In association with the journal Physics in Medicine & Biology Autumn 2011

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medicalphysicsweb review

Safety fi rst for SRS and SBRT Stereotactic therapies come with robust QA requirements, explains Timothy Solberg. Stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT) are specialized forms of radiotherapy in which high doses are delivered over a small number of treatment fractions (fi ve or less). SRS, which has been used success-fully for several decades to treat brain metastases, is defi ned as irra-diation of the brain or spine. SBRT, a newer modality that is also showing clinical promise, refers to treatment elsewhere in the body.

The delivery of high dose fractions does, however, mean that the margin of error for both of these stereotactic techniques is significantly smaller than for conventional radiotherapy. Even small inaccuracies in target localization can lead to serious under-treatment of the tumour or severe overdose to adjacent normal tissues. With such a risk of minor errors causing catastrophic out-comes, there is a real need to ensure rigorous training standards and robust quality assurance (QA) for all SRS and SBRT treatments.

With this aim in mind, the Ameri-can Society for Radiation Oncology (ASTRO) has commissioned a White Paper looking at quality and safety considerations in SRS and SBRT. Tami Freeman talked to Timothy Solberg, professor of radiation oncology at the University of Texas Southwestern Medical Center (Dallas, TX) and co-author of the report, to fi nd out more.

TF: What prompted ASTRO to commission this report?TS: Radiosurgery and SBRT are rap-idly growing speciality disciplines within our field. It’s essential to address quality and safety aspects up front so that the fi eld doesn’t grow so rapidly that we lose sight of those things. There have been international efforts over the last several years look-ing at quality and safety in radiother-apy, and in my opinion, it’s important for the US and its professional organi-zations to participate as well.

With all that said, of course there are several incidents that motivated this, and several other reports, including those described in a series of newspaper articles in the New York Times over the last 18 months. It’s defi -nitely time to step up, take responsi-bility and address those things.

What makes SRS and SBRT so susceptible to even small errors?The major factor is the high dose-per-fraction that’s delivered. This can be as high as 90 Gy in a single fraction in radiosurgery, and there are protocols

for SBRT that deliver doses as high as 60 Gy in three fractions or 34 Gy in a single fraction. The biological proc-esses that occur when you deliver one or a few high-dose fractions are fundamentally different from those resulting from delivery of 2 Gy per day. Because of this, there’s really no room for error.

Are the QA procedures stricter than for standard radiotherapy?Certainly the tolerances that you’d want your equipment and processes to meet are more rigorous. But I think the thing that differentiates the QA process is the interlinked aspect.

Historically, we could evaluate individual aspects of a treatment process and still have some confi-dence that it is working. But now, because the simulation, treatment delivery, image guidance and motion management are so tightly linked, they have to be managed in an inte-grated fashion as uncertainty in one can dramatically affect the others.

Does image guidance play a big role in stereotactic treatments?I would say it was really the advent of image guidance that facilitated SBRT – without image guidance you can’t perform SBRT. It also plays an increasing role in SRS. But any image guidance procedures must be assessed within the context of the overall process. End-to-end test-ing that really evaluates the patient process is critical: does the image guidance put the delivery beam where it’s supposed to go, when it’s

supposed to be there, and so on.

What are the important factors to consider when initiating an SRS or SBRT programme?One of the key points that we tried to make is that it requires a lot of plan-ning up front. You need to assemble a team well in advance – including phy-sicians, physicists and administrators – and decide on the programme goals, the resources needed to achieve those goals, and the quality assurance and safety management required. Having the right people involved is vital.

One of the things that the report emphasizes is that institutions should implement processes on a disease-site-specifi c basis. For example, spinal radiosurgery is typically done with IMRT delivery in a single fraction, and there are some very important critical structures nearby to consider. That’s different from implementing SBRT for the lung, where the impact of dose errors to critical structures

may not be as profound, but you have other issues such as motion manage-ment to contend with.

How can equipment vendors help?With many of the incidents that have come to light, much of the responsi-bility lay with the users. So there’s a lot that we need to do for the users: training and education, credential-ing, independent verification, and making sure that institutions and practitioners have enough resources. But the vendors are one of the many stakeholders and they also have a clear responsibility.

We recommended that vendors take a much stronger role in train-ing – not just training on operation of their equipment, but training on how to use their equipment for SRS and SBRT. They also need to take a greater responsibility with regard to QA; specifi cally, the QA associated with the applications and processes for which they’re selling and market-ing these systems.

How do you see the ASTRO document being implemented?I think that it’s going to be important for guiding institutions and prac-titioners in how best to establish and maintain their SRS and SBRT programmes, and in emphasizing the importance of safety and QA in general. I hope that it will be widely adopted by our profession as a guid-ance document. Certainly it’s not a regulatory document, but there are aspects discussed that I personally hope will become a de facto standard.

“It’s an ongoing responsibility of anyone practising medicine to always be actively taking steps to improve quality and safety.”

SBRT beams: high dose-per-fraction delivery means that there’s no room for error with stereotactic therapies.

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

This issue, distributed at the ASTRO annual meeting in Miami Beach, FL, brings you a taster of our recent online content. If you like what you see, why not register for free as a member at medicalphysicsweb.org. Or visit us at booth #1002 where we’ll be celebrating out fi fth birthday. You could win a personal electronic subscription to our sister-journal Physics in Medicine & Biology, or a set of miniature scientist action fi gures – so come and see us now.Tami FreemanEditor, medicalphysicsweb

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Physics in Medicine & Biology focuses on the application of physics to medicine and biology and has experienced outstanding growth in recent years. The journal continues to build on its reputation for publishing excellent research rapidly. Our 2010 impact factor stands at a record 3.056.

Editor-in-Chief: S WebbInstitute of Cancer Research

and Royal Marsden NHS Trust, UK

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* As listed in ISI®’s 2010 Science

Citation Index Journal citation reports3.056*

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focus�on:�proton�therapy

Intensity-modulated proton ther-apy using a reduced beam spot size (rsIMPT) has shown promise as a means for improving quality of life in head-and-neck cancer patients (Int. J. Radiat. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2011.05.005).

“The results of this study show that rsIMPT has the potential to sig-nificantly spare the parotid and sub-mandibular glands and that this can significantly reduce the probability of both salivary flow dysfunction and patient-rated xerostomia,” explained PhD candidate Tara van de Water.

The collaborative study by researchers from the University Med-ical Center Groningen in the Nether-lands and the Paul Scherrer Institute (PSI) in Switzerland consolidates pre-vious findings that three-field IMPT provided significant parotid gland dose reduction compared to seven-field photon intensity-modulated radiotherapy (IMRT), while provid-ing comparable target coverage. This study sought to demonstrate whether the introduction of three-field rsIMPT could also reduce sub-mandibular gland dose and the risk

of patient-rated xerostomia and sali-vary flow dysfunction.

IMPT uses a scanned proton beam to irradiate the tumour and, in essence, the use of a smaller beam spot size provides a steeper dose gra-dient that can conform more closely to the treatment target.

The researchers generated two treatment plans, one IMPT and one rsIMPT, for each of 10 patients with oropharyngeal cancer. The initial spot size in air of the rsIMPT plans was 3.5 mm – identical to the initial spot size of the IMPT plans. However, the

rsIMPT beam spots were not subject to the degradation and hence enlarge-ment observed in IMPT plans, which result from the use of range shifter plates necessary for range modula-tion. The two plans used identical prescriptions, beam arrangements and dose-volume objectives with one exception: in the rsIMPT plans, stricter objectives were allowed for the submandibular glands.

For all patients, rsIMPT dem-onstrated superior target dose conformity over IMPT. A mean conformity index of 1.23 was calcu-

lated for rsIMPT, compared to 1.40 for IMPT. In addition, rsIMPT dem-onstrated significantly lower doses to the parotid and submandibular glands over IMPT. Mean dose in the parotid glands was reduced signifi-cantly (from 16.8 to 14.7 Gy), as was the mean submandibular gland dose (from 54.6 to 46.9 Gy), upon the introduction of rsIMPT.

Based on the submandibular and parotid gland doses provided by each treatment plan, the research-ers calculated the normal tissue complication probability (NTCP) for each scenario in each patient. The results were striking: assuming an NTCP reduction of 10% as clinically relevant, they predicted the use of rsIMPT would result in clinically sig-nificant reductions in submandibu-lar salivary dysfunction in 100% of the patients studied. A reduction in xerostomia incidence for 70% of the patients studied was also predicted.

Clinical studies are still some way off yet; producing smaller beam spots of the order modelled here is still a work in progress – the new PSI gantry, which can produce such spot sizes, is not yet clinically available. The researchers also need to analyse the robustness of the plans produced using rsIMPT.

Model eases proton dosimetryPET imaging provides an effective means to verify beam delivery in proton therapy, by imaging positron emitters produced as the proton beam travels through the patient. The technique requires an efficient way to infer delivered dose from recon-structed PET images. This is not a straightforward task, however, as PET activity is not directly proportional to the delivered dose distribution.

Analysis is currently performed by comparing measured PET images with predicted images calculated using Monte Carlo (MC) simulations – a computationally heavy process. Now, an international research team has developed an analytical model that provides a powerful and fast alternative to MC calculations (Phys. Med. Biol. 56 5079).

The model describes positron activity as a convolution of the planned dose distribution with a small number of nuclear reaction-dependent filter functions. Each fil-ter function calculates the amount of a particular positron emitter pro-duced during irradiation, starting from a series of one-dimensional filtering operations on the planned dose distribution calculated on the planning CT.

This approach was initially pro-posed for predicting 11C-distribu-tions. Now, with the introduction of in-room (and in-beam) PET systems that can detect very-short-lived iso-topes, the researchers have extended the method and calculated filter functions for 15O, 13N, 38K and 30P.

“The MC method can verify that the measured PET image is in accord-

ance with the treatment parameters, but it doesn’t really say anything about the dose distribution from the treatment planning system, which is the basis for clinical approval,” explained researcher Francesca Attanasi, from the University of Pisa in Italy. “The convolution method, on the other hand, can verify more directly the dose distribution from the planning system.”

To calculate the expected PET image, a MATLAB-based architec-ture is used to sum the activity con-tributions from each of the positron emitters. The routine also accounts for tissue-dependent factors, as well as several other parameters.

The researchers examined two phantoms composed of PMMA, and lung-, water- and bone-equivalent tissue slabs. One phantom was irra-diated with a spread out Bragg peak of 80 × 80 mm aperture, and the other with a pencil-like proton beam of 10 mm radius.

Predicted 11C, 15O and 13N yields per unit path length were obtained for both phantoms. Excellent agreement in depth (better than 1 mm) between filter-calculated and MC-simulated activity profiles was seen in all cases. In terms of absolute intensity (in the distal region), agreement was within 1.5% between filtered and simulated profiles.

Next, the researchers examined two head-and-neck tumour patients. The first was treated with an antero-posterior proton field, with a total dose of 2.7 Gy delivered in 63 s. The filter calculation was employed to determine positron activity for all

isotopes that can potentially be measured using in-room PET: 15O, 13N, 38K and 30P. Shifts between filter-based predictions and MC-simulated distributions for all activity profiles were, on average, less than 1 mm in all positions.

The second patient was treated for a brain tumour, using a total dose of 2 Gy in about 55 s. The MC-simulated and filter-predicted distributions were found to be similar. Currently, the lack of in-beam data makes it impossible to directly compare fil-tered distributions with experimen-tal data. The long delay between the

end of irradiation and the start of acquisition prevents the detection of shorter β+-isotopes. However, the good agreement between the 11C filter-predicted distribution and pre-vious experimental data implies that the method will also work with the other isotopes.

The researchers concluded that the predictions of the filter-based tool were generally in good agree-ment with MC calculations. The goal now is to develop an inverse filtering approach, thus enabling direct infor-mation about dose localization to be derived from the measured activity.

Paranasal tumour: MC-calculated dose deposition (top right) in the CT axial plane indicated by the arrow. The bottom row compares MC activity distributions (left) and filter predictions (right) in the same axial plane.

Use of a beam-specific planning target volume (bsPTV) can sig-nificantly improve proton therapy efficacy, report researchers at the MD Anderson Cancer Center (Int. J. Radiat. Oncol. Biol. Phys. doi:10.1016/j.ijrobp.2011.05.011). Systematic uncertainties in proton range arise from set-up errors and organ motion. Most significantly, compared to pho-tons, proton range is highly depend-ent on tissue composition along the beam path. If the beam path deviates from the ideal treatment plan geom-etry, proton range can be quite differ-ent from that intended.

Consequently, the conventional PT V concept is inappropriate. “Because range uncertainties only happen along the beam direction, the traditional PTV geometric concept used in photon treatment planning, which is independent of beam direc-tion, does not work well for proton therapy,” explained senior investiga-tor Lei Dong. “In order to apply the PTV concept to proton therapy, we have to incorporate beam direction to this concept.”

The researchers compared the dosimetric performance of their beam-specific PTV (bsPTV) against a conventional PTV in a single-field proton treatment plan in a virtual water-equivalent phantom. To introduce variation in proton path length across the beam, a high- density sphere was placed in the beam, proximal to the PTVs. Both PTVs were derived from an expan-sion of the same hypothetical clinical target volume (CTV). Each included lateral margins to account for set-up error and internal target motion, and proximal and distal margins to account for systematic range errors.

The bsPTV had an extra margin component, proximal and distal to the CTV, which accounted for devia-tions in proton range arising from misalignment of the inhomogeneity in the treatment beam. The radio-logical path length was calculated for each ray line in the beam aperture. Distal to the CTV, each radiologi-cal path length was replaced with the maximum for the neighbouring area, as defined by the magnitude of the set-up errors and target motion, and the CTV expanded accordingly. A similar approach provided a proxi-mal margin.

The difference in CTV dose cover-age between the bsPTV and PTV was notable. While the use of a conven-tional PTV expansion demonstrated a drop in minimum CTV dose from 99 to 67% upon the deliberate intro-duction of a set-up error and target motion, the use of a bsPTV corre-sponded to a much smaller drop to 94% . The researchers deliberately misaligned the CTV, for a range of offsets, to mimic the effects of set-up error and target motion. Upon com-paring CTV dose coverage with PTV and bsPTV coverage, the bsPTV pro-vided markedly better results.

New PTV tackles range uncertainty

Plan comparison: Tara van de Water, from the University Medical Center Groningen, examines dose distributions for different sized beam spots.

Smaller spot size improves results

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MPWRAut11_p03.indd 3 07/09/2011 15:54

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focus�on:�radiotherapy

DMLC tracking: in vivo demonstrationAn international collaboration has demonstrated in vivo dynamic mul-tileaf collimator (DMLC) tracking of a treatment target surrogate, using a linear accelerator, for the first time. The megavoltage (MV) image-based approach showed marked gains in targeting accuracy over stand-ard non-tracked approaches (Int. J. Rad. Oncol. Biol. Phys. doi: 10.1016/j.ijrobp.2011.03.023).

DMLC tracking has great poten-tial to ameliorate the deleterious effects of tumour motion in radio-therapy patients, by continuously monitoring intra-fractional tumour motion and applying appropriate corrections to the MLC aperture position. Until now, only phantom studies have been used to assess DMLC tracking efficacy. Physicist Per Poulsen of Aarhus University Hospital, Denmark, explained: “The challenges for robust real-time tar-get localization are typically sub-

stantially larger in a clinical setting than for phantoms, especially for image-based tracking, where target segmentation can be hampered by poor contrast or overlapping struc-tures such as bones. Our primary goal was to advance DMLC tracking towards clinical implementation by demonstrating tracking in a set-up that mimicked that of stereotactic body radiotherapy (SBRT).”

The dynamic tracking technology works as follows. An in-house semi-automated segmentation algorithm is applied to a set of continuously acquired MV images, captured prior to therapeutic irradiation. The algo-rithm identifies the treatment target surrogate – in this study, a 7 mm long nickel-titanium (NiTi) alloy stent – and produces a template.

In the intra-fractional MV images that follow, the template is used to locate the surrogate. A dedicated tracking computer converts the

resulting 2D surrogate position to an estimated 3D location. At this point, a kernel density estimation-based prediction algorithm predicts the new surrogate location, accounting for the 400 ms latency of the track-ing system. Individual leaf positions are then moved accordingly to cor-rect for surrogate motion. Predic-tion only occurs after eight seconds of radiation delivery, in which time training data are acquired for the prediction algorithm. During this initial eight second period, MLC motion lags stent motion.

The researchers implanted NiTi stents into the bronchia of three anaesthetized pigs to test the DMLC technology. Each pig underwent a 4DCT scan, which was used to plan a single fraction conformal treatment, with the isocentre positioned at the stent. Dynamic MLC tracking was implemented upon delivery of the treatment plan.

The researchers assessed tracking efficacy for each intra-field MV image as the distance between the stent and the centre of the MLC aperture. For comparison, the same discrepancy observed after pre-treatment kilo-voltage (kV)-guided positioning was used as a measure of non-tracked tar-geting accuracy.

Overall, study findings were promising. The implementation of DMLC tracking in a clinical scenario mimicking that of SBRT proved to be feasible and safe. For 11 out of 15 planned treatment fields where stent segmentation was performed cor-rectly, marked improvements in tar-geting accuracy were observed. For the two imager dimensions, system-atic error values of 0.5 and 0.4 mm were obtained for the tracked case, versus 1.7 and 1.4 mm for the non-tracked case.

The researchers predicted even greater targeting accuracy for

future work with the application of improved corrections for gantry sag and irreproducible imager posi-tioning. The stents, intended for kV imaging applications, proved to be inadequate for this clinical applica-tion, producing images with sub-optimal contrast that prevented correct segmentation and therefore tracking, in four of 15 treatment fields.

Poulsen told medicalphysicsweb about the group’s ongoing work in the field. “Our work towards clini-cal implementation of DMLC track-ing includes further development of automatic marker segmenta-tion methods, simulation of DMLC tracking based on clinical real-time target position signals, in the form of images and electromagnetic transponders, and reconstruction of dose distributions delivered to moving targets during DMLC tracking.”

A system that can map dose distribu-tion in three dimensions and record the integrated dose over time could prove invaluable in modern radio-therapy. Optical CT of radiochromic gel phantoms shows great promise for such 3D dose verification, par-ticularly for small-field dosimetry. But clinical adoption of this method calls for the utmost confidence in the equipment.

Phantoms have been employed for quality assurance (QA) of optical CT scanners, but the complexity achiev-able by mechanically manufactured test objects is limited. Now a research team headed up at the UK’s Univer-sity of Surrey has shown how PRES-AGE – a robust plastic dosimeter – can be used to create intricate test samples (Phys. Med. Biol. 56 4177).

“I and colleagues around the world have been developing such systems for some years now,” said Simon Doran, senior scientist at the UK’s Institute of Cancer Research. “It has always been somewhat frustrat-ing that a true comparison of our respective scanners – obtained by imaging the same, well character-ized, sample on each one – has not so far been possible. With the advent of the PRESAGE dosimeter, there is now a real possibility of bringing 3D dosimetry techniques into the clinic.”

PRESAGE is based on clear poly-urethane combined with a dye that changes colour upon exposure to ionizing radiation. The research-ers irradiated five 60 mm diameter cylindrical PRESAGE samples, using a synchrotron X-ray microbeam at the European Synchrotron Radia-tion Facility (ESRF) in Grenoble. The resulting test samples were used to characterize the University of

Surrey’s parallel-beam optical CT scanner.

Test samples were designed to investigate the scanner’s response linearity, to assess the modulation transfer function (MTF), a measure of image sharpness, and to measure geometric distortion. Optical CT images of samples 1 and 2 revealed that all pattern features were faith-fully imaged. Results indicate that the overall process of converting dose into optical CT image intensity – via the chemical response of PRES-AGE and the scanning – is highly linear.

The three patterns used to meas-ure MTF led to different results. “There are a wide variety of methods for measuring MTF,” Doran noted. “We chose three different methods, initially as a demonstration of what could be achieved using the dose-painting facilities at the synchro-tron.” Results also showed that the scanner can image features as small as 0.2 mm and that geometric distor-tion is not a significant problem in optical CT.

The researchers point out that creating test samples via synchro-

tron irradiation is not economically viable for a commercial QA pro-gramme. As such, they investigated the possibility of creating similar samples using UV irradiation.

Three PRESAGE samples were illu-minated for 20 minutes with 365 nm light, through low-cost masks cre-ated by laser-printing patterns onto acetate sheets. Preliminary imaging revealed good correlation between optical densities measured by the CT scanner and the expected UV “dose” delivered. The researchers highlight the excellent resolution achieved by the UV-irradiated test objects. The next step will be to perform accurate measurements of the masks’ trans-mission, to establish exactly how much UV radiation the phantoms receive.

“At present, what we have is an interesting proof of concept,” explained Doran. “A significant amount of very careful work is needed to move to the stage where we can directly relate the UV irra-diation measured at the surface to a clinical dose from a linac. But this is certainly a promising avenue that we wish to pursue.”

Modulated electron radiotherapy (MERT) should be considered as an option for delivering tumour bed boost in breast cancer patients. That’s the verdict of a team from McGill University in Canada, which has published the first study to com-pare the dosimetry of few-leaf elec-tron collimator (FLEC)-based MERT with both conventional direct elec-tron (DE) irradiation and VMAT (Radiother. Oncol. doi: 10.1016/j.radonc.2011.05.081).

“Our current study examined FLEC-based MERT plan quality using data from 14 patients, and impor-tantly, MERT plans specific to one treatment site,” said Andrew Alex-ander from McGill’s Medical Physics Unit. “This has allowed us to exam-ine the inter-patient reproducibility of MERT plans.”

MERT is an energy and/or inten-sity-modulated electron therapy that’s limited to superficial treat-ment sites. Although currently con-fined to the research arena, MERT has been shown to increase target homogeneity and increase organ-at-risk sparing. While these advantages are greatest when MERT is compared with the likes of DE and 3D confor-mal therapy, there is an increasing need to compare MERT with emerg-ing modalities such as VMAT.

Alexander and colleagues con-sidered 14 patients, each requiring whole-breast radiation and tumour bed boost following breast conserv-ing surgery for early-stage breast cancer. The goal of treatment was to deliver 10 Gy over four fractions to the tumour bed dose evaluation vol-ume (DEV, defined as the tumour bed within a 1.5 cm margin), with the aim of covering at least 95% of the target volume with the prescription dose.

Following a treatment-planning CT scan after surgery, MERT plans were created for each patient using an in-house McGill treatment plan-ning system known as MMCTP. DE and VMAT plans were then gener-ated and imported into MMCTP to ensure a common platform was used to evaluate and compare data.

Results showed clearly that the DE plans were inferior to both MERT and VMAT. The result was less clear-cut, however, when MERT was compared with VMAT, with each technique proving beneficial in specific situa-tions. The authors report a dosimet-ric advantage in using MERT over VMAT for increased DEV conform-ity and low-dose sparing of healthy tissue, but add that this is often at the cost of an increase in the ipsilateral lung high-dose volume.

“ M E RT can compete w ith advanced photon VMAT techniques for breast boost, which validates the continued efforts on MERT research worldwide,” said Alexander. “How-ever, inter-patient variability can drastically affect MERT plan quality.” The team concluded that guidelines are needed to outline when MERT plans could be clinically advanta-geous, adding that in the future, departments could set a cut-off depth for MERT planning, with deeper tumours planned with VMAT.

Precise QA for gel dosimeters

MERT lines up for breast boost

UV irradiation: (a) PRESAGE sample positioned under the UV lamp of a mask aligner with a UV mask placed on top; (b) close-up of the sample.

FLEC-based MERT: the few-leaf electron collimator used at McGill contains four copper leaves and produces rectangular apertures.

(a) (b)

MPWRAut11_p05.indd 3 07/09/2011 15:55

6 focus on: radiotherapy

Gold nanoparticle (AuNP) radio-sensitization provides a novel means for enhancing the efficacy of radiation therapy. Gold has an increased photoelectric absorp-tion cross-section relative to tissue. When irradiated, this results in a highly conformal energy deposition around the AuNPs, caused by a local-ized spray of escaping photoelectric products.

The effectiveness of this radio-sensitization process, however, var-ies widely with nanoparticle size, concentration and localization, as well as with source energy. A Cana-dian research team has now per-formed Monte Carlo simulations to determine how irradiation energy and nanoparticle size influence the deposited energy, and how much gold is required for dose enhance-ment (Phys. Med. Biol. 56 4631).

“Gold nanoparticles are an excit-ing new field of research in radiation oncology. Using nanotechnologies we can construct nanoparticles bound to targeting agents, such that cancer cells could be specifically targeted,” explained Jean-Philippe Pignol from Sunnybrook Health Sciences Centre (Toronto, ON). “We are looking to use gold nanoparticles to increase the therapeutic index of radiation treatments. But the right

pharmaceutical and clinical sce-narios have to be clearly defined and optimized.”

The researchers studied AuNPs of 1.9, 5, 30 and 100 nm in diam-eter. They also simulated six clini-cal photon sources: 300 kVp and 6 MV external beams; 192Ir and 169Yb high-dose-rate brachytherapy sources; and 125I and 103Pd low-dose-rate brachytherapy seeds. The 103Pd, 125I, 169Yb, 300 kVp, 192Ir and 6 MV sources had average energies of 20.6, 27.0, 100.7, 127.1, 324.3 and 1861 keV, respectively.

Using MCNP-5 Monte Carlo code, the team simulated the rate of pho-toelectric absorption in AuNPs within tissue. Results revealed a large increase in absorption for lower-energy sources and larger AuNP diameters. For example, to generate a single photoelectric event with the 6 MV source required approximately 39 500 nanoparticles (of 30 nm diameter). With a 125I source, about 39 such nanoparticles were needed – a 103 increase in the rate of pho-toelectric absorption. Photoelectric absorption as a function of particle size followed a radius-cubed rela-tion, with nearly four orders of mag-nitude increase observed between 5 nm and 100 nm particles.

The energy from an absorbed pho-

ton will either be internally absorbed by the nanoparticle, or released as Auger and delta electrons, photo-electrons or characteristic X-rays. The researchers used the PENELOPE Monte Carlo code to examine the characteristics of the escaping spray of photoelectric products, and the resulting dose enhancement in sur-rounding tissue.

Lower-energy sources emitted a larger percentage of Auger and delta electrons, which deposit energy up to 2 µm from the AuNP surface. This

energy has an increased relative bio-logical effect due to the high linear energy transfer of these particles. As AuNP size increased, these low-energy electrons were increasingly internally absorbed.

As the incident photon energy increased, a larger percentage of the escaping energy was due to photo-electrons and characteristic X-rays (and mostly unaffected by AuNP size). Photoelectrons travel up to hundreds of microns and cause sig-nificant DNA damage at the ends of their tracks.

Simulations revealed a general trend of increased dose enhance-ment with lower-energy sources. For instance, with a 6 MV source and 1.9 nm AuNPs, 7.59 × 1010 AuNPs per cell were needed to double the pre-scribed dose to the tumour. With a 125I source and 100 nm AuNPs, only 1.83 × 103 nanoparticles per cell were required.

In terms of milligrams of AuNPs per gram of tumour needed to double tumour dose, the worst-case scenario – the 6 MV source and 100 nm AuNPs – required a clinically infeasible 1760 mg/g of AuNPs. The most effi-cient scenario, 125I and 1.9 nm AuNPs, required only 5.33 mg/g of AuNPs.

The researchers suggest two potential clinical strategies for

AuNP radiosensitization. The first uses clinical sources with incident energies below the k-edge of gold (80.7 keV), where photoelectric absorption is most efficient. Here, the dominance of short-range Auger electrons requires internalization of a large number of small AuNPs, localized close to the cell nucleus.

The second strategy, involving higher-energy photon sources above the k-edge, exploits photoelectrons, which can reach the cell nucleus from outside the cell. This approach requires much higher concentra-tions of AuNPs, but doesn’t neces-sitate internalization in the cancer cells. The AuNP size is less crucial in this scenario.

“We believe that techniques using higher-energy sources, such as 169Yb, and larger nanoparticles massively loaded in cancer cell cytoplasm are just around the corner,” said Pignol. “The scenario of loading a very large number of targeted smaller nanopar-ticles inside the nucleus needs more molecular biology and nanotech-nology research.” The ultimate goal of the Canadian team, Pignol told medicalphysicsweb, is to use AuNPs to treat early-stage breast cancer exclu-sively via seed brachytherapy and without surgery, as is the case for prostate cancers.

escapingelectrons

30 nm

Energy release: an Auger electron leaving a 30 nm gold nanoparticle. Simulation by Eli Lechtman.

Simulations boost AuNP radiosensitization

A community website from IOP Publishing

To celebrate, we’re giving away a 2012 personal electronic subscription to our sister-journal Physics in Medicine & Biology, plus 3 runner-up prizes of the ‘Giants of Science’, a miniature scientist action figure set. We have some on display at the IOP Publishing booth #1002: come and take a look.

To be in with a chance of winning, simply register as a member of medicalphysicsweb by visiting medicalphysicsweb.org/birthday or scan the barcode below. You can also enter our prize draw at the booth if you prefer.

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focus�on:�radiotherapy 7

The development of radiation- resistant tumours is an ongo-ing problem in cancer treatment. Interactions between tumour and endothelial cells can lead to angio-genesis – a major source of radiother-apy resistance as tumour cells create additional blood vessels that support their survival. To study this process in more depth, a German research team has compared the effects of carbon-ion and X-ray therapies on the angiogenic response of human lung-cancer cells (Int. J. Radiat. Oncol. Biol. Phys. 80 1541).

“In addition to treatment with photon irradiation, carbon-ion irradiation therapy is emerging as

an alternative option for various tumour entities, including non-small cell lung cancer,” said Florentine Kamlah, from Philipps-University in Marburg, Germany. “Experimental radiobiological studies are needed to evaluate the best treatment options.”

The researchers irradiated human lung adenocarcinoma (A549) cells with biologically equivalent doses of 9.8 MeV/u carbon ions or 6 MV X-rays. To determine biological equivalence, they first measured the relative biological effectiveness (RBE) for carbon ions and X-rays, finding an RBE of approximately three for 10% cell survival. Based on this value, cells were irradiated to 6 Gy for X-rays and 2 Gy for carbon ions.

After irradiation, the cells were mixed with a basement membrane matrix and injected into mice to gen-

erate a plug. After 10 days, histological sections of the plugs were analysed to assess blood vessel formation.

With biologically equivalent doses, irradiating A549 cells with X-rays – but not carbon ions – induced ang-iogenesis. A significant increase in blood vessel formation was seen in plugs derived from X-ray-irradiated cells (36.44±3.44 per microscopic field), while vessel formation in plugs derived from carbon-ion-irradiated cells (16.33±1.03) did not differ from that seen in a control group (20.71±1.55). The researchers also noted that X-ray irradiation to a dose of 2 Gy (as used for carbon ions) still induced a significant increase in blood vessel density. This result implies that the above was not sim-ply a dose-dependent effect.

Kamlah and colleagues next

attempted to identify possible angiogenesis-promoting factors. They assessed the expression levels of vascular endothelial growth fac-tor, placenta-like growth factor, stro-mal cell-derived factor-1, and stem cell factor (SCF). Among these, only SCF expression was significantly induced after irradiation with X-rays but not with carbon ions.

To test this mechanism, the researchers examined blood ves-sel formation in the presence of ISCK03, a pharmacologic inhibitor of the SCF receptor that mediates pro-angiogenic effects. They gener-ated plugs from native and X-ray- irradiated A549 cells, with and with-out ISCK03.

ISCK03 treatment resulted in a significant decrease in blood vessel density, both in the native and the

irradiated cells, with vessel formation more strongly decreased in the latter. These data provide further evidence that SCF is an X-ray-induced media-tor of angiogenesis in A549 cells.

The researchers concluded that in this experimental setup, X-ray irradiation of A549 cells resulted in enhanced tumour angiogenesis, while carbon-ion irradiation did not. The effect was likely mediated by X-ray-dependent induction of SCF, suggesting that SCF signalling may represent a therapeutic target for the inhibition of X-ray-induced tumour angiogenesis. Kamlah told medicalphysicsweb that the researchers now plan to analyse their findings in an in vivo mouse model. Studies of the effect of proton irradiation on ang-iogenesis may also be performed in the future.

In most branches of medicine, inno-vations are introduced through phased trials. Consider the drug discovery process, for example. In order to bring a new pharmaceutical to market, extensive and expensive testing is required. These tests inevi-tably involve, at some stage, animal experiments. Only when sufficient evidence has demonstrated that a new drug is safe will it become a part of the clinical arsenal deployed to treat patients. Such stages are essential to weed out the least suc-cessful or, potentially, even harmful treatments.

In radiotherapy, however, where lethal doses of radiation are har-nessed to control and eliminate malignant tumour growths, it may come as a surprise that things are done somewhat differently. Often, new treatment modalities are intro-duced based purely on theoretical or technological arguments. Proton therapy is but one example. Here, calculated dose distributions indi-cate that protons can focus dose bet-ter in the tumour than photons can achieve. The argument, therefore, is that proton therapy must be superior to photon therapy – despite there being little or no evidence to support the succession of photons by protons in clinical radiation therapy.

The introduction of these types of novel radiotherapeutic technolo-gies has allowed radiotherapy to move into new, unexplored, albeit exciting, areas of practice. Such advances, however, can lack a solid foundation of historical, research-based evidence that demonstrates their long-term benefit or consid-ers the radiobiological perspective. Although there are exceptions, animal radiation experimentation seldom serves to introduce new radiotherapy techniques.

But as the baby boomer cohort ages, there will be increased pres-sure on radiation therapy facilities to develop methods that meet the

required capacity, along with an urgent need to test these new treat-ment strategies in pre-clinical small-animal tumour models.

Until recently, sophisticated devices that administer precise radiation doses to complexly shaped targets in animals in the same way as is performed in the clinic today simply didn’t exist. Small-animal imaging, on the other hand, is a well established discipline with major developments across several imag-ing modalities. These imaging tech-niques have greatly aided our ability to longitudinally track the response of new pharmaceuticals in small-animal disease models.

In stark contrast, very little effort has been invested in small-animal radiation research, despite the fact that vast numbers of cancer patients are treated with radiotherapy. In fact, the majority of animal data acquired from radiation research were derived

from imprecise irradiations that bear almost no resemblance to modern fractionated clinical radiotherapy using complex model-based dose calculation algorithms. In the past, many tumour response studies in animals were hindered by high doses delivered to healthy tissue. It is, therefore, questionable to what extent existing animal studies still have relevance for modern radio-therapy practice.

In order to faithfully mimic mod-ern clinical radiotherapy in small-animal disease models, a dedicated small-animal research platform is required – separate from any avail-able clinical external-beam device. This means that the radiation beams not only need to be downscaled in geometry, but also in energy. Fur-thermore, the technical precision required to deliver precise millime-tre-sized beams to localized regions within a small animal far exceeds the

tolerances needed in patient radio-therapy, as do the requirements on image resolution for image-guided radiotherapy of mice, for example.

Sma l l - a n i ma l r ad iot her apy research is the subject of discus-sion in a new Topical Review paper (Phys. Med. Biol. 56 R55). In the paper, Frank Verhaegen and Patrick Gran-ton from Maastro Clinic and Erik Tryggestad from Johns Hopkins University, discuss the development of this exciting field. The authors also describe the pioneering efforts by groups at Stanford University, Johns Hopkins University and the Princess Margaret Hospital in Toronto, Canada, to develop power-ful research tools for small-animal radiotherapy research, work that has led to commercial products by two companies.

Small-animal radiotherapy is an emerging field and the literature does not yet reflect the current activ-

ity using these advanced irradiation/imaging systems. We estimate that about 15 of these systems are now in use for research worldwide, with more on order. Our review reveals that treatment planning to target small structures within animals is far from routine, and that much more work is needed before complex dose distributions can be administered with confidence.

Studies that have been reported include: precision irradiations of lesions in the mouse lung; irradia-tion of half/whole mouse brains; and induction of radiation necrosis in rat brain. These types of stud-ies may help to develop a better understanding of the radiobiology implications of a wide range of appli-cations, including: hypofraction-ated radiotherapy; the bystander effect; the use of gold nanoparticles to enhance both CT image contrast and therapeutic dose deposition; the effect of radiation on novel trans-genic tumour models; the synergy of radiation with other agents; the exploration of novel fractionation schedules; and studies of relative biological effectiveness.

Much work lies ahead in order to develop versatile research platforms and devise research protocols from which we may draw important con-clusions concerning human dis-ease. On the technological side, it may be envisaged that co-ordinated stage/beam motion may enable true intensity-modulated radiotherapy in small animals, potentially with highly heterogeneous dose distri-butions for dose painting studies. Treatment planning is in its infancy for these kinds of studies. Precision small-animal radiation technology may also open many other, perhaps as yet unimagined, avenues of radio-biological research.

Frank Verhaegen is head of clinical physics research at the Maastro Clinic in Maastricht, the Netherlands.

Angiogenesis: X-ray induced

Small-animal irradiation matters

Invaluable tool: the SARRP platform, developed at Johns Hopkins and built by Xstrahl, provides image-guided micro-irradiation. It is one of just two commercially available small-animal irradiation research systems.

Xstr

ahl

MPWRAut11_p07.indd 1 07/09/2011 15:55

8 Five-year update

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It is now five years since the launch of medicalphysicsweb in 2006. One of the first articles published on the site discussed how advanced radiotherapy delivery modalities, such as intensity-modulated radio-therapy, demand equally sophisti-cated dosimetry systems. Another examined the effect that respiratory motion has on radiotherapy dose and discussed some early workarounds.

Five years down the line, small-field dosimetry and motion management are still areas of paramount impor-tance in radiotherapy research. These challenges – along with many other technological and biological aspects of the radiotherapy process – have been the subject of significant progress during this time.

Alongside these examples, what other technology advances have really made an impact in the field of radiation therapy? And what developments can we expect to see emerge over the next few years? Tami Freeman talked to three lead-ing experts in radiation therapy research, to find out what they think.

Image guidanceWhen asked to choose a develop-ment that has been of compelling benefit to radiotherapy, one answer

was unequivocal: image guidance. “I do think that volumetric image guidance has really been the major advance of the last five years,” said Marcel van Herk, head of physics at the radiotherapy department of the Netherlands Cancer Institute. “I think imaging is making a major difference, people are seeing what is going on inside the patients from day to day, I think that is a major breakthrough.”

Gino Fallone, director of the medi-cal physics department at the Cross Cancer Institute in Alberta, Canada, concurred, highlighting the benefits provided by recent advances in MR guidance. “I think that the advent of soft-tissue, real-time visualiza-tion for image guidance in radio-therapy, and also in proton therapy, is going to make a big, big difference to all of radiation oncology,” he told medicalphysicsweb.

According to Dirk Verellen, direc-tor of the medical physics group at UZ Brussel in Belgium, it’s hard to choose just one technology development that has made a dif-ference. Rather, small steps have combined to provide a big step for-ward. “Image-guided radiotherapy, gated radiotherapy, adaptive radio-therapy – these are all new develop-

ments, but they happened gradually because of the synergy of imaging with new computing power and new approaches in dose delivery,” he said.

Verellen emphasized that as more precise dose distributions are deliv-ered, more accuracy is needed in knowing exactly where that dose is delivered to. “It’s the combination of dose sculpting techniques and more accurate imaging during treatment that enables radiotherapy to become much more powerful,” he explained, adding that imaging can now also be used to monitor a patient’s response, allowing individual tailoring of future treatment fractions.

Challenges todayWhile image guidance has enabled many advances, there is still plenty of work to be done in this area, and research efforts are ongoing. “If I give a talk at this moment about what we need in radiotherapy, it’s imaging and imaging and imaging. The top 10 priorities are imaging, all 10 of them. We need to see the tumour during treatment,” said Verellen.

Real-time imaging can also help address another prominent issue in radiotherapy: target motion. This includes fast movement, such as respiration-induced shifts in the tumour and surrounding organs,

where on-board imaging enables gat-ing and tracking of moving targets. Imaging also helps visualize slower changes, such as tumour shrinkage and other anatomical deformations over the course of therapy, effects that van Herk says can have the larg-est impact on treatment outcome.

Another challenge, according to Verellen, is that incremental tech-nology advances can be hard to qualify. “The fact that it’s little steps that together make a big difference means that there are no randomized trials. We are not trying to prove that a new approach is better than an old standardized approach, because there is no standardized approach. It’s a gradual evolution. And that is maybe one of the frustrations of radiotherapy,” he said.

What’s next?So how will radiotherapy technolo-gies likely progress over the next few years? According to van Herk, the next big challenge is not just for the medical physicists, it’s for every-body in radiation oncology. “We are getting so good at hitting what we want to hit, that now the next major step is finding out what we actually want to hit,” he said. “I think medi-cal physicists should also be involved in radiology and MR sequences and

PET scanning. We have to have better images to know where the target is and not try to be ultimately accurate at hitting something when we don’t even know where it is.”

Fallone pointed out that soft-tissue-based image guidance could allow radiation therapy to expand into new areas, enabling treatment of many disease sites that were not previously treatable.

Finally, Verellen highlighted the emergence of individualized treat-ment, aided by advances in func-tional imaging. In the past, treatment was not only population-based, but tumours were considered as a mass of homogenous cells, which is now known not to be the case. Rather, tumours are highly heterogeneous, with regions that respond well to radiation and radioresistant regions containing less oxygen that need a boosted dose.

“Functional imaging allows us to look at not only the patient anatomy, but also the function of tumours, so we can adapt our treatment to those regions,” said Verellen. “We are not there yet, there’s a lot of work to be done to be able to actually quantify this heterogeneity of the tumour. This quantification needs to be very accurate and we’re still sorcerer’s apprentices in that field. But we’re getting there, and that is the future.”

Five years on: radiotherapy advances…

Dirk Verellen: director of medical physics at UZ Brussel in Belgium.

Marcel van Herk: head of physics at NKI’s radiotherapy department.

Gino Fallone: the Cross Cancer Institute’s medical physics director.

“Real-time soft tissue image guidance will allow radiotherapy to treat a whole area of new disease sites.” Gino Fallone

“With these imaging modalities, we can really individualize the treatment to the patient.” Dirk Verellen

The anatomy of patients receiving radiotherapy for head-and-neck tumours often varies significantly during their several-week-long treat-ment course. As a result, significant deviations in dose to the treatment target and organs-at-risk (OAR) from that originally planned can occur. Whether or not to use adap-tive planning – that is, the replan-ning of a patient’s treatment during the course of therapy, once or several times – to correct for these changes is a key question, given the time con-suming, complex nature of this tech-nique and its associated costs.

A study by researchers at the Université catholique de Louvain, Brussels, Belgium, has sought to address this question, by investigat-ing the consequences of anatomical

changes, the potential benefits of adaptive strategies, and evaluating the merit of CT versus FDG-PET assisted adaptive treatment plan-ning (Radiother. Oncol. doi: 10.1016/j.radonc.2011.06.011).

For the study, the researchers selected 10 patients with stage III–IV head-and-neck squamous cell carcinoma, who were receiving intensity-modulated radiotherapy (IMRT). Each patient was scanned using both CT and FDG-PET before, and at weekly intervals during, treatment.

The planned dose distribution for each patient was compared with the delivered dose distribution to examine the effects of any anatomi-cal changes during the treatment course. Delivered dose was calcu-lated using the original plan, applied to the new anatomy obtained from CT images acquired during treat-ment. The researchers found a con-

sistent increase from planned to delivered dose across the irradiated anatomy, illustrated by the increase in tissue volumes receiving certain dose levels.

For example, averaged over all patients, the volume of tissue receiv-ing 95% of the prescribed dose increased from 246.5 cc to 261.4 cc. Dose to OARs reflected this change too – parotid glands, oral cavity and spinal cord all demonstrated, to some degree, higher delivered doses than those originally planned.

The researchers also assessed the benefits of adaptive radiotherapy, using each patient’s mid-treatment scans. Over the total volume of tis-sue irradiated, replanning produced doses significantly lower than the delivered doses, indicating the supe-rior dose conformity of the adaptive replans. For example, the 95% iso-dose enclosed only a 202.0 cc volume in the adaptive case, compared with

261.4 cc for the delivered dose.Despite these observations, when

mean parotid doses were examined, the researchers found that adaptive planning benefited only a subset of patients. Interestingly, they identi-fied a correlation between reduc-tions in parotid gland dose on the introduction of adaptive planning and the slope of absolute gross tumour volume (GTV) shrinkage, proposing the latter as a potential flag of patients who would gain most from adaptive planning. Similar cor-relations were observed between GTV shrinkage and dose integrated over the treated anatomy, and spinal cord and spinal cord planning risk volume doses.

Finally, the researchers compared the relative benefits of CT versus FDG-PET by using the two modali-ties, independently, to outline the GTV in each patient for each of their mid-treatment scans. Although an

analysis of the data is not explicitly described, the researchers concluded that while FDG-PET was a valuable tool for treatment target delineation prior to treatment, typically, the use of CT alone was valid for plan adap-tation during a patient’s treatment course.

Overall, the researchers conclude that indeed there were significant differences in dose between what was planned, what was delivered, and what could be delivered using adaptive planning. But is adap-tive planning worth the effort, as the authors ask in their title? Their answer is a qualified “yes”, for selected patients, but they rec-ommend further studies to assess patient outcomes and cost-effec-tiveness, in order to identify an opti-mal strategy.

Jude Dineley is a medical physicist based in Sydney, Australia.

Is adaptive IMRT worth the effort?

MPWRAut11_p08-09.indd 8 07/09/2011 15:56

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Five-year�update

Proton therapy is an evolving treatment modality that has both expanded its reach and undergone considerable technical advances over the last five years.

In 2006, there were about 25 facilities around the world treating patients with proton beams. By the start of 2011, there were 38 operating particle therapy facilities, 32 offering proton therapy and the remainder treating with carbon ions. Impor-tantly, 24 more sites are currently in a planning stage or under construc-tion. The number of patients treated with protons has come close to dou-bling over this time, with more than 74 000 patients treated to date.

Alongside the growing number of facilities in operation, the last five years have seen the development of new accelerator systems, advances in beam delivery and dose monitoring techniques, and increased clinical applications. Tami Freeman spoke to Tony Lomax, head of medical physics at the Paul Scherrer Institute’s Center for Proton Therapy in Switzerland, and Thomas Bortfeld, director of the physics division at Massachusetts General Hospital (Boston, MA), to find out more.

Scanned beamsAccording to Lomax, the most sig-nificant recent advance in proton therapy has been the implemen-tation of scanning techniques, in which a narrow proton beam is scanned throughout the target vol-ume. This ability to “paint” the dose has opened up the possibility of per-forming intensity-modulated proton therapy.

“The flexibility of the modulation of pencil beams allows us to really conform the dose very accurately to the tumour and spare critical struc-tures, much as we do with IMRT with photons, but also reducing the dose further against IMRT,” Lomax

told medicalphysicsweb. “I think this is where, for me at least, the biggest breakthrough has been made.”

Lomax noted that the Paul Scher-rer Institute is still one of the few sites that can perform proton scan-ning. “However, of the new facilities coming online, three to four to five of them in the future will certainly be doing scanning, only scanning,” he said. “And large centres like the MD Anderson Cancer Center in Houston,

and also [the Northeast Proton Ther-apy Center] in Boston, are just begin-ning to use scanning.”

Bortfeld took a different slant on the same question. He highlighted

how the equipment vendors’ intro-duction of “off-the-shelf” beam-delivery systems has helped bring proton therapy into the main-stream. He also pointed out the important role played by companies such as ProCure in providing end-to-end design, construction, staff training and ongoing operation of proton facilities.

Ongoing challengesDespite the gradually increasing uptake of proton therapy, there still remains a need for more facilities to come online and bring the benefits of protons to a far wider population. But does the high cost of setting up a proton therapy facility impede further implementation? Could the introduction of compact, lower-cost treatment systems from the likes of Still River Systems, CPAC and ProTom increase deployment?

Bortfeld agrees that cost is cer-tainly a big factor hindering more widespread use of proton therapy. “Clearly, if proton therapy cost about the same as IMRT, say, then every-body would do proton therapy,” he said. “The new developments of compact proton accelerators are very promising, but we haven’t seen their clinical promise realized yet. So we are waiting for that.”

He added that, even though pro-ton therapy has been the subject of much research for many years now,

there’s still a lot of technical work to be done. “I am a little concerned that if proton therapy gets into the hands of too many people too early then we might make some unneces-sary mistakes,” he said. “I think we need developments to make proton therapy more robust and more reli-able before we can spread it more widely.”

Lomax also cited cost as a chal-lenge that needs to be addressed, but pointed out that lower-cost sys-tems must be able to maintain the current treatment quality. He also emphasized the need for increased implementation of imaging tech-niques to monitor patients during treatment and ensure that the finely tuned Bragg peak is delivered in the right place.

Protons prevailBoth Lomax and Bortfeld concur that proton therapy is likely to become more prevalent in years to come. “There are an awful lot of centres in planning, facilities that are being built, facilities that will very shortly be online,” said Lomax. “Some will use passive scatter-ing, some scanning and some will combine the two. I think it’s going

to become much more widespread, it’s going to become much more mainstream.”

Lomax suggested that in the longer term, imaging with protons, rather than photons, as part of the treat-ment planning process could prove beneficial. “I believe that if we’re treating with protons we should be imaging with protons – they have the same physical characteristics,” he emphasized. Another possible future development could be online imaging during proton beam deliv-ery, enabling real-time adjustment of treatment.

“If you had asked me 10 years ago, I would have said that there’s no way that proton therapy would ever be a strong competitor with IMRT,” Bort-feld told medicalphysicsweb. “But now things have changed quite dramati-cally. Now I think that in about five years, most or all of the major centres will have proton therapy, or maybe carbon-ion therapy.”

He continued: “I don’t think that I want to take a guess as to when pro-ton therapy will take over and most patients will be treated with protons as opposed to photons. But I think that might also happen, some time in the future.”• To hear more from these experts, view the articles on medicalphysicsweb.org to listen to our exclusive audio interviews.

…and developments in proton therapy

Thomas Bortfeld: director of the physics division at MGH in Boston.

Tony Lomax: medical physics head at PSI’s Center for Proton Therapy.

“Proton therapy has reached the stage where it’s a commercial product and everybody realizes it is there.” Thomas Bortfeld

“The key challenges are two – one financial and one scientific.” Tony Lomax

“We don’t know always where protons stop, I think we need to do more imaging.” Tony Lomax

Researchers at the University of Florida ( Gainesville, FL) have published details of eight compu-tational phantoms of the human foetus at ages ranging from eight to 38 weeks post conception. These new UF models will be used to establish a comprehensive database of photon and electron absorbed fractions for assessing organ self-dose and organ cross-dose when radionuclides, or potentially radio-pharmaceuticals, enter the foetus following placental transfer (Phys. Med. Biol. 56 4839).

“Our new UF series of foetal phantoms provides explicit treat-ment of individual internal organs, and had to be constructed from image segmentation of true foetal anatomy,” Wesley Bolch, the direc-

tor of the Advanced Laboratory for Radiation Dosimetry Studies within the Department of Biomedi-cal Engineering, told medicalphysics­web. “Our models are the first to include anatomic representation of the foetal thyroid and skeleton, where the latter includes age and bone-specific modelling of ossi-fication centres for bone marrow formation.”

Although a number of models of the developing foetus have been pub-lished in the past, Bolch and his col-league Matthew Maynard were keen to address the lack of organ-level definition in previous work.

The team undertook a compre-hensive imaging and modelling study lasting three years to produce its series of computational hybrid phantoms. “Hybrid phantoms have the scalability of a traditional styl-ized or mathematical equation-based phantom while retaining the

anatomical realism of voxel-based phantoms,” commented Maynard.

The first step in this process was to perform MR and CT imaging of well preserved 11.5- and 21-week foetal specimens in order to cre-ate specimen-specific phantoms. In the case of the 11.5-week speci-men, high-field strength MRI was required to produce image sets of internal anatomy with acceptable quality.

The researchers then segmented the 11.5- and 21-week image sets to obtain 3D polygon mesh repre-sentations of individual bone sites and major soft-tissue organs. They then converted all soft-tissue organs and the majority of the bone sites to deformable NURBS (non-uniform rational B-spline) surfaces and cor-rected any image artefacts in the skeleton.

“The major time-limiting step wa s const r uc t i ng t hese t wo

specimen-specif ic phantoms,” explained Maynard. “Unlike post-natal CT image sets where the skel-eton is automatically segmented via contrast thresholding, each specimen-specific MR image set had to be hand- segmented due to difficulties in isolating the skeleton contrast values. Also, the majority of the bone sites in the specimen- specific phantoms had to be con-ver ted to defor mable N U R BS sur faces a nd ha nd- cor rec ted for image artefacts introduced by the small physical size of the specimens.”

Bolch explains that the final steps in the process involved adjust-ing and repositioning a UF hybrid newborn phantom to represent a 38-week in utero foetus. “To create the complete series of phantoms representing a foetus at eight tar-get gestational ages (namely eight, 10, 15, 20, 25, 30 and 38 weeks) we

volumetrically scaled and adjusted the 11.5-, 21- and 38-week phan-toms, while accounting for vari-ations in weight percentile, total mass, individual organ masses and bone- specific levels of relative ossi-fication,” he added.

The Bolch group is currently using its set of phantoms to provide esti-mates of internal dose to multiple foetal organs. This work is part of an EU-funded radiation epidemiology study of pregnant females exposed in utero in villages along the Techa River in the Southern Ural Moun-tains of the former USSR. The pur-pose of this study is to evaluate the radiation-induced risk of childhood cancers following in utero exposures to environmental radionuclide sources.

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

Foetal phantoms assess the dose

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10 focus on: nuclear medicine

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Researchers at University College London (UCL) reported progress in the development of a portable pixel-lated high purity germanium (HPGe) Compton camera (Phys. Med. Biol. 56 3473). Unlike conventional gamma cameras, the UCL Compton camera is particularly suited to radioisotope imaging with high-energy photons and does not require the use of bulky, heavy mechanical collimators.

“We intend to use our portable Compton imaging system for a vari-ety of high-energy applications including thyroid imaging, using iodine-131 (364 keV), and infection and inf lammation imaging using monoclonal antibodies labelled with indium-113m (393 keV),” said PhD candidate Mashari Alnaaimi.

The Compton camera differs in principle from conventional gamma cameras. It contains two photon detector planes, rather than one, the additional layer acting as an electronic collimator, rather than a mechanical one. The first detector scatters incident photons, while the second absorbs them. If the pair of detectors can provide accurate infor-mation on the location and energy of photons interacting with them, and the detector separation is known, Compton scattering theory can be applied to locate the origin of the photon and subsequently map radio-isotope distribution in the patient.

The HPGe semiconductor detec-tors were chosen for their par-ticularly high-energy resolution. Segmentation of each detector into arrays of 4 × 4 mm pixels enables scatter and absorption events to be localized. Based on a pre-determined scatter angle range that optimized detector efficiency, a detector plane separation of 9.6 cm was used. Coin-cidence detection identifies and allo-cates scatter and absorption events to individual photon trajectories; the researchers used rear detector inter-action events as a trigger, perform-ing offline filtering of front detector events to identify those occurring within fixed time and energy win-dows of the trigger.

A point caesium-137 source posi-tioned 3 cm in front of the camera measured the FWHM as 4.9 mm. Two point sources were used to dem-onstrate a resolving power to within 3.5 mm for sources positioned 3 cm from the front detector.

Key limitations of the current camera design were highlighted by the study. Readout electronics exhibited suboptimal performance at high count rates, such that very long acquisition times were neces-sary. The coincidence detection technique employed also proved to be time-consuming. Finally, image reconstruction using list mode back projection resulted in artefacts.

“Current investigations focus on optimizing the camera performance by treating the limitations encoun-tered in our study” said Alnaaimi.

PET imaging using the radiotracer 18F-FDG is the current standard for diagnosis and staging of patients with non-small cell lung cancer (NSCLC). The number of PET scan-ners available, however, is currently lower than ideal.

In the late 1990s, when PET and FDG were first approved for oncol-ogy applications, there was already concern that the high cost of PET devices may limit the number of sites that could utilize this technol-ogy. As such, researchers at the MD Anderson Cancer Center began work on creating an alternative imaging agent that would make access to can-cer staging more widely available.

The MD Anderson team, working in collaboration with US biophar-maceutical company Cell>Point has now developed just such a molecu-lar imaging agent. The new agent – Tc-99m-ethylene-dicysteine-glu-cosamine (ECG) – can be imaged using SPECT systems, which are lower in cost and have a far greater installed base.

Phase II clinical trials examining NSCLC diagnosis with ECG have now been completed. “The first applica-tion focused on lung cancer because it represents approximately 80% of all staging procedures performed

with FDG,” explained Cell>Point’s president David Rollo.

The Phase II trial compared the diagnostic and staging accuracy of ECG-SPECT/CT with that of FDG-PET/CT in 22 patients with biopsy-proven NSCLC. Standard protocols were used for FDG imaging. The ECG protocol involved performing SPECT/CT three hours after injection

of 1 mg of ECG labelled with 25 mg of Tc-99m. The study included SPECT/CT systems from all three major ven-dors at six participating sites.

Independent expert readers at a core lab assessed the images for location, size and confidence that the detected lesions were cancer. For pri-mary lesions, results showed 100% concordance between ECG and FDG

on all three parameters, independ-ent of the SPECT device used. In 17 patients with metastatic lesions, 90% agreement was seen for location, size and confidence that detected lesions were metastases. No adverse drug-related events were reported.

The Cell>Point team also exam-ined the uptake mechanism of the two radiotracers. Uptake of 99mTc-ECG increases in cells undergoing rapid regeneration, thus the agent targeted the tumour, with minimal localization in infection or inflam-mation, no normal-brain or bone uptake and slight cardiac uptake. Increased FDG uptake occurs in cells with increased glucose metab-olism, resulting in its localization in tumour, inflammation, normal brain and normal cardiac tissue. “Because ECG is not taken up in inflammation or infection, unlike FDG, it has the potential benefit of fewer false posi-tives,” said Rollo.

With the Phase II trial completed, Cell>Point has now prepared the Phase III protocol. “We are simul-taneously beginning the recruiting process for up to 45 sites in the US and Canada,” said Rollo. “It is our plan to have the final FDA approved protocol in place soon and to begin the Phase III in Q4 2011.”

Camera easesisotope imagingSPECT tracer could cut costs

Phase II results: 99mTc-ECG-based SPECT/CT (right) is at least as good as PET/CT with FDG (left) for detecting primary NSCLC tumours.

For the first time, a peptide receptor-targeted combination of PET/CT imaging and molecular radiotherapy has been shown to be safe and feasi-ble in the selection and treatment of children with relapsed and aggres-sive primary neuroblastoma. The targeted approach promises lower toxicity levels compared to conven-tional chemotherapy and radiother-apy ( J. Nucl. Med. 52 1041).

The University College London Hospitals study was motivated by the successful track record of pep-tide receptor radionuclide therapy (PRRT) in selected adults with neu-roendocrine tumours, and the need for improved therapy for children with neuroblastoma, a disease with a long-term survival rate less than 40%. “The outcome of this proof of concept study was very reassuring. It has allowed us to initiate Phase I and II of this study with confidence,” said co-author Jamshed Bomanji.

Eight children aged 2–14 years old, with either relapsed or pri-mary refractory neuroblastoma, and no other treatment options available, were recruited for the study. Key to this study was the use of DOTATATE, a somatostatin analogue. Somatostatin is a neuro-transmitter synthesized by neurob-lastoma, and somatostatin receptors are expressed on the surface of some tumours. This makes them attractive targets for radiolabelled somatosta-

tin analogues, both for imaging and therapeutic purposes.

The children had PET/CT scans within an hour of intravenous injection of 100 MBq of gallium-68 labelled DOTATATE, to assess their suitability for DOTATATE molecu-lar radiotherapy. Scan timing was dictated by the 68-minute half life of gallium-68. Levels of radiotracer uptake in the liver were used as a reference level; if gallium-68 DOTATATE uptake at the disease sites was greater than that in the liver, the child was deemed eligible for lutetium-177 DOTATATE therapy. Six children fulfilled this criterion and proceeded to receive treatment.

The therapeutic radioisotope lutetium-177 is predominantly a beta emitter with a primary maxi-mum energy of 497 keV and a half life of 6.71 days. Prior to treatment, each child received an intravenous infusion of amino acids to lessen radiation dose to the kidneys. A treatment regimen of four cycles of 7.4 GBq of lutetium-177 labelled DOTATATE, repeated every 8–10 weeks, was planned. However, due to problems associated with radiophar-maceutical reconstitution, a range of 4.04 –7.5 GBq activities (median 7.3 GBq) administrations were made. Most children were too unwell to complete the treatment course.

A f t e r e a c h l u t e t i u m -17 7 DOTATATE administration, each

child underwent a whole-body pla-nar nuclear medicine scan and a SPECT/CT scan to assess the extent of radiopharmaceutical uptake. Based on the pre-treatment gallium-68 DOTATATE PET scans, the research-ers successfully confirmed therapeu-tic radiopharmaceutical uptake at the disease sites in each child.

Six to eight weeks following treat-ment the researchers performed a second gallium-68 DOTATATE scan, and in some cases F-18-FDG PET and/or I-123-MIBG scans, to evaluate treatment response. Maxi-mum standardized uptake values, SUVmax, derived from the scans were used as a quantitative measure of response. The treatment response in children with soft-tissue disease was also clinically graded.

The primary aim of the study was realized; to demonstrate that the techniques used were safe and fea-sible. From the six children selected, five had stable disease following treatment, while one had progres-sive disease. Four children developed haematological toxicity. Promis-ingly, none developed renal toxicity.

The researchers plan to con-solidate their findings with a phase I-II clinical trial, “We have ethics approval and are in the process of obtaining approval from other pae-diatric cancer bodies. The next big-gest hurdle is to seek funding for this study,” said Bomanji.

PET guides targeted therapy

Future look: Mo-99 will be created in a thimble installed next to the core. Credit: Andrea Voit/TUM.

Funding tacklesMo-99 demand

The German Federal Ministry of Health has awarded more than €1 m for researchers to develop efficient techniques for producing the radio-isotope molybdenum-99 (Mo-99) at the research neutron source FRM II in Garching. The Technische Univer-sität München has already demon-strated that the neutron source can produce about half of the European demand of Mo-99, the parent isotope of technetium-99m. The aim now is to produce significantly higher spe-cific activity than existing produc-tion facilities. Plans include measures for efficient cooling of the material in a position with highest neutron flux, as well as developing more efficient packaging for safe delivery of the short-lived isotope for further radi-opharmaceutical processing. The State of Bavaria is also supporting the construction with €1.2 m.

MPWRAut11_p10.indd 14 07/09/2011 15:57

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focus on: imaging techniquesVPA identifi es plaque

Researchers from Purdue Univer-sity have developed a method called vibrational photoacoustic (VPA) microscopy that offers tissue pen-etration depth on the millimetre scale, making it possible to acquire precise three-dimensional images of plaques lining arteries (Phys. Rev. Lett. 106 238106). “This is the fi rst demonstration of VPA microscopy,” said Han-Wei Wang from Purdue’s School of Biomedical Engineering. “Our technique offers deep-tissue, label-free, bond-selective molecu-lar imaging. Millimetre penetration depth is a breakthrough of over one order of magnitude compared with other vibrational microscopy and offers great translation potential in disease diagnosis and in tissue interventions.”

Exploiting the photoacoustic effect in imaging and microscopy is not a new idea, but what the research-ers do differently is to target specifi c molecular overtone transitions to provide contrast. For example, the team uses a nanosecond-pulsed laser to excite the second overtone of a carbon-hydrogen bond at around 8400 cm–1 (1190 nm), where absorp-tion by blood and surrounding tissue is minimal. The laser pulses cause the sample of interest to heat and expand locally, generating pressure waves at ultrasound frequencies that are detected by a transducer.

“Targeting specifi c chemical bonds is expected to open a completely new direction for the fi eld,” commented group leader Ji-Xin Cheng. “Measur-ing the time delay between the laser and the ultrasound waves gives you a precise distance, which enables you to image layers of tissue and create

three-dimensional pictures using just one scan.”

To demonstrate the potential of 3D VPA imaging, carotid arteries were removed from Ossabaw pigs with profound atherosclerosis. The team reported that it could detect a strong VPA signal from lipids located 1.5 mm below the lumen and was able to identify different levels of lipid accumulation. The VPA tech-nique clearly differentiated a con-fl uent lipid core in an atheromatous artery, a scattered lipid deposition in an arterial wall and the formation of mild fatty streaks in early atheroma. In an additional set of experiments, the researchers used VPA micros-copy to map the distribution of lipids in fruit-fl y larvae.

Because the location and depth of any lipid deposit are essential pieces of information, the Purdue group is now looking to miniaturize its sys-tem and develop a catheter-based imaging device. “We are looking to build an endoscope to put into blood vessels,” said Cheng. “This would enable us to see the exact nature of plaque formation in the walls of arteries and better quantify and diag-nose cardiovascular disease.”

Wang adds that the spatial resolu-tion of the VPA system is suitable for such future work. “The lateral reso-lution is very fl exible from the order of a micron to tens of microns,” he said. “The resolution is an improve-ment compared with current clinical imaging methods such as intravascular ultrasound. Our spa-tial resolution will be enough for atherosclerotic applications, and will be a great option as a compli-mentary imaging modality.”

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A German collaboration has devel-oped a multiphoton microscope that can image activity from many neurons simultaneously, with single-cell resolution and at corti-cal depths of more than twice that previously achieved. The research-ers, from the Max Planck Institute for Biological Cybernetics in Tübin-gen and the Max Planck Institute for Medical Research in Heidelberg, combined regenerative amplifica-tion multiphoton microscopy with genetically encoded calcium indica-tors. This approach enabled them to study neural cell activity in layer L5b in an adult rodent. Until now, most imaging studies were restricted to the upper third of the cortex in layers L2

and L3 (Nature Neuroscience 14 1089).The cortex receives and processes

information from the senses, but the underlying principles are not fully understood. The scientists devel-oped a method to see exactly which cell is active and, importantly, what cells are not active, during a stimu-lus up to 1 mm from the cortical surface. This enabled them to meas-ure the spatiotemporal organiza-tion of activity in these deep layers. “We express a genetically encoded fl uorescent activity reporter in the neurons of interest and with this we can measure the activity of many neurons at the same time”, explained researcher Jason Kerr, noting that changes in brightness of the fl uores-cent marker are related to neuronal activity. The goal is to record activity from populations of neurons located in all cortical layers, from L6 to L1.

Microscope sees neuronal activity

Cardiovascular disease: VPA image showing plaque in an arterial wall.

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MPWRAut11_p13.indd 3 07/09/2011 16:01

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focus on: imaging techniquesDeep tissue imaging

Fluorescence microscopy offers noninvasive, cost-effective imaging of optical molecular probes and, as such, is employed in both pre-clinical and clinical applications. However, fl uorescence light diffuses after prop-agating a few hundred micrometres in tissue, making the technique unsuitable for imaging biological samples thicker than 1 mm.

Now, Alex Cong and colleagues from Virginia Tech have proposed a f luorescence microtomography technique that uses Monte Carlo sim-ulations to reconstruct molecular probe distributions in thick biologi-cal samples, with sub-millimetre res-olution ( J. Biomed. Opt. 16 070501).

“We use f luorescence tomogra-phy to visualize engineered ves-sels in a bioreactor, and need high spatial resolution to map live cells in tissue scaffold,” explained cor-responding author Ge Wang. Ide-ally, spatial resolution should be on the micron to sub-millimetre level, through a depth of a few millimetres to centimetres.”

Fluorescence microscopy involves focusing on a region-of-interest (ROI) in a sample and acquiring sur-face fl uorescence scattering signals emitted from probes within this volume. The ROI can be divided into fi nite volumetric elements and the acquired photon fl uence rate consid-ered as a linear combination of fl uo-rescence source intensities.

Cong and colleagues used Monte Carlo simulations to trace the com-plex paths of photons propagating through tissue. They note that while Monte Carlo methods are compu-tationally demanding, their recent implementation of a multi-GPU (graphic processing unit) system enabled them to speed up calcula-tions by over 800 times.

One obstacle when localizing f luorescent sources is that the f lu-ence rate is measured from photons collected on an external surface of the sample, while the sources are actually distributed in three dimen-sions within the ROI. As such, source reconstruction is an ill-posed prob-lem with multiple solutions.

To find a stable solution, they introduced a well posed inverse model (i.e. one in which a unique solution exists). The model states that if the sample’s optical param-eters – including absorption coef-

ficient, scattering coefficient and anisotropic factor – are known, and the number of luminescent sources in the ROI is known, then the posi-tions and powers of these sources can be determined from the meas-ured surface signal.

Based on this concept, the research-ers created an optimization model for light source reconstruction, and developed a differential evolution-based reconstruction algorithm to solve it. “Differential evolution drives the Monte Carlo forward solver iter-atively during the reconstruction process,” explained Cong. “Because of its fast converging behaviour, DE signifi cantly reduces the number of Monte Carlo runs needed.”

The researchers tested the accu-racy of their fl uorescence microto-mography approach on biomimetic tissue scaffolds. They created scaf-folds with thicknesses of 0.65, 0.8 and 1.4 mm, and containing 90 µm fl uorescence microbeads. The scaf-fold’s absorption coefficient, scat-tering coefficient and anisotropic factor were measured as 0.01 mm–1, 15.0 mm–1 and 0.9, respectively.

They then illuminated the scaf-fold with 473 nm laser light, and cap-tured the emission signal using an electron-multiplying CCD camera. The microbead distribution was reconstructed from each set of cap-tured emission signals, a process that took about 20 minutes.

Results showed no significant difference in localization accuracy across the three scaffold thick-nesses. Comparisons with the actual microbead distribution (imaged with a fl uorescence microscope) revealed maximum positional errors of 250, 275 and 500 µm for the 0.65, 0.8 and 1.4 mm scaffolds, respectively.

In real biological samples, the number of luminescent sources is not necessarily known in advance. This figure can, however, can be determined by solving the optimiza-tion problem for a gradually increas-ing number of sources.

The Virginia Tech team is now applying this method to tissue engi-neering. “We are interested in using a high-magnifi cation optical micro-scope to enhance image resolution, scan through a tissue scaffold sample to expand the fi eld-of-view, and test state of the art compressive sensing techniques,” said Wang.

High resolution: calibrating the fl uorescence microtomography system.

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