fea-sibility study, one new avenue of research for the team is to identify the earliest time at which there is sig-nificant contrast between irradiated and non-irradiated liver tissue. “If we could detect an MR signal inten-sity change during a typical treat-ment regime of five fractions in 11 days, this would open the door to an immediate assessment of unaccepta-ble discrepancies between planned and detected dose,” said Yuan. “We know we can see the effects of radiation two to three months post- treatment, but no data for earlier time points are available in the lit-erature. Joao Seco, Christian Richter and other colleagues are now run-ning a trial to see if similar changes can be seen as early as one or two weeks after the start of treatment.”

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

Scanned ion beam delivery, in which the beam paints the tumour in a raster fashion, is the most precise external-beam radiotherapy tech-nique currently available. As part of the commissioning of such scanned beams, the planning system records the pencil beam spot width. How-ever, fluctuations in the beam trans-port and extraction systems may change the spot size, potentially impacting the delivered dose.

To assess the clinical impact of spot size variation, researchers at the University of Marburg in Ger-many have performed a detailed simulation study to investigate the dosimetric consequences of changes in the delivered spot size from the nominal values used for planning. They examined the impact of spot size variation on both target cover-age and sparing of critical structures, for scanned protons and carbon ions (Phys. Med. Biol. 58 3979).

“For the last few years, our group has been working primarily on radi-otherapy with protons and carbon ions, in preparation for the upcom-ing opening of a particle therapy centre on the medical campus of the University of Marburg,” explained researcher Urszula Jelen. “This prompted us to focus on potential delivery-time uncertainties and their clinical relevance, for the sake of patient safety and improved treat-ment quality. This study on the effects

of geometric f luctuations at beam extraction was a natural next step.”

Jelen and colleagues prepared proton and carbon ion treatment plans for 12 patients with skull base tumours and 12 with prostate car-cinoma. Next, they recomputed all plans with spot size changes of ±10, ±25 and ±50% , ref lecting typical fluctuations, peak fluctuations and

fault conditions, respectively, for synchrotron-based particle therapy. They then fed the modified plans back into the planning system and recomputed dose distributions.

The primary effect of spot size vari-ation was a loss of conformity and homogeneity in the delivered dose, mainly near the target edges. For an example skull base case, dose distribu-

tions revealed areas of overdosage as spot size decreased and reduced target coverage with increased spot size.

For both ion species, skull base plans recomputed with spot size changes of ±10% continued to ful-fil the clinical objectives. Spot size increases of +25% and +50% resulted in a clinically relevant reduction in mean CIPTV-95% (planning target volume (PTV) receiving 95% of the prescribed dose) to 92.3% and 81.9%, respectively, in carbon ion plans, and 90.3% and 80.6% in proton plans. Spot size changes of +25% , +50% and –50% reduced CICTV-98% (clini-cal target volume (CTV) receiving 98% of the prescribed dose) to 91.0%, 77.2% and 91.7% , respectively, for carbon ion plans, and to 90.2% , 78.0% and 87.6% for proton plans.

Differences were also seen in the dose delivered to critical structures near the target. For all patients and both ion species, brainstem dose increased as spot size decreased. For carbon ions, maximum increases in Dnear-max (the dose received by 2% of the volume of interest) of 1.0, 2.5 and 5.4 percentage points (pp) were seen for spot size changes of –10%, –25% and –50%, respectively. For proton plans, the respective increases were 1.1, 2.6 and 4.4 pp.

Plans for prostate cases behaved similarly to the skull base plans, with decreasing spot size leading to over-dosage, increasing spot size result-

ing in underdosage and no changes to mean PTV dose. For carbon ions, spot size changes of ±10% and ±25% did not induce a clinically relevant deterioration in CTV and PTV cov-erage. Changing the spot size by +50% reduced the mean CIPTV-95% to 87.5%, while changing it by –50% reduced CICTV-98% to 81.7%.

In the proton plans, no deterio-ration in PTV coverage was seen for any spot size reductions or an increase of 10%. Increases of +25% and +50% reduced PTV coverage to 91.6% and 85.0%. For protons, a spot size decrease always resulted in pro-nounced reduction of CICTV-98%, to 92.0% , 88.1% and 78.3% for –10, –25% and –50%, respectively.

Again, the team observed dose modifications in nearby critical structures. In carbon ion plans, the maximum increase of Dnear-max to the rectum in one patient was 1.8, 4.8 and 10.4 pp, for spot size changes of –10%, –25% and –50%, respectively. For proton plans, the maximum respective increases were 1.1, 2.5 and 4.1 pp.

“The observed effects on target cov-erage are reassuring and let us believe that cure should not be affected by typical everyday fluctuations,” said Jelen. “As to the possible overdosage to critical healthy structures, their proximity and the overall treatment region anatomy definitely play an important role in some patients.”

MRI shows beamrange in the liver

Investigations into spot size variations

Skull base case: carbon ion dose distributions with original and modified spot sizes. PTV is in white, brainstem in blue (in the transversal view).

Mevion secures $55 m in funding

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focus on: proton therapy 5

Accounting for systematic and ran-dom setup errors as well as range uncertainties is vital when evaluat-ing proton treatment plans. A new study published in the Red Journal, which takes a statistical approach to this issue, has shown that while target coverage for most of the patients involved was acceptable even when uncertainties were taken into account, the dose received by organs-at-risk varied significantly (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2013.04.009).

“In our approach, we seek to quan-tify the effect of uncertainties in dose and other dosimetric parameters such as the dose volume histogram through widely accepted statisti-cal metrics,” Lei Dong from Scripps Proton Therapy Center, told medical-physicsweb. “We have developed what is perhaps the simplest, yet most comprehensive, method of evalu-ating proton plans in a clinically meaningful and realistic way based on statistics.”

The study presented in the Red Journal builds on work published by researchers at the MD Anderson Cancer Center in Houston, Texas.

The MD Anderson team had pre-viously developed a fast dose cal-culation method (Phys. Med. Biol. 57 3555) that is applicable when a dose distribution has already been calculated, and you require to know how this dose distribution will change when a setup or range error is introduced.

The Scripps-MD Anderson collab-oration used its fast dose calculation approach to evaluate the treatment plans generated for 20 lung cancer patients, 10 prostate cancer patients and one brain cancer patient, all of

whom had received a course of pro-ton therapy.

“For each patient, different sys-tematic setup and range errors were randomly generated and assigned,” explained Peter Park, a researcher at MD Anderson. “We followed each of these patients through multi- fractionated radiotherapy and at each fraction a random setup error was introduced. The cumulative dose (i.e. summed dose over all frac-tions) for each patient represents one sample dose of a population. In total, 600 dose calculations were per-

formed per treatment plan.”The resulting uncertainties in the

dose were then visualized spatially on a planning CT image as a probabil-ity map, which shows the likelihood of not meeting the plan’s dosimetric goal for an individual voxel.

“Because our method is based on a large number of simulations, it can provide a realistic assessment of treatment errors,” commented Park. “For example, if one asks ‘what is the probability of this patient receiving a dose greater than 40 Gy to 60% of his rectum under the assumed setup and range uncertainties? ’, our proposed method can provide a good estimate to such question.”

For the 31 treatment plans consid-ered, Park and his colleagues found that the expected target coverage when uncertainties were considered was consistently lower than the nom-inal value determined from the origi-nal treatment plan. Mean differences of –1.1% (–0.9% for breath hold), –0.3% and –2.2% for the lung, pros-tate and brain cases were observed.

“Our analysis showed that tar-get coverage for most patients was acceptable even under uncertain-

ties,” said Park. “On the other hand, dose to organs-at-risk can be easily overlooked during the planning pro-cess and indeed we observed large deviations of dose to organs such as the rectum and brainstem.”

It is worth noting, however, that anatomical deformation and rota-tional errors are not considered in this approach. “Our estimated uncertain-ties reflect only what can be captured through the planning CT images, but we know patient anatomy changes constantly throughout the course of treatment,” commented Park. “Any issues related to breathing motion were also not considered. Many of these issues can be factored into the framework that we propose and such an effort is underway.”

Park also says that it is the team’s intention to re-evaluate some dosi-metric studies that compare IMRT with proton therapy. “Many stud-ies fail to incorporate the effect of a plan’s robustness under uncertainty and draw conclusions solely based on the nominal situation,” he said. “The treatment uncertainties are real and must be included in any plan comparison studies.”

The finite range of a proton beam means that even small geometric and anatomic variations can lead to dose discrepancies when delivering pro-ton therapy. Speaking at the PTCOG 52 meeting in Essen, Germany, Mar-tijn Engelsman described how pro-ton therapy can benefit from various image-guidance techniques.

“The machine is not the problem,” said Engelsman, from Delft Univer-sity of Technology in the Nether-lands. “The problem is the patient.” He explained that while modern treatment systems can deliver pro-tons with an accuracy of less than 0.5 mm, range uncertainties arising from set-up errors, CT number-to-proton stopping power conversions, intra-fraction motion and interfraction anatomy variation can all degrade the proton dose distribution.

Engelsman began by discussing some basic range uncertainties. Cur-rently, the total background error, due to uncertainties in CT imaging, conversion of CT data to proton stop-ping power and dose calculation, is estimated to be in the range of 3 to 3.5% plus 1–3 mm. “Improvements in image guidance can probably reduce this by a factor of two,” he explained.

To realize an accuracy gain of around ±3 mm, one option is to use dual-energy CT for dose calcula-tions. This method is more robust to uncertainties in tissue composi-tion than standard CT because it incorporates elemental composi-tion information when calculat-ing proton stopping power ratios.

Engelsman noted, however, that the accuracy of this technique has not been fully validated under clinical circumstances such as beam hard-ening, scatter and noise.

Another possibility would be to implement proton radiography or proton CT, which offer direct meas-urement of proton stopping power. On the downside, these methods suf-fer from limited spatial resolution and long reconstruction times; they are also still in the development phase.

Engelsma n descr ibed some medium- and long-term goals. He noted that his five-year goals aim to significantly improve accuracy, but more importantly to help us under-stand how best to use advances in imaging, and to help define the right questions. The 10-year goals, meanwhile, represent “the sky is the limit” aims.

In five years’ time, he says, we should be using 5 mm-resolution proton CT or radiography as a one-time, per-patient rough evaluation of CT conversion. In 10 years, we should aim for low-dose, daily iso-centric proton CT for dose recal-culation. Another option could be to implement one-time, high-res-olution proton CT, which is then deformably registered onto a daily imaging set.

The next stage in improving treat-ment accuracy lies in the use of in vivo proton dosimetry. Visualization of the beam during delivery would pro-vide real-time validation of machine behaviour and proton stopping power conversion, and indicate any significant anatomy changes.

Engelsman described the two main technologies being lined up for

in vivo dosimetry. The first is the use of PET imaging to visualize positron emitters generated as the therapeu-tic beam travels through the patient. This method is already being applied clinically, both on-line and off-line, and can deliver an accuracy of 1–2 mm in favourable locations. It does, however, suffer from biological washout of the signal and low count-ing statistics.

The second option under investi-gation is prompt gamma imaging, which is performed on-line and provides immediate data. Engels-man noted that while this method is particularly suitable for determin-ing beam range, it is still in the early stages of development. “There are plans to bring a prompt gamma pro-totype into the clinic in the next one or two years,” he said.

In five years’ time, says Engelsman, we should aim for routine use of lim-

ited accuracy (10 mm and above, for example) in vivo dose monitoring, to complement off-line plan and field quality assurance (QA). The 10-year goal, he suggests, is millimetre-accuracy real-time dose reconstruc-tion. This could provide a basis for implementing dose-guided proton therapy, along with in vivo QA of the adapted treatment plan.

Finally, Engelsman explained how imaging can address inter-fraction anatomy variations arising from patient weight changes, for exam-ple, or tumour shrinkage. Options include performing cone-beam CT in the treatment position or an out-of-room diagnostic CT, which offers higher contrast and image quality, and can be used for dose recalculation.

The goal for today, says Engels-man, is to ensure a rapid roll-out of cone-beam and diagnostic CT. In five

years, we should have clinical experi-ence in routine, full 3D/4D imaging, along with smooth image acquisi-tion and image matching. In 10 years, he envisions, we may perhaps see the integration of MR-guidance into proton therapy.

Much more important than volu-metric imaging, Engelsman contin-ued, is how we will use these images, especially for replanning. Currently, replanning is an off-line process that can take two to three days. In five years, we should achieve online evaluation of plan accuracy and daily selection of a plan-of-the-day based on in-room CT.

In 10 years, says Engelsman, we should be aiming to achieve 10 s automated on-line plan re-optimi-zation, while the patient is on the treatment couch. He noted that this level of automation would effectively remove the physicist and the physi-cian from the treatment preparation process, thus requiring a high level of faith in the treatment-planning system. Furthermore, in vivo dosim-etry then becomes a necessity as a replacement for off-line dosimetric plan-specific QA.

Engelsman emphasized that the main priority at present is to be able to retrieve information regarding the quality of dose delivery – even by simply introducing existing 3D imaging technology into the pro-ton therapy workflow – by means of rapid dose recalculation, and to replan where required. “The five-year goals are certainly within reach,” he concluded. “They’re certainly not the end result, but they will help us to formulate what we want to achieve in 10 years’ time.”

A thorough evaluation of proton plans

Proton plan: a lung cancer plan (a) shows that the risk of losing target coverage at 74 Gy is about 10%, as shown in blue (b). The fraction of dose exceeding the 65 Gy limit for the oesophagus is much higher (c).

Keynote talk: Martijn Engelsman speaking at the PTCOG meeting.

The benefits ofimage guidance

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7focus on: radiotherapy

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Skin measurements help monitor motionMeasurements of subcutaneous tis-sue thickness have the potential to improve the accuracy of real-time optical markerless tracking of patient motion during intracranial radio-therapy. In new work, researchers in Germany have provided proof of concept for a laser-based system, with simulated measurements of tissue thickness reaching accuracies of up to 18 µm (Biomed. Opt. Express 4 1176).

“This will be the first fully non-invasive and contact-free approach to accurately monitor motion during treatment in real-time,” said Tobias Wissel, electrical engineer at the Uni-versity of Lübeck.

Markerless optical tracking of motion in patients receiving radia-tion therapy has potential as a prac-tical alternative to methods that either involve exposure to ionizing radiation, require patient immobi-lization or attachment of markers to the patient’s skin. Currently, the approach relies on measurements of skin contour alone and tracks motion by determining the transformation of a set of locations – or point cloud – on the patient’s skin between two successive scans. However, shadow-ing and the deformable nature of skin limit the accuracy of the approach.

“Our approach tackles this weak-ness by uncovering subcutaneous structure,” explained Wissel. “Incor-porating these additional features into the registration process makes it more robust and accurate.”

The new technique determines the thickness of subcutaneous soft tissue

overlying bone by reflecting a near infra-red laser beam off the patient’s forehead. The diffusely ref lected beam spot is recorded by a camera. Tissue thickness is determined from the spatial variations in the inten-sity of the reflected laser spot, using a machine learning algorithm that deduces the relationship between the reflected light and tissue thickness.

Envisaged primarily as a tool for tracking head motion during intrac-ranial irradiation, Wissel told medi-calphysicsweb that the technique could also be used to verify patient setup prior to treatment and extended for use at other treatment sites.

The researchers simulated the laser-tissue interaction using previously developed Monte Carlo code that they adapted for the study. An eight-layer tissue model, extending down to the subcutaneous fat and bone, was used to test technique performance for 101 tissue thicknesses, ranging from 2.1 to 7.1 mm, and a range of incident beam angles. A 750 × 750 array of 20 µm wide pixels was used to record the reflected intensities, simulating the presence of a camera.

Corrections were made to the reflected laser spot for non-orthog-onal angles of incidence that distort the spatial variations in intensity and

once corrected, energy-based fea-tures were extracted. The features equalled the light intensity inte-grated over each of seven 0.1 mm-wide concentric regions-of-interest (ROI) centred on the reflected spot.

The features were inputted into the Support Vector Regression machine learning algorithm to determine the thickness of the simulated tissue lay-ers, based on a regression model that relates the features to skin thickness. The model is built using a training data set of known skin thicknesses.

Technique accuracy, quantified using the root mean square (RMS) error was, at worst, 90 µm when all angles of incidence were taken into account. This error dropped as low as 33 µm for the same measurements when strategies that further reduced the effect of non-orthogonal inci-dence were introduced, and as low as 18 µm when only beams orthogonal to the skin were considered.

In collaboration with Varian Medi-cal Systems, the group is working on advancing the technology towards clinical implementation. “We are currently working on a first func-tional prototype by combining fast laser scanning with optical meas-urement of tissue thickness,” said Wissel. “Preliminary in vivo results on data analysis for our first few sub-jects will be published by the end of the year.”

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

The Lübeck team: (clockwise from bottom right) Tobias Wissel, Benjamin Wagner, Patrick Stüber, Ralf Bruder, Floris Ernst and Achim Schweikard.

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December 2010 May 2012

Defining deformable image registration since 2002

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edical Center

Previous Dose Current Dose Composite Dose

Beta treatment is a safe option

R a d io - i m mu no t h e r apy w it h the low- energy beta emitter 177Lu-DOTA-rituximab is safe and effect ive for ly mphoma patients, according to a study from Sw itzerland. T he researchers evaluated the maximum toler-ated dose and clinical response to 17 7Lu- DOTA-r it u x imab in 31 patients with relapsed or refrac-tory CD20 -positive B-cell lym-phoma ( J. Nucl. Med. 54 1045).

All patients received an initial dose of 740 MBq/m2 body surface area of 177Lu-DOTA-rituximab, and then doses were increased. The maxi-mum tolerated dose was 1665 MBq/m2. Clinical responses occurred at all dose levels for patients with follicu-lar (82% overall response rate) and mantle cell (21% response rate) lym-phomas. With a median follow-up of almost seven years, the estimated median time of survival after radio-immunotherapy was four years.

The image shows a follicular lym-phoma in a patient treated with 177Lu-DOTA-rituximab. (A) FDG PET shows disseminated relapsing disease. (B) 177Lu scintigram four days after 177Lu-DOTA-rituximab depicts 177Lu in tumour masses. (C) FDG PET two months later shows complete remission.

SNM

MI

MPWRAut13_p07.indd 11 22/08/2013 15:05

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focus on: radiotherapy8

An interactive take on hot spot correctionInverse radiotherapy planning can achieve excellent adherence to specified clinical constraints. It’s not uncommon, however, to end up with hot spots in organs-at-risk or cold spots in targets. These localized dose insufficiencies can be hard to correct, since plan optimizations are based on global indicators such as equivalent uniform doses, for exam-ple, or dose-volume constraints for whole structures.

Researchers at the Fraunhofer Institute for Industrial Mathematics (ITWM) in Germany have developed a new approach for correcting any hot and cold spots in a treatment plan. The aim is to create a locally improved plan while retaining previously estab-lished trade-offs between critical structure sparing and target confor-mality (Phys. Med. Biol. 58 1855).

The current process for dealing with hot and cold spots can be ardu-ous, says ITWM’s Philipp Süss. “In a first step, the optimization param-eters for the structure containing the critical spot are modified,” he explained. “If the spot cannot be corrected by that, an additional vol-ume-of-interest is defined solely for the purpose of being able to modify the dose more locally. This process is cumbersome and bears the risk of new hot or cold spots just outside the helper volume.”

The approach proposed by Süss and colleagues starts by examining the initial “almost acceptable” plan generated by the treatment planning system to find any subregions with dose deficiencies. The researchers formulated a mathematical optimi-zation problem – the critical region

correction (CRC) problem – that obtains one or more locally cor-rected plans, based on the initial clinical trade-offs plus new speci-fied dose constraints in any hot/cold spots. Unwanted hot spots are removed by applying upper bounds and local cold spots eliminated by enforcing lower bounds.

After generating the alternative plans, which are similar to the initial plan but without the local deficien-cies, the planner then faces the task of deciding how much change in the initial characteristics are acceptable to obtain local improvements. Süss and colleagues suggest that this con-flict should be explored interactively, and propose the use of a slider.

By manipulating on-screen sliders,

users can explore trade-offs between plans while inspecting changes in the dose distribution and dose-volume histograms (DVHs) in real time. In cases where one alternative plan was calculated, one end of the slider posi-tion corresponds to the original plan and the other to the alternative, with positions in between corresponding to a mix of both. If more than one alternative plan is generated, addi-tional sliders can be implemented.

The scheme was evaluated using a clinical example of a meningioma at the base of the skull. The original optimization problem consisted of equivalent uniform dose (EUD) objectives for all risk structures, plus objectives to minimize underdose and overdose in the target.

The researchers first created a plan with similar overall character-istics to that used to deliver the actual treatment. A dose slice close to the isocentre revealed a hot spot where the high dose contour entered non-target tissue. Using prototype soft-ware developed by the ITWM team, a 9 × 9 × 9 mm subvolume with a dose of between 45.5 and 60.8 Gy was revealed. Four voxels in this region overlapped with the target contour and the remaining 23 voxels were defined as the hot spot.

To eliminate this hot spot, the researchers solved the CRC prob-lem, using an ambitious upper limit of 30 Gy for all 23 voxels. Two plans were generated, one using a constant voxel weighting, and the other cal-

culated by exponentially increasing the voxel weights with increasing distance to the critical region. These plans represent extreme cases of keeping changes local and spreading the changes out.

In both cases, the CRC problem could be solved without violating the original underdose and overdose constraints. DVHs showed that the target curves had barely changed and that the dose in structures far from the hot spot changed significantly more in the plan where changes were allowed to spread out.

The researchers then investigated the optimal mix of each two new plan and the original, using two slid-ers: one to control the “degree of cor-rection” of the local insufficiencies (α slider), and another representing the “spread of allowed change” (β slider). Moving the α slider revealed that the dose in the hot spot could be reduced by 10 Gy without reducing the mini-mum dose in the target. The maxi-mum spinal cord dose increased significantly for plans where changes were spread over larger areas.

They also created two “compro-mise” plans, in which the dose was reduced by about 20 Gy. Süss notes that it’s also possible to create a plan that combines all three plan options, by moving both sliders. “If you image a continuous morphing between the two compromise plans, you get the right impression of the effect of pull-ing the � slider,” he explained.

The researchers conclude that it is possible to eliminate a hot spot outside the target volume while con-trolling the dose changes to all other parts of the treatment plan.

Compromise plans: (a) spread out changes; (b) keeping changes local. The arrow shows the declared hot spot.

Adapting treatment to compensate for intra-fraction motion is cru-cial to minimize the dose received by healthy tissue. One emerging motion compensation technique, which involves continuous inter-action between a radiotherapy delivery system and the patient, is real-time tumour tracking (RTTT). Some commercially available linac systems now feature RTTT func-tionality, and a growing volume of research is appearing that assesses the technology’s performance.

One such study has been published by researchers at the UZ Brussel, Vrije Universiteit Brussel, in Belgium. The team evaluated the performance of a Vero stereotactic body radio-therapy (SBRT) system equipped with dynamic tracking technology under clinical conditions. The study involved five patients, and has led to the system being used on a routine basis (Radiother. Oncol. 106 236).

“Our results gave us the confidence to start treating patients with the dynamic tracking solution, which we

have been doing since May 2012,” said Tom Depuydt from the Radiotherapy Department at UZ Brussel. “Based on the data acquired at UZ Brussel and at Kyoto University in Japan, we want to further improve the current Vero tracking hardware/software solution and optimize our respiratory corre-lated SBRT protocols. The combina-tion of tracking and state-of-the-art delivery techniques like IMRT and VMAT will definitely be part of our future research.”

The study performed by Depuydt and colleagues focused on workflow

in a clinical setting. Specifically, the team looked at the length of time before treatment could be initiated; the increased dose received by the patient due to tumour tracking; and the tracking performance in terms of residual tracking error.

Five patients (three with liver can-cer and two with lung cancer) were enrolled in the study and the com-plete dynamic tracking process was performed, albeit without activating the 6 MV treatment beam. First, each patient was positioned using both optical methods and cone-beam CT

or orthogonal X-ray imaging. Next, the so-called 4D modelling (4DM) commenced.

During the 4DM process, the patient ’s breathing signal was acquired using infrared markers placed on their upper abdomen. When a valid breathing signal had been obtained, X-ray imaging was used to localize the position of a pre-viously implanted fiducial marker located in the gross tumour volume (or as close to it as possible). Both of these factors were then used to generate a model that correlates the external breathing signal and the internal tumour motion and which in turn drives the gimballed-linac tumour tracking.

The team reports that the average time to build the correlation model was 3.2 min and that the elapsed time from the patient entering the treat-ment room until the beam would be turned on was around 9 min. The researchers believe that both these times could be reduced.

That said, Depuydt stresses that for any type of respiratory corre-lated treatment it is important to ensure that the patient has estab-lished a stable breathing regime. This

is particularly relevant as the Vero’s current dynamic tracking technol-ogy does not update the correlation model during treatment delivery. However, depending on the visual-ized deviations between the actual position of the fiducial markers and their predicted position, the operator can decide to rebuild the model dur-ing the treatment fraction.

Tracking errors were found to be below 3.08 mm and the additional imaging skin dose could be kept below 30 mGy for a 20 Gy fraction. “Compared with the levels of skin dose we give per fraction in SBRT schemes, the additional 30 mGy is a low price for increasing the accu-racy of the treatment,” said Depuydt. “The interplay between dosimetrical coverage of the tumour and track-ing error is the subject of ongoing research at UZ Brussel. As with any form of uncertainty in aiming the beam at the tumour, this depends on the applied CTV-PTV margin.”

Other avenues of future research include developing an efficient qual-ity assurance protocol with minimal additional workload, as well as RTTT without the need for implanted markers.

Study initiates routine therapy

Clinical use: Vero system in a treatment room at Vrije Universiteit Brussel.

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9focus on: radiotherapy

A recent study by University of Michigan researchers has shown that the survival of non-Hodgkin’s lymphoma patients receiving I-131 tositumomab radio-immunother-apy increases with administered activity. But the activity of the beta emitter that can be safely admin-istered is limited by the radiotoxic response of the patient’s active bone marrow and, to date, there’s been no accurate way to predict active mar-row dose, or response, on a patient-by-patient basis.

Now, in the first steps towards pre-dicting marrow toxicity, the same group has developed a Monte Carlo model that calculates patient-specific dose rates. The model uses measure-ments of the patient’s bone volume fraction, a measure of bone density, and active marrow cellularity, the fraction of total bone marrow that is active (Phys. Med. Biol. 58 4717).

“We have shown that we can account for patient-to-patient vari-ations in bone and active marrow fractions when calculating active marrow dose,” said Scott Wilder-man, nuclear engineer at the Univer-sity’s Ann Arbor campus. “The doses we compute can differ from those computed by even the best of the previous methods by 20% or more, depending on the specifics of each patient’s bone anatomy.”

Several models can already esti-mate active marrow dose, based on SPECT/CT images that provide distributions of marrow-bearing bone, or spongiosa, in the patient. However, they rely on approximate models of the structure and compo-sition of the spongiosa, which con-tains bone and inactive marrow, as well as active marrow, and do not use direct, patient-specific measure-ments of spongiosa characteristics like cellularity.

“Even the more sophisticated models that we could have used were inadequate, because they didn’t properly deal with anatomical varia-tions in spongiosa between patients,” said Wilderman.

The researchers adapted DPM, a

previously developed Monte Carlo dosimetry program, to calculate the dose rate in active marrow in 14 patients receiving radio-immu-notherapy. The original model cal-culates a single dose for each image voxel containing spongiosa, assum-ing a homogeneous composition. In the new, modified version energy deposition is calculated separately for the three distinct components of the spongiosa, the active marrow included.

The calculation is based on a set of electron absorption fractions for each component. A function of electron energy, cellularity and bone volume fraction, the param-eter describes the fraction of an incident electron’s energy absorbed

by the tissue.Values for the fractions were

derived from the literature and a sep-arate Monte Carlo simulation using the EGS5 code, based on patient-specific cellularity and bone volume fractions. Cellularity was measured in every patient from a pelvic biopsy sample. Bone volume fractions were derived from the measured cellu-larity and CT densities, observed voxel-by-voxel in SPECT/CT scans acquired pre- and post-treatment.

The researchers compared the active marrow dose rates calculated using their patient-specific approach with the dose rates calculated using the original DPM model. In the lat-ter case, spongiosa dose was used as a surrogate for active marrow dose, an approach previously studied by the group.

The patient-specific approach resulted in active marrow dose rates that varied significantly from those obtained with the original model. For one individual, a discrepancy of 18.5% between the two approaches was revealed. Marrow cellularity in particular had a marked effect on the calculated dose rates.

The researchers have since moved on to more detailed investigations of marrow dose and response. Their ultimate aim is for the model to ena-ble personalized prescriptions that avoid high-grade marrow toxicity, while delivering the maximum pos-sible dose to the tumour and maxi-mizing disease control.

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A novel drug may help increase the efficacy of radiation therapy for the most deadly form of brain cancer, report scientists at VCU Massey Cancer Center. They used an experi-mental drug, KU-60019, to block the activation of ATM, an enzyme that helps repair DNA damage. In mouse models of human glioblastoma mul-tiforme (GBM), the drug extended survival two- to three-fold over con-trols when used in combination with radiotherapy. The new approach was particularly effective against gliomas with a mutation in the p53 tumour suppressor gene, which accounts for approximately 30% of all glioma cases (Clin. Cancer Res. 19 3189).

“Sadly, the average life expectancy of patients diagnosed with glio-blastoma is just 12 to 15 months,” explained lead researcher Kristoffer Valerie. “By limiting the tumour’s ability to combat DNA damage caused by treatments such as radia-tion, we are hopeful that we can enhance our ability to specifically target the glioma, prolong survival and reduce damage to surrounding brain tissue. We are encouraged by these early findings and will con-tinue to move forward with our research. However, more studies are needed before we can proceed with testing this new therapy in humans.”

Drug enhances brain treatment

GammaPod offers breast-specific SBRTAccelerated partial breast irradia-tion (APBI), used to treat patients fol-lowing breast-conserving surgery, is commonly performed using multi-catheter interstitial brachytherapy or balloon-based brachytherapy devices. But now there’s another option: GammaPod, a breast-specific stereotactic body radiation therapy (SBRT) device that delivers radiation using rotating Co-60 sources.

Developed by the University of Maryland School of Medicine and Xcision Medical Systems, Gam-maPod also includes tungsten col-limators, a dynamically controlled patient support table, and a breast immobilization cup that addition-ally functions as the stereotactic frame. In collaboration with the University of Maryland researchers, medical physicists at Karolinska University Hospital in Sweden have performed a comparative analysis of the dose distributions provided by GammaPod and brachytherapy-based APBI techniques (Phys. Med. Biol. 58 4409).

“The ability of GammaPod to concentrate the dose where we want it to be opens new opportu-nities beyond post-operative APBI, such as pre-operative treatment, or even ablating the gross tumour vol-ume and sterilizing the tumour bed simultaneously without surgery,”

said Karolinska medical physicist Jakob Ödén.

GammaPod comprises a hemi-spherical source carrier containing 36 Co-60 sources. The source assem-bly rotates in synchrony with the collimator structure (which offers apertures of 1.5 or 2.5 cm), giving rise to 36 non-coplanar, concentric arcs focused at the isocentre. The patient is treated in prone position with the breast positioned inside the hemispherical assembly and immo-bilized using negative pressure.

Ödén and colleagues modelled spherical targets with diameters of 2, 4, 5.6 and 6.5 cm for GammaPod. They evaluated the 2 cm target in a central position close to the chest wall, while the other targets were also evaluated in four peripheral positions with different skin prox-imities. The dosimetric output of GammaPod was modelled using a Monte Carlo based treatment plan-ning system.

For comparison, they created 3D models of single and multi-lumen balloon devices, with various bal-loon diameters, as well as multi-catheter devices with one central and 6, 8 and 10 peripheral catheters. Applicator-to-skin distances cor-responding to those considered for GammaPod were examined for each device.

The researchers first examined dose coverage for the different irra-diation techniques. All modalities fulfilled the dosimetric goals for all targets. The average value of V95 (the target volume receiving at least 95% of the prescribed dose) was 95% for the three brachytherapy techniques and 96% for GammaPod. Dose vol-ume histograms (DVHs) showed that while GammaPod exhibited simi-lar dose coverage to the other tech-niques, it demonstrated considerably

improved target dose homogeneity.They then examined dose fall-off

profiles beyond the target. For cen-tral targets, at small distances from the target edge (up to about 1 cm) the brachytherapy techniques exhibited a slightly steeper dose fall-off gradi-ent than GammaPod; at greater dis-tances, the relation was generally the opposite.

“Sharp dose fall-off immediately adjacent to the target may be impor-tant to tumours at other sites, but

not necessarily for breast cancer because the planning target vol-ume definition of 1 cm expansion from the surgical cavity is rather arbitrary. The probability of finding residual tumour foci in the breast post-surgery does not drop abruptly at 1 cm from the cavity wall,” Ödén explained. “At larger distances, how-ever, we do want the dose to be as low as possible to minimize dose to the lung and heart. Doses at these larger distances are much smaller with GammaPod, giving it a potential clinical advantage.”

The team also calculated skin doses for the four scenarios with targets close to the skin. For all tar-get sizes, relative skin doses were considerably lower for GammaPod than for any of the brachytherapy techniques.

“GammaPod delivers, non-inva-sively, more uniform dose distri-bution to the target and faster dose fall-off at a distance away from the target, as well as lower skin dose,” said Ödén. “A clinical consortium has been formed to design clini-cal trials to explore the Gamma-Pod’s dose focusing abilities and its geometric accuracy, as well as the possibility of delivering ablative doses to intact breast cancer, which has a low α /β-ratio,” Ödén told medicalphysicsweb.

Stereotactic radiotherapy device: an artistic rendition of the GammaPod.

Personalized approach: the marrow dosimetry model uses SPECT/CT images. Here, spongiosa regions are outlined on a coronal lumbar image.

Model predictsmarrow dose

MPWRAut13_p09.indd 7 22/08/2013 15:06

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focus on: thermal therapies 11

Focused ultrasound (FUS) can induce a number of bioeffects for use in therapeutic applications. Acoustic cavitation, the interaction between ultrasound and microbubbles, for example, can disrupt the blood-brain barrier (BBB) and potentially enable targeted drug delivery. How-ever, before this technique can be applied clinically, reliable methods are needed to localize and character-ize the microbubble oscillations.

Currently, the only clinically rele-vant methods available for monitor-ing cavitation activity are ultrasonic, such as passive cavitation mapping. This technique employs the FUS device as a source and uses an array of receivers to passively record the acoustic emissions produced dur-ing sonication to produce maps of cavitation activity. These emissions and reconstructed maps provide information regarding the location, strength and type of microbubble oscillation and, importantly, can be obtained fast enough to provide real-time control over clinical procedures.

With this aim, researchers from Harvard Medical School have inte-grated a passive cavitation imaging system into a clinical MR-guided focused ultrasound (MRgFUS) sys-tem and, for the fi rst time, performed transcranial mapping of microbub-ble activity in the brain (Phys. Med. Biol. 58 4749).

“Passive cavitation mapping allows us to visualize microbubble activity during treatment, to ensure that the

effect is not occurring outside the tar-geted area and, we hope, to provide an effective method to monitor and control BBB disruption and other FUS therapies that involve microbub-bles in real-time,” explained Costas Arvanitis, from Harvard’s Focused Ultrasound Laboratory.

Acoustic cavitation occurs when a microbubble expands and contracts in an ultrasound field, with stably oscillating microbubbles (stable cav-itation) producing strong harmonic and/or ultraharmonic emissions. At higher acoustic pressures (above about 300 kPa), the microbubbles can collapse, a phenomena known as inertial cavitation and which produces characteristic broadband emissions.

To study the cavitation process, which occurs over millisecond or microsecond timescales, Arvani-

tis and colleagues used a clinical MRgFUS system (ExAblate 4000), modified to provide low-power sonications. For passive cavita-tion mapping, they incorporated a 128-element linear ultrasound array into the therapeutic phased array.

The researchers tested FUS-induced BBB disruption in three macaques. They delivered two 50 s sonications to each target, combined with infusion of microbubble ultra-sound contrast agent.

The acoustic power level was set initially to achieve BBB disrup-tion without inertial cavitation – as desired in clinical applications. For subsequent sonications, the researchers used higher powers, including those slightly above the inertial cavitation threshold where minor vessel damage is expected. Overall, they sonicated 20 targets

in the cingulate cortex of the three animals, with acoustic powers of 0.5–2.2 W (estimated pressure amplitudes of 190–330 kPa).

The researchers generated cavi-tation activity maps for each ultra-sound burst. The maps revealed the strength and position of the emis-sions produced by microbubble oscillations. Analysis of the corre-sponding normalized power spectra enabled distinction between stable cavitation (harmonic components only) and inertial cavitation (har-monic and broadband components). The size of the region with detected activity was more localized for iner-tial than for stable cavitation.

Arvanitis and colleagues then compared the location of the cavi-tation maps with the site of BBB disruption, as measured using post-sonication MRI. Fusing the cavita-tion maps with MR images showed that microbubble activity was indeed confi ned to the targeted area, and that the peak cavitation activ-ity overlapped with the location of MR-evident BBB disruption. The mean axial and transverse distances between the locations of the maxi-mum cavitation activity and the MR contrast enhancement were 0.5±7.5 and 0.3±1.5 mm, respectively.

Each targeted location was classi-fi ed as having BBB disruption only or BBB disruption plus tissue dam-age. When broadband emissions were observed, hypointense spots were also seen, indicative of minor

vascular damage induced by inertial cavitation.

In a clinical situation, this approach could be used to ensure that BBB dis-ruption occurs without inducing inertial cavitation. “We anticipate that one can increase the pressure amplitude until strong harmonic emissions are detected, and then if broadband emissions are detected, immediately reduce it or stop the sonication,” Arvanitis explained. “Moreover, the correlation we found previously between the strength of the harmonic emissions and the amount of agent delivered to the brain suggests that such monitoring might be able to control the ‘level’ of the disruption to ensure a predict-able and uniform treatment.”

The authors conclude that their study demonstrated the feasibility of constructing maps of stable and inertial cavitation in a large animal model, under clinically relevant conditions. They note that introduc-ing the ultrasound imaging probe into the MRgFUS system did not sig-nifi cantly affect either the MR image quality or the ability to produce localized BBB disruption.

They are now developing ways to account for skull thickness and other subject-specific factors, to enable quantifi cation of acoustic emissions. “We are also interested in expanding this integrated ultrasound/MRI sys-tem to other FUS applications in the brain and elsewhere,” Arvanitis told medicalphysicsweb.

How to control FUS-induced cavitation

Cavitation maps: average of all bursts applied during the highest powersonication applied at two targets in the cingulate cortex in one monkey.

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Magnetic hyperthermia is an attrac-tive approach for treating certain cancers; however, until now there’s been no clear theoretical under-standing of how it actually works. Now, physicists from the Univer-sity of York, UK, have performed a study to identify and quantify the heat-generating mechanisms. Mag-netic hyperthermia involves inject-ing magnetic nanoparticles directly into a tumour and then placing the patient in an alternating magnetic fi eld. The nanoparticles oscillate and create heat inside the tumour. When the temperature exceeds 42 °C, the tumour cells begin to die and the tumour size reduces ( J. Phys. D: Appl. Phys. 46 312001).

The study showed that the amount of heat generated by magnetic nano-particles can be understood when both the physical and hydrodynamic size distributions for the samples are known to high accuracy. “Through our study we have produced the fi rst comprehensive assessment of how the heating effect in magnetic hyper-thermia works. This understanding is critical to produce particles with optimized properties for specific applications at minimal dose,” said

lead author Gonzalo Vallejo-Fernan-dez. “We are now in a position where we can do further work to calculate accurately the dose of magnetic nan-oparticles and length of treatment required.”

The study used magnetic nanopar-ticles produced by Liquids Research of Bangor, North Wales. The particles are highly uniform in size and well separated, which enabled detailed experiments to be performed that broadly confi rmed the accuracy of the calculations. “The development of this new theory coincided with our work on the new process to fabri-cate the nanoparticles enabling us to ‘design’ almost ideal particles for this application,” said Vijay Patel, director of Liquids Research.

Insight into the heating effect

TEM image: the new nanoparticles produced by Liquids Research for hyperthermia applications.

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focus on: pre-clinical therapy 13

Earlier this year, the inaugural Sym-posium on Small Animal Radio-therapy was held in the Netherlands. Organized by a team led by Frank Verhaegen of the Maastro Clinic and Marc Vooijs of Maastricht University, the symposium provided the oppor-tunity for researchers in this emerg-ing field to meet up and define clear research goals. Attended by about 110 people, the symposium sparked much enthusiasm among attendees, but also highlighted some caveats, such as the difficulty in translation from small animals to humans.

The symposium kicked off with a keynote address from John Wong (Johns Hopkins University), who presented an overview of techno-logical progress in small-animal research equipment. Next up, invited speaker Robert Jeraj (University of Wisconsin, Madison) gave a pres-entation entitled “Guiding radio-therapy through molecular imaging today and tomorrow”.

Jeraj’s presentation was prefaced with the intention of causing a little controversy and stimulating discus-sion, and it succeeded. He began by discussing the well known phenom-enon in which target definitions of solid tumours differ widely between clinicians when based on CT alone. Complementary molecular imaging-based approaches like FDG-PET/CT can dramatically improve agreement and can also assist with identifying radio-resistant regions of tumour. However, prescribing radiation dose based on standardized uptake values requires a well understood relationship between the tumour micro-environment and molecular imaging information, which hith-erto has not been discovered.

Jeraj went on to suggest that this lack of knowledge presents an opportunity for animal models to potentially improve our under-standing of molecular imaging bio-markers. However, this task is not straightforward, as different cell lines have differential responses depending upon the particular treat-ment and molecular marker. The relevance of such a tumour model is also questionable.

Jeraj highlighted a recent publica-tion that demonstrated just how dif-ferent some animal models are from the human counterpart, using a sim-ple study of inflammatory response and gene changes following burns, trauma and endotoxin. The findings

suggested that gene expression pat-terns in response to such traumas differ dramatically between mouse and human tissues.

Pre-clinical experiments do, how-ever, provide for a greater degree of experimental control when com-pared to clinical data, enabling, for example, intense imaging schedules, use of multiple molecular markers, longer acquisition time and superior registration using anaesthesia.

Jeraj described research in dogs that showed distinct population groups of regional agreement in SUV between three molecular markers, CT-ATSM (hypoxia), FDG (metabo-lism) and FLT (proliferation), dem-onstrating a complex inter-patient dependence and suggesting a means to distinguish different phenotypes in sarcomas. Significant correlations were also found between tumour response and molecular imaging three months post-treatment.

As exciting as these observations are in small animals, the prevailing feeling in the discussion was that researchers and clinicians should remain cautious when extrapolat-ing the findings of animal research to the care of human disease.

The symposium incorporated sev-eral biology sessions, during which, various small-animal models passed centre stage. A number of normal tis-sue studies were reported, as well as pre-clinical models for cancer, while two studies used a precision irra-diator to study radiation-induced lung damage. Other presentations covered: dose response effects on breathing rate, especially at later time points; measurement of late effects (fibrosis); and a model for radiation-induced erectile dysfunc-tion in prostate radiotherapy.

Karen Gabriels (University Maas-tricht) told attendees about the effects of radiotherapy on athero-sclerotic plaque formation/rupture in ApoE-/- deficient mice. This is highly relevant, as radiotherapy can cause plaque progression and insta-bility leading to coronary embolism, and cancer patients are often elderly and may already suffer from coro-nary disease.

Therapy studies in mice included xenograft and orthotopic mod-els using human cancer cell lines, as well as murine cell lines from genetically engineered mouse mod-els. Most concentrated on glioblas-toma; a devastating incurable brain

tumour. For example, Olaf Van Tellingen (NKI, the Netherlands) described the testing of new tar-geted agents in an orthotopic synge-neic model using murine glioma cell lines in conjunction with chemora-diation. He reported growth delay for ABT-888, a phase I PARP inhibi-tor. Using drug transporter deficient mice, he elegantly showed that the blood-brain barrier is an important limitation for obtaining maximum therapeutic effect.

A fair amount of discussion dealt with “what constitutes a good pre-clinical model for cancer” and “what are the appropriate endpoints”. First, it was clear that biology-based ques-tions on radiation effects/response mechanisms needed to be separated from clinical questions on modelling human endpoints and therapeutic efficacy.

Second, there is a great need for defining relevant clinical endpoints in the animal models. Tumour growth delay is the closest endpoint to progression-free survival, which is a measurable clinical parameter that’s perhaps more useful than survival. Biomarkers are urgently needed to define intermediate pre-dictive endpoints, rather than sur-vival alone.

Clinical trials in oncology have the highest failure rate compared to other therapeutic areas. As Jeraj noted, this is in part due to the het-erogeneity within tumours and between patients. Thus there is a need to develop models with higher predictive value. Animal models that mimic tumour heterogeneity are likely to be more predictive of treat-ment success.

Small-animal radiotherapy has taken off with a flying start and many groups now have operational equip-ment. New challenges lie ahead, in using proper animal models and novel irradiation schemes com-bined with radiosensitizing drugs to enhance tumour response or reduce normal tissue damage. To achieve this, a continued dialogue between radiation oncologists, biologists and physicists is essential.

Marc Vooijs is professor and head of laboratory research at Maastricht University; Patrick Granton is a PhD candidate in radiation therapy at Maastricht University; Frank Verhaegen is head of clinical physics research at the Maastro Clinic.

SmART symposium launches in Maastricht

Inaugural event: delegates at the Symposium on Small Animal Radiotherapy in Maastricht, the Netherlands.

Small-animal radiotherapy is an important emerging research field, and one that relies heavily on the provision of high-accuracy equip-ment for irradiation and the associ-ated image-guidance. Delegates at the Symposium on Small Animal Radiotherapy heard about some key developments in the underlying hardware and software technologies.

Focusing first on hardware, Anthony Kavanagh (University of Oxford) presented a new treatment head assembly for the Xstrahl Small Animal Radiation Research Plat-form (SARRP). The assembly incor-porates an X-ray shutter to reduce timing errors and allows for beam gating during imaging and treat-ment. A motorized filter assembly allows for automated changing of a combination of beam hardening fil-ter and beam shaping filter.

Furthermore, the assembly pos-sesses an integrated transmission chamber to measure treatment pro-gress plus a targeting laser that exits the centre of the beam collimator for easy and precise specimen alignment. To allow for motion compensated radiotherapy, a system of optical fibres was developed to monitor ani-mals’ breathing cycles by measuring the intensity of diffuse reflected light through the fibres. Kavanagh noted that all of these tools are automated and software controlled.

Invited speaker David Jaffray (University of Toronto), described developments to extend the micro-irradiator X-RAD 225Cx (from Precision X-Ray) with a high-speed automated beam collimator, which is being developed in a collaboration with IKOMED. The device allows for dynamic rectangular field collima-tion during treatments. Similar vari-able collimator technology was also presented by keynote speaker John Wong (Johns Hopkins University) as work-in-progress for the Xstrahl SARRP.

On the image-guidance side, researchers are working to integrate multimodal imaging equipment into micro-irradiators. Ken Wang (Johns Hopkins University) presented his group’s work on optical (f luores-cence or bioluminescent) imaging integrated with CT for radiotherapy guidance. He emphasized the poor tissue contrast of CT, which results in it being unable to differentiate the tumour from surrounding soft tis-sues. Integrated cone-beam CT and optical tomography provide better image guidance.

Optical imaging has advantages and challenges, said Wang. It is ideal for longitudinal studies of tumour progression, since it does not use ionizing radiation. It’s also relatively inexpensive. The main challenge is the photon penetration of only a few centimetres, which renders the technique useful only in pre-clinical studies. Most of the imaging probes are not FDA approved.

Wang discussed integrated X-ray/optical tomography systems on the SARRP platform, where cone-bean CT provides anatomical structures and diffuse optical tomography (DOT) is used to reconstruct 3D vol-umes of the absorption and scatter-ing properties of biological tissues in the near-infrared spectrum.

Robert Weersink (Princess Mar-garet Hospital, Toronto) presented work on bioluminescent imag-ing (BLI) using injection of a light-emitting enzyme to track tumour progression. His team combined BLI with cone-beam CT to improve assignment of optical tissue prop-erties and improve targeting and response monitoring. Karl Butter-worth (Queen’s University, Belfast) noted that BLI also provides an accurate non-invasive technique to measure tumour burden and treat-ment response in pre-clinical stud-ies. He described a study comparing BLI tumour volumes to mechanical measurements, following exposure of a heterotopic prostate xenograft model to uniform and non-uniform radiation fields. Butterworth showed differences in BLI volumes for the two dose distributions and hopes to elucidate these with experiments using a precision irradiator.

The speakers also took a look at some of the exciting new tools for small-animal treatment planning that are now available and under fur-ther development.

Peter Kazanzides ( Johns Hop-kins University) presented a small-animal treatment planning system for use with the Xstrahl SARRP. By implementing their dose calculation on a graphics processing unit (GPU), Kazanzides and colleagues can per-form dose calculations in approxi-mately 10 s.

Stefan van Hoof (Maastro Clinic) presented another new small-animal treatment planning system, Smart-Plan, which was developed in col-laboration with Precision X-Ray.

RaySearch Laboratories also showed their initial integration of small-animal treatment planning into their advanced RayStation treat-ment planning system.

Stefan van Hoof and Pouya Jelvehgaran are scientists, and Frank Verhaegen is head of clinical physics research at the Maastro Clinic.

Developments in micro-irradiation

SARRP: the Xstrahl Small Animal Radiation Research Platform.

MPWRAut13_p13.indd 1 22/08/2013 15:07

14 focus on: PET

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PET response monitoring: care requiredPET imaging is being investigated for assessing treatment response in cancer patients, with changes in standardized uptake value (SUV) typically used to quantify response. Most studies measure the change in either maximum SUV (SUVmax) or mean SUV (SUVmean), some quantify the change in peak SUV (SUVpeak) and a few examine changes in total SUV (SUVtotal). But do these different measures provide the same response classifications?

To answer this question, a team at the University of Wisconsin, Madi-son, has investigated the impact of different SUV measures on quantifi-cation and classification of PET-based treatment response ( J. Nucl. Med. 54 1188).

“Different researchers have used different measures to assess whether tumours respond or not, which makes cross-comparison between different studies almost impossible,” explained lead author Robert Jeraj. “The main goals of our study were to show how much more tumour char-acterization informative is provided using multiple measures, and to establish the level of ambiguity that different response measures provide.”

Jeraj and colleagues examined 16 patients with advanced solid malig-nancies who were treated with a molecular targeted agent. They per-formed whole-body PET/CT scans on the subjects at baseline, during treatment and after treatment, using the cellular proliferation marker 18F-fluorothymidine (FLT). An expe-

rienced physician then segmented lesions on the PET images, and a 3D volume-of-interest (VOI) was created for each lesion.

The researchers calculated PET response values for each lesion, based on four SUV measures: SUVmax, the maximum value from all voxels within the VOI; SUVmean, the mean of all voxels in the VOI; SUVtotal, the sum of all voxels in the VOI; and SUVpeak, the mean of all voxels within a 1 cm3 sphere centred in the high-est uptake region. Relative changes in SUV from baseline were used to classify patients into categories – PET complete response, PET partial response, PET stable disease and PET progressive disease – separated by

quantitative thresholds defined by EORTC or PERCIST.

They found that PET response was highly sensitive to the SUV meas-ure used. On average, different SUV measures caused a 20% variation in individual tumour PET response, with the most extreme variation seen of 90%. On average, differences were greatest between SUVmean and SUVtotal and smallest between SUVmax

and SUVpeak.The authors presented an exam-

ple case of a uterine tumour. From pre- to mid-treatment, the four SUV measures decreased by differing amounts, but all indicated a PET par-tial response. Pre- to post-treatment SUV measures, however, varied

widely and led to multiple classifica-tions. SUVmax and SUVpeak increased by 42% and 53%, respectively, indi-cating progressive disease. SUVmean

decreased by 34%, indicating partial response, while SUVtotal decreased by 22% , indicating stable disease. Similar ambiguous PET response categorizations were seen in more than 80% of tumours assessed in this study.

The researchers also calculated the population average PET response for each SUV measure. Here, the use of different SUV measures resulted in small variation in the PET response with slightly greater variation seen at mid-treatment than post-treatment. Differences were greatest between SUVmean and SUVtotal (average of 16%) and smallest between SUVmax and SUVpeak (average of 2%).

The researchers point out that the ambiguous PET-based treatment response categorization of individual tumours illustrates the shortcomings of relying on a single SUV measure to quantify response – particularly as such response classifications are often used to guide subsequent treat-ment decisions.

“The impact of this study is tre-mendous, as it indicates that multiple tumour PET tracer uptake measures need to be monitored in the context of treatment response assessment,” Jeraj told medicalphysicsweb. “Each of these measures represents a poten-tial response biomarker; which one is most accurate needs to be tested in clinical trials.”

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Individual responses: mid-treatment, all SUV measures indicated partial PET response (below –30%, green line). Post-treatment, wide variations in SUV measures resulted in ambiguous PET response classifications.

TOF PET paper wins PMB prizeResearchers from the Vrije Univer-siteit Brussel and the Katholieke Universiteit Leuven in Belgium have won the 2012 Roberts Prize for the best paper published in Physics in Medicine & Biology (PMB) last year. Michel Defrise, Ahmadreza Rezaei and Johan Nuyts won the prize for their work on quantitative PET imag-ing (Phys. Med. Biol. 57 885).

To perform quantitative PET, it’s necessary to carry out accu-rate attenuation correction of the recorded tracer distribution – a task most commonly achieved using CT data. But in some cases, for example when using a PET/MR system, CT data are simply not available. Defrise and colleagues showed that for time-of-f light (TOF) PET scanners, this attenuation can be estimated, except for a constant, using just the TOF emission data.

The authors developed a simple analytic method for estimating the attenuation sinogram and dem-onstrated the feasibility of their approach on a software phantom. Defrise notes, however, that the specific algorithm proposed in this study is likely to be superseded by iterative maximum-likelihood algo-rithms currently being developed.

As such, the researchers are now working with Siemens Molecular Imaging to investigate a discretized version of the problem that accounts for the discrete sampling of the tomography data acquired by a PET scanner and also models the Poisson noise that affects these data.

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