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medicalphysicsweb reviewRadiation oncology special edition

Protons cut second cancer riskProton therapy can reduce the risk of second cancers in paediatric brain tumour patients.

Today, around 80% of paediatric cancer patients survive long term, spurring concern over adverse radi-otherapy-related late effects. Due to their small size, longer life expec-tancy and highly radiosensitive tis-sues, young patients are particularly susceptible to developing second cancers, especially in organs close to the treatment site. Researchers from Massachusetts General Hospital and Harvard Medical School, have per-formed a detailed evaluation of the second cancer risks for paediatric patients with brain or head-and-neck tumours (Phys. Med. Biol. 59 2883). They compared four treat-ment modalities: passive scattered and pencil-beam scanned proton therapy (PPT and PBS), intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc ther-apy (VMAT).

“Our main motivation was to potentially reduce the lifetime risk of radiation-induced malignancies by enabling a quantitative assessment of this risk for individual patients, and compare all possible radiother-apy modalities,” explained assis-tant physicist Maryam Moteabbed. “Decreasing this risk could poten-tially be set as a treatment planning objective to help physicians decide on the optimal choice of modality.”

Previous studies have suggested that proton therapy generally yields a lower risk of second cancer incidence than IMRT. In this work, Moteabbed and colleagues quantified the risks of young patients developing second-ary tumours in the vicinity of the pri-mary radiation field (in this case, the skull and cranial soft tissues), where most second cancers occur.

The researchers chose six paedi-atric patients originally treated with PPT and created additional proton and photon plans for each. They used RayStation2.5 to create IMRT plans with five and seven fields and a VMAT plan. PBS plans were gener-ated with MGH’s in-house treatment planning software ASTROID, using field arrangements identical to the PPT plan. They also created a new PPT plan for each patient by increas-ing the number of fields.

While all plans provided equally good target coverage, different modalities led to distinct dose dis-tributions. Analysis of dose-volume histograms (DVHs) showed that in general, protons irradiated smaller volumes of healthy tissue than IMRT

and VMAT. Proton therapy was par-ticularly superior at the lower-dose end of the DVH curves, with 1.5–4 times less soft tissue volume and 5–6.5 times less skull volume irradi-ated by protons relative to photons. The integral dose to normal tissues was generally lower for PBS than for PPT, and PPT plans with different numbers of fields were dosimetri-cally equivalent.

To calculate the risk of second malignancies, the researchers used existing organ equivalent dose (OED) models for carcinoma and sarcoma induction to approximate the risks for radiation-induced brain and skull tumours, respectively. They calcu-lated the excess absolute risk (EAR) as the product of OED and the initial slope of the dose-response curve. As another aim of this study was to com-

pare a widely used full dose-response model with a linear dose-response model based on recent childhood cancer survivor study (CCSS) find-ings, they used both models in the calculation of OED.

Plotting EAR at an age of 60 for all modalities revealed an increas-ing risk when moving from proton to photon modalities. PBS showed smaller EAR than PPT for most cases, while VMAT and IMRT had compa-rable EAR. Both PPT and IMRT with fewer fields had smaller EAR than plans using more fields. Averaged over all tissues and models, EAR was approximately 2.3 (cases per 10,000 person years) for protons and 4.9 for photons.

The team next calculated the life-time attributable risk (LAR) – the excess likelihood over the baseline risk of developing a second malig-nancy. For all tissues, LAR was low-est for proton plans (0.01–2.8%) and highest for IMRT and VMAT (0.04–4.9%). For most patients, PBS showed equal to or slightly lower risk than PPT, while, on average, VMAT and IMRT showed comparable risk. The number of fields used in either proton or photon therapy had mini-mal impact.

To minimize uncertainties in esti-mating absolute risks, the research-ers calculated relative LAR (rLAR), defined as the LAR for each modality

relative to that of PPT. The three pro-ton modalities had roughly equiva-lent rLAR, of slightly above or below unity. Values of rLAR for IMRT and VMAT plans were generally compa-rable, at 2.1–30 for skull and 1.3–4.6 for soft tissue. For soft tissue, average rLAR values for proton plans were a factor of 1.3–4.6 smaller than for photon plans. The lifetime risk of bone cancer was, on average, 3.5–9.5 times larger for photons than for protons.

Comparing the full and linear dose-response models revealed that the linear model generally generated larger EAR values for both tissues. The authors note that while absolute LAR values were larger when using the linear model (e.g. approximately 10 times larger for sarcomas), rLAR values were not as affected by the model used.

The risk assessment model could be implemented in the planning process when comparing two treat-ment plans. “Recently, we have been working on a comprehensive plan-ning study comparing proton PBS with passive scattering for paediat-ric patients. We also aim to address how institution-specific PBS param-eters, such as spot size and the addi-tional use of apertures, could impact the organ-at-risk dosimetry and hence the patient side effects,” said Moteabbed.

“Our motivation was to potentially reduce the lifetime risk of radiation-induced malignancies.”

Plan comparisons: dose distributions from PPT (2- and 3-field), PBS (2-field), IMRT (5- and 6-field) and VMAT plans for an example paediatric patient. The colour scale represents 0 (dark blue) to 50.4 Gy (dark red).

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This issue, distributed at ASTRO’s 56th Annual Meeting in San Francisco, CA, brings you a taster of our recent online content. If you like what you see, check out the website to read more in-depth news and research articles. Or why not register for free as a member – simply visit medicalphysicsweb.org or come and see us at booth #208 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 2013 impact factor stands at 2.922*.

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The clinical information provided is indicative and is not intended to replace medical advice offered by physicians. The publishers make no representations or warranties with respect to any treatment or action, by any person following the information offered or provided. The publishers will not be liable for any direct, indirect, consequential, special, exemplary, or other damages arising therefrom.Although inspired from real cancer patient stories, characters appearing in this work are fictitious. Any resem-blance to real persons, living or dead, is purely coincidental.

Thanks to PROTON THERAPY after chemotherapy, Simon, firefighter, is living a normal life in New Jersey, NJ, USA. He was diagnosed with a bone sarcoma on his tailbone in 2007.

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3focus on: particle therapy

Clinical studies support promise of protonsThe theoretical dosimetric advan-tages of proton therapy are undeni-able: a proton beam deposits almost all of its energy at a particular depth, defined by the protons’ initial energy, sparing nearby tissues and organs. Now, researchers are also observing favourable clinical outcomes for pro-ton treatments, as evidenced by two newly published studies.

In the first study, from the Uni-versity of Florida Proton Therapy Institute, proton therapy was used to treat patients with Hodgkin lym-phoma. The phase II study showed that the use of proton therapy after chemotherapy in such patients has a similar success rate to the con-ventional treatments, with reduced radiation dose outside of the target area, potentially reducing the risk of radiation-induced late effects (Int. J. Radiat. Oncol. Biol. Phys. 89 1053).

The study tracked five children and 10 adults who received involved-node proton therapy (INPT) - which targets initially involved lymph node(s) containing the Hodgkin lymphoma - after completing chem-otherapy. The researchers compared the radiation dose to surrounding healthy tissue from proton therapy

with that from intensity-modulated radiation therapy (IMRT) and 3D conformal radiotherapy (3D CRT). Although the benefits of reduced car-diac disease, secondary cancers and other chronic problems will not be evident for decades, proton therapy clearly reduced treatment toxicity. Protons reduced the average integral body dose by 49% compared with IMRT and by 57% compared with 3D CRT.

Proton therapy also reduced the dose to specific organs-at-risk. The mean heart dose was lowered by 7.6 Gy (46%) and by 3.3 Gy (27%) com-pared with 3D CRT and IMRT, while

the mean lung dose was reduced by 4.5 and 2.7 Gy compared to 3D CRT and IMRT, respectively.

In addition to demonstrating clini-cally relevant reductions in radiation dose to non-target tissue, the proton therapy regime demonstrated simi-lar control rates to those expected with conventional radiation treat-ment. With a median follow-up of 37 months, the data showed a three-year relapse-free rate of 93% and a three-year event-free rate of 87% . In addition, no patients developed grade three or higher toxicity during follow-up.

The authors note that while several

dosimetry studies have previously reported proton therapy’s ability to reduce dose to the heart, breast and lungs in Hodgkin lymphoma patients, none of these studies actu-ally treated the patients with pro-tons. This study was the first to offer patients treatment with whichever plan accomplished target coverage and best spared the organs-at-risk: the proton therapy plan in all cases.

“All 15 patients derived ben-efits from using proton therapy,” said radiation oncologist and lead researcher Bradford Hoppe. “The results show that the use of protons, as opposed to similar conventional photon therapy, reduced the risk of long-term side effects by reducing or eliminating radiation doses to healthy tissue without compromis-ing the cure rate.”

Elsewhere, radiation oncologists at the Mayo Clinic have performed a systematic literature review com-paring the outcomes of skull base cancers treated with proton therapy or IMRT. They found that proton therapy significantly improved disease-free survival and tumour control (Lancet Oncol. 15 1027). “We undertook a systematic review and

meta-analysis to compare the clini-cal outcomes of patients treated with proton therapy with patients receiv-ing photon IMRT,” said senior author Robert Foote.

Foote and colleagues identified studies of nasal cavity and parana-sal sinus tumours through exten-sive database searches. They used random-effect models to pool out-comes across studies and compared event rates of combined outcomes for proton and photon therapy using an interaction test.

The analysis revealed that pooled overall survival was significantly higher for charged particle therapy than for proton therapy, both at five years and at longest follow-up. At five years, disease-free survival was significantly higher for patients receiving proton therapy than those receiving IMRT (72% versus 50%). Tumour control did not dif-fer between treatment groups at five years, but was higher for proton ther-apy than IMRT at the longest follow-up (81% versus 64%).

“Our findings suggest that the theoretical advantages of proton beam therapy may in fact be real,” concluded Foote.

Radiotherapy for paediatric patients is a double-edged sword: it has the potential to cure existing cancer and the potential to cause secondary cancers later in life. For this reason, a presentation about the potential use of helium ions to reduce radiation exposure generated much interest at this year’s ESTRO 33 meeting.

Hermann Fuchs from the Medi-cal University of Vienna presented a treatment planning study that showed how helium ions may pro-vide superior dose distributions to proton therapy. Fuchs and colleagues developed a method for calculat-ing the optimal dose of helium ions for use in radiation treatment. They then created plans for 10 paediatric patients using their previously devel-oped pencil-beam algorithm for pro-ton therapy and scanned helium ion beam therapy.

The researchers created five paedi-atric neuroblastoma and five Hodg-kin’s lymphoma treatment plans based on pencil-beam scanning. The same beam configurations (two beams from the anterior-posterior or lateral direction) were used for helium and proton therapy. The dose prescription to the planning target volume (PTV) was 21 Gy for neu-roblastoma and 19.8 Gy for Hodg-kin’s lymphoma patients. The liver, kidneys, heart, lungs and thyroid were considered as organs-at-risk (OARs) depending upon the tumour position.

The researchers determined that

more stringent OAR constraints could be employed for plan opti-mization using helium ions instead of protons. Helium ions provided improved PTV coverage and slightly lower doses for all OARs. The dose distribution outside the PTV was notably different between helium ions and protons, with reduced entrance doses for helium.

Fuchs explained that due to the increased mass of helium ions com-pared to protons, spreading of the beam is reduced by a factor of two. Helium ions also have an increased biological effectiveness at the end of their range.

“After three years of extensive research and validation efforts, we produced a treatment planning algo-rithm that enabled us to investigate the possibilities for using helium ion therapy in children treated with low-dose radiation, “Fuchs told medicalphysicsweb. “Our study offers the first step toward exploring the potential of helium ions for paediat-ric patients. We chose patients with low-dose radiation schemes for this first investigation, but would like to include patients treated with higher doses, like brain tumour patients, in a future study. The good results that we achieved are motivating us to take a more in-depth look at the clinical potential of helium ions.”

“A long-term goal would be the future implementation in clinical trials in order to improve treatments, especially for young patients. We think that helium ions may provide superior, better targeted treatment for paediatric patients and we hope that this will be validated,” said Fuchs.

Researchers in Germany have devel-oped technology that quantifies the dosimetric impact of tumour motion, the interplay effect, on scanned-beam carbon ion therapy in prostate tumours. The 4D dose computation (4DDC) method will enable researchers to investigate the phenomenon more closely in the tumours, which exhibit aperi-odic and widely varying motion, and develop measures for its miti-gation. In clinical practice, the tool could also be used to verify delivered treatments.

Developed by Filippo Ammaz-zalorso and Urszula Jelen of the Uni-versity of Marburg, the application incorporates tumour motion data recorded by implanted radiofre-quency fiducials and data on beam delivery timing to estimate the bio-logically-weighted dose to the pros-tate (Phys. Med. Biol. 59 N91).

Other research has assessed the interplay effect in lung tumours, whose motion is periodic, using short 4D-CT scans acquired at treat-ment planning. However, the aperi-odic motion that prostates exhibit would necessitate long scanning times and unacceptable dose to the patient. Also, pre-treatment scans provide no indication of prostate motion during treatment. Fiducials, however, provide detailed 3D motion data over entire treatment fractions, enabling retrospective calculation of the delivered dose.

To simulate tumour motion,

the 4DDC application moves each beam spot relative to the tumour – rather than moving the tumour. For tumour movement perpendicular to the beam, the beam is shifted by the same amount in the opposite direc-tion. Movements in the beam direc-tion are simulated with changes in beam energy.

The strategy generates a single treatment plan and corresponding biologically weighted dose distribu-tion that encompasses all tumour motion. This approach was chosen as relative biological effectiveness (RBE) – which relates absorbed dose to biologically weighted dose – var-ies with the magnitude of absorbed dose, in addition to several other physical parameters. Therefore, individual phases of biologically weighted dose cannot be summed.

The researchers verified the 4DDC method in the treatment plans of 12 prostate patients with three in vivo fiducial data sets. They used absorbed dose calculated on quasi-

4DCT scans as a reference standard where tumour motion was simulated by moving the clinical target volume contours in each patient’s planning CT scan. The doses calculated for each movement phase were summed for comparison with absorbed dose calculated by the 4DDC method.

In all plans, when dose was cal-culated assuming a uniform patient composition equivalent to water, the maximum difference in dose between the two methods was 0.2 percentage points (pp). For the imaged patient composition, the maximum difference was 0.8 pp and the researchers estimate a corre-sponding uncertainty in biologically weighted dose of 3 pp.

With the 4DDC method validated, Jelen’s group have investigated the interplay effect for different motion patterns and measures to reduce its impact. In future work they plan to assess the impact of the effect on a typical population of prostate radio-therapy patients.

Comparing treatments: plans using 3D CRT (left), protons (middle) and IMRT (right). The clinical target volume is contoured in red, the planning target volume in blue, with a colour-wash dose distribution.

The authors: Urszula Jelen and Filippo Ammazzalorso at a recent seminar.

Can helium ions improve results?

Quantifying the impact of motion

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5focus on: particle therapy

Active pixel sensors track single protonsProton therapy is an attractive treat-ment for certain cancers. However, it cannot reach its full clinical potential due to uncertainties in the X-ray CT-derived proton stopping powers used to calculate treatment dose. Proton imaging may hold the key to more accurate stopping power data.

Funded by the Wellcome Trust, the Proton Radiotherapy Verification and Dosimetry Applications (PRaVDA) consortium is designing and build-ing the first proton transmission CT scanner based on silicon-based CMOS active pixel sensor (APS) tech-nology. In their latest research, the UK and South Africa-based researchers have provided proof of concept that the DynAMITe sensor can resolve individual protons passing through it (Phys. Med. Biol. 59 2569).

Developed by PRaVDA research-ers, the radiation-hard pixellated sen-sor has a 12.8 x 12.8 cm area and two wafer diode layers, one with 100 µm pixels and another with 50 µm pixels. The pixelated design allows proton-sensor interactions to be localized within the sensor area. “This allows you to measure the passage of more than one proton in the device at once,” said Gavin Poludniowski, first author and physicist at the University of Surrey. The capability is an advan-tage over calorimeter-based sensors that handle one proton at a time.

“[For these] it has been a challenge to get the event rate high enough to take a scan in a practicable time,” he explained.

In the planned proton CT scanner, a stack of CMOS sensors (a “telescope”) will determine proton energy loss in the patient. Combined with other detectors, data from the telescope will also determine the direction of protons exiting the patient. With this information, the path of the pro-ton in the patient – that is a result of multiple coulomb scattering events – can be reconstructed, generating

images with superior spatial resolu-tion to those achievable by detectors that assume an unscattered, linear trajectory.

The researchers demonstrated the sensor’s proton counting ability by irradiating it with a 36 MeV beam produced by the MC40 cyclotron at the University of Birmingham in the UK and a therapeutic 200 Mev beam at the iThemba treatment facility in Somerset West in South Africa. Low beam currents and high frame rates of 1400 Hz – achieved by read-ing 10 of the 2520 rows on the sen-

sor – maximized the ability of the sensor to resolve individual proton interactions.

Detected events increased linearly with beam current up to a nominal current of 0.1 nanoamps, then fell off with further increases. The observa-tion is consistent with pulse pile-up in the sensor pixels that, in turn, indi-cates the detection of individual pro-tons. Experimental observations also agreed with Monte Carlo simulations of the same set-up, providing further evidence of proton counting by the sensor.

When two DynAMITe sensors were stacked together – double DynAMITe – event distributions in the two matched. Eliminating fluc-tuations in beam current as a con-founding factor, the high correlation that the researchers observed indi-cated that the pair was detecting the same protons, confirming its track-ing ability.

With proof-of-concept established, the researchers are redesigning the DynAMITe sensors for improved performance, with increased frame rates a major focus of their efforts. Estimating that the proton CT scans will require tens of millions of image frames, their goal is to achieve a 1000 Hz frame rate for the readout of the entire sensor area to limit scan dura-tion to a few minutes. “We are inves-tigating various aspects of hardware design to get the frame rate we need. Pixel size and bit-depth are factors,” said Poludniowski. “Substantial inno-vations are [also] being made in the read-out design and electronics.”

The researchers plan to build a device and perform the first scans by the end of 2015, then commercialize the technology with an industrial partner.

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

Multifield optimization intensity-modulated proton therapy (MFO-IMPT) may be as safe and effective a treatment as intensity-modu-lated radiation therapy (IMRT) for patients with head-and-neck cancer. And it is much less toxic, according to researchers from the University of Texas MD Anderson Cancer Center in Houston. Precise radiation dose targeting to avoid healthy tissue and reduce acute late toxicities can mean a world of difference in the quality-of-life of these patients, many of whom are young in age.

Steven J Frank, assistant profes-sor of radiation therapy and medical director of the MD Anderson Pro-ton Therapy Center and colleagues reported the early outcomes of 15 consecutive patients enrolled in a progressive study. After a median of 28 months, all patients were alive, 14 were cancer-free, and none had required hospitalization as a result of treatment. “The study provides addi-tional evidence that proton therapy for head-and-neck cancers is safe and effective,” he said. MD Anderson has treated approximately 300 such patients since it initiated MFO-IMPT in 2010 (Int. J. Radiat. Oncol. Biol. Phys. 89 846).

“In the United States, more than 100,000 cases of head-and-neck cancer are diagnosed annually,

making it the sixth most common form of cancer. The rising incidence of human papillomavirus (HPV) -associated oropharyngeal tumours in the United States and Europe has reached epidemic proportions. In Asia, the Epstein-Barr virus is driv-ing a huge increase in nasopharynx cancer,” Frank stated. “While cure rates are high, patients may suffer with a range of acute and often late morbidities that can be the cause of substantial misery for decades.”

IMRT is the current standard of treatment for head-and-neck can-cer because of its ability to tightly conform the dose to target volume, sparing normal structures such as the parotid glands. IMPT further refines treatment by avoiding high doses of radiation to normal tissue

structures. Because of this, neuro-cognitive function, vision, swallow-ing, hearing, taste and speech can be better preserved.

Compared to photon radiotherapy, proton therapy has the potential to deliver superior dose distributions, due to the shape of the dose deposi-tion curve of a proton pencil beam. IMPT offers more precise delivery of photons than passive scattering beam techniques, and is used when the dose must be sculpted away from a nearby critical structure. Scanning beam proton therapy with MFO can further shape the dose in cases that involve treatment of such complex targets as the bilateral aspects of the neck. The question has been whether IMPT is as safe and effective as IMRT for the treatment of head-and-neck

cancers.The study included 10 patients

with squamous cell carcinoma (SCC), who had tumours located in the oropharynx (eight patients), nasopharynx (one patient) and one unknown with cervical metasta-ses. All had comprehensive proton therapy extending from the base of the skull to the clavicle. Five patients with adenoid cystic carcinoma (ACC) were treated with concurrent chemotherapy and MFO-IMPT for unresectable disease and received 70 Gy (RBE) in 33 fractions to gross disease with margin but no treat-ment to the regional lymphatics. For all patients, proton beam energies ranged from 72.5 to 221.8 MeV.

All patients experienced grade 1 to grade 3 xerostomia and mucosi-tis. Other toxicities experienced by some patients included dysgeusia, dysphagia, vomiting, radiation der-matitis and weight loss. Toxicities were less severe than those experi-enced by patients who underwent IMRT. With the exception of one patient with ACC who was being re-irradiated for a recurrent paranasal sinus tumour, all patients had a clini-cal complete response.

MD Anderson Proton Therapy Center was one of the first in the world to offer MFO-IMPT treatment. But Frank says that with the new gen-eration of proton therapy systems, he expects this to become a standard offering at all proton therapy cen-tres. Although the treatment deliv-

ery is more expensive compared to IMRT, when the episodic costs of care are considered, proton therapy may be less expensive.

Frank explained: “We performed a cost analysis of treatment for the first two patients of a randomized trial comparing outcomes of IMPT-treated patients versus IMRT-treated patients, using actual costs and time-driven activity-based costing analysis. What we were able to dem-onstrate was that while the incre-mental cost of delivery of protons was more, the curves cross at about 31 days. The IMRT-treated patient experienced more toxicity that required emergency department visits, hospitalization and feeding tubes.” And this cost analysis did not include costs incurred by the patient (transportation costs, loss of income or health insurance co-payment), which would have been greater for IMRT.

Due to the steep dose fall-off of a photon beam, IMPT is more sensi-tive to treatment planning errors than IMRT. Frank told medicalphys-icsweb that his team is continuing to improve internally developed robust optimization software that identi-fies, arranges and analyses uncer-tainties in the treatment planning and delivery process. Active inves-tigation of robust analysis, image guidance, optimal beam angle selec-tion, advanced mobilization tech-niques and adaptive planning are also ongoing.

Showcasing science: a model of the proton CT telescope was displayed at the Royal Society’s Summer Exhibition.

Patient immobilization: the immobilization mask, developed for proton therapy by Steven Frank and his team, minimizes movement of the tongue and pushes it away from the radiation field.

IMPT minimizes treatment toxicity


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6 focus on: particle therapy

Arc therapy for proton pencil beamsProton therapy plans are typically designed to deliver the appropriate dose distribution to a pre-defined tumour target. But therapeutic out-come does not necessarily depend on dose alone. Speaking at the 2014 AAPM Annual Meeting, Alejandro Carabe-Fernandez from the Uni-versity of Pennsylvania presented a radiobiologically optimized treat-ment planning approach that also brings the proton linear energy transfer (LET) into consideration.

“In traditional proton therapy, we treat the target by making sure that we have full dose coverage of the target geometry,” he explained. This can be achieved by placing the plateau region of a spread-out Bragg peak (SOBP) over the target, with the distal edge of the SOBP aligned with the edge of the tumour. How-ever, at the distal edge of the proton beam, proton LET is at a maximum, thereby placing the high-LET region within normal tissue.

While the relative biological effec-tiveness (RBE) of a proton beam is conventionally taken as 1.1, proton RBE actually increases with increas-ing LET. “This LET effect is wasted in normal tissue,” said Carabe-Fernan-dez. “There’s also the question of whether the decrease in dose to an

organ-at-risk [OAR] may be negated by an increase in LET and the associ-ated increasing biological effect.”

Carabe-Fernandez suggested that by moving the high-LET region into the target itself, it may be possible to decrease the required prescribed dose without reducing biological effectiveness. This shift should also reduce both the LET and the dose to surrounding normal tissues and OARs.

The next task is planning the treatment so as to bring the high-LET protons into the target. Carabe-Fernandez proposed a split-target approach, in which the clinical tar-get volume (CTV) is divided into two, and two proton beam fields are targeted to place their distal edges at the internal edge of each “half target” – effectively meeting in the centre of the tumour. Taking this idea a step further, the CTV could be split into four or seven sections.

Comparing dose distributions from a standard full-target proton therapy plan with those from 2-, 4- and 7-field split-target plans revealed that as the tumour is divided into an increasing number of targets, dose to the target is maintained while the high-LET region shifts from outside to inside the target. Dose-volume

histograms also revealed a reduction in overall dose to normal tissue.

So how far can we take this approach? Carabe-Fernandez sug-gested that it’s possible to move from discrete beams to continuous beam delivery, describing the technique as “proton-modulated arc therapy”, or PMAT. He then examined the fea-sibility of performing PMAT using proton pencil-beam scanning (PBS) delivery.

If multiple energy layers need to be delivered at each angle, the gan-try cannot rotate continuously and PMAT is not feasible in PBS mode, he explained. However, it should be possible to use PBS if a mono-

energetic beam is employed and the gantry rotation is used to paint the dose. Nevertheless, patients are not spheres and a single proton energy will not be sufficient to cover a target within an irregular body shape.

As such, Carabe-Fernandez pro-posed the use of two proton beam energies delivered over subsequent gantry rotations. He presented an example comparing PMAT and PBS treatment plans for a brain tumour located near several critical struc-tures. The PMAT plan used two arcs: the first delivering a constant energy of 113.2 MeV over 180°; the second delivering an energy of 110.2 MeV, over part of the returning 180

to 0° arc. Carabe-Fernandez and colleagues are currently working on single mono-energetic solutions that will help to substantially reduce the number of monitor units and treatment time compared to multi-ple-beam PBS treatments.

Even when using just two ener-gies, the PMAT plan achieved 90% target coverage. Dose-volume his-tograms showed that CTV cover-age was very similar to the PBS plan. Doses to OARs, in particular the brain stem and optic chiasm, were greatly reduced for the PMAT plan compared with the PBS plan. As expected, LET in the target was higher for the PMAT plan. Carabe-Fernandez noted, however, that some of the OARs also had higher LET. He concluded that while full RBE-based proton plan optimi-zation might yet not be realistic, LET-guided treatment planning is achievable.

“PMAT is an interesting option that might allow simultaneous dose and LET painting of a target while delivering the dose in an efficient manner,” he concluded. “Other advantages include a lower number of monitor units and reduced room time, which could increase patient throughput.”

The finite range of a proton beam provides one of the main dosimet-ric advantages of proton therapy over photon techniques. But while the beam range in water can be well defined, this is not the case in a patient. To exploit the full poten-tial of proton therapy, the in-patient range must be predicted as accu-rately as possible during treatment planning, with appropriate mar-gins employed to account for range uncertainties.

Proton therapy is typically planned using analytical dose calculation algorithms, which are often opti-mized for speed rather than accu-racy. Such algorithms determine range based on water-equivalent depth and are less sensitive to com-plex patient geometries. As such, they do not correctly predict range degradation caused by multiple Cou-lomb scattering, which broadens the proton beam as it travels through tissue.

Researchers from Massachusetts General Hospital (MGH) and Har-vard Medical School have investi-gated the range uncertainties due to such analytical algorithms. To do this, they assessed over 500 pro-ton treatment fields, comparing the range predicted by an analytical pen-cil-beam algorithm with that calcu-lated using Monte Carlo simulations (Phys. Med. Biol. 59 4007).

“The goal of this paper was to vali-

date current generic range margins for individual treatment sites and to explore whether and for which sites we can reduce current treatment margins using current analytical treatment planning, without the use of more sophisticated tools such as Monte Carlo simulations,” explained lead author Jan Schuemann.

Schuemann and colleagues ana-lysed seven disease sites: liver, pros-tate, breast, spine, whole brain, lung and head-and-neck, with 10–27 plans per site and each plan contain-ing 2–17 passively scattered fields. They performed voxel-by-voxel comparisons between distal dose surfaces calculated by the analytical algorithm and the simulations.

For each field, they determined the average range difference (ARD) and root mean square deviation (RMSD) between values predicted by the two algorithms. They calculated these

parameters at R90 and R50, the dis-tal positions at which the dose falls below 90% and 50% of the prescribed dose, respectively.

Analysing 248 head-and-neck fields, for example, revealed an ARDR90 of –1.5% of the prescribed range and an ARDR50 of –0.5% . RMSDR90 and RMSDR50 were 3.2% and 1.8%, respectively. Both RMSDs correlated positively with the pre-scribed range, while no correlation was observed between the ARDs and the prescribed range. “We found that RMSD was a better estimate for the overall range fluctuation than ARD,” said Schuemann.

They also studied two head-and-neck fields in more detail. The first was a small field with the largest RMSDR90 (11.3%). For this field, the proton beam passes through various layers of soft tissue, bone and air. XiO incorrectly modelled protons travel-

ling through these changing tissue densities. The authors note, however, that while range differences can be substantial for individual beams, the impact is mitigated somewhat when using multiple fields.

The second, larger field exhibited the lowest ARDR50 (0.01%). However, range profile difference plots showed areas of clear over- and under-shoot of R90. This again suggests that ARD alone is not ideal for assessing dose distributions and that RMSD is a more clinically meaningful param-eter. For this field, RMSDR90 and RMSDR50 were 3.2% and 2.8% of the prescribed range.

The MGH team performed simi-lar analyses for the other treatment sites. For relatively homogenous sites, such as the brain, prostate and liver, ranges calculated by the ana-lytical algorithm and Monte Carlo simulations agreed reasonably well. For lung fields, the analytical algo-rithm led to large dose fluctuations downstream of high-density gradi-ents. Large range differences were also seen in some breast fields. For spine treatments, results indicated that superior and inferior spine fields should be considered separately in terms of range uncertainties.

Based on their findings, the researchers evaluated the current practice of implementing generic range margins (typically 3.5% of the prescribed range in water plus 1 mm) to deal with uncertainties. They concluded that if generic range margins are used, they should at least be site-specific, with complex geom-

etries also requiring patient-specific adjustments.

As RMSDR90 appeared to be the most relevant parameter for quan-tifying range error, the researchers assessed the relationships between prescribed range and RMSDR90 for each treatment site. Based on this analysis, and also consider-ing non-dose-calculation-related uncertainties, they presented rec-ommendations for site-specific margins.

For liver, prostate and whole brain fields, the treatment planning sys-tem accurately predicted the range. The researchers suggest that current range margins could be reduced to 2.8% ± 1.2 mm for liver and prostate, and 3.1% ± 1.2 mm for whole brain treatments. For these sites, routine use of Monte Carlo dose calculation will only be of limited value.

For heterogeneous treatment sites (lung, breast and head-and-neck), current generic margins appeared insufficient for some patients. If case-specific margins cannot be used, then an increased generic margin of 6.3% ± 1.2 mm is needed to ensure target coverage. For these patients, the authors recommend using Monte Carlo simulations for routine verifications of treatment plans.

“We are now working on new algorithms to allow treatment plan-ners to adjust their range margin on a patient-by-patient basis, and to select beam angles that are less prone to range uncertainties,” said Schuemann.

Two rotations: a PMAT plan for treating a brain tumour employs two arcs.

The team (left to right): Clemens Grassberger, Harald Paganetti, Chul Hee Min (on screen), Jan Schuemann and Stephen Dowdel (on screen).

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9focus on: nuclear medicine

Heterogeneity predicts tumour response A multi-institutional study from Germany has joined a growing number of evaluations of tumour heterogeneity as a tool to assess can-cer treatment responses. This study investigated textural parameters of tumour heterogeneity in 18F-FDG PET/CT images of patients with locally advanced rectal cancer, and adds further merit and validity of the use of tumour heterogeneity assess-ment to facilitate personalized can-cer therapy ( J. Nucl. Med. 55 891).

The study of 27 patients with rectal cancer revealed that the coef-ficient of variation (COV) – defined as the standard deviation of uptake divided by the mean uptake in the tumour volume – showed a statisti-cally significant capability to evalu-ate disease progression in patients receiving neoadjuvant chemo-radiotherapy. COV also was used to identify patients with a high risk for disease progression and death.

PET has been used to assess tumour

heterogeneity because it can visual-ize functional information directly, providing information about the surface structure of cells, receptor density and cell metabolism. The study’s lead author Ralph Bunds-chuh, from the Universitätklinikum Bonn, and colleagues investigated the role of tumour heterogeneity in the assessment of therapy response on pre-therapeutic 18F-FDG PET, as well as images recorded during and after therapy.

Three textural parameters were estimated within the tumour vol-ume: the COV; skewness, a measure of the asymmetry of activity dis-tribution in the lesion; and kurto-sis, a measure of the peakedness of the activity distribution. All were assessed in 3D volumes. Five addi-tional conventional parameters were used for comparison: maxi-mum lesion diameter; morphologic volume of the lesion; maximum SUV (SUVmax); mean SUV (SUVmean); and

total lesion glycolysis (TLG), the product of tumour volume and mean uptake.

The researchers performed ROC analysis to estimate optimal cut-off values for individual parameters for assessment of histopathologic response, disease progression and survival for all investigated param-eters, and also for changes in the parameters during therapy.

Nineteen of the 27 patients, or 70.4% , responded to treatment based on histopathologic analy-sis. The parameters that showed a statistically significant predictive capability, as well as the highest val-ues, were TLG, tumour volume and COV. At optimal cut-off values, the sensitivity for predicting histopatho-logic response was 53% for TLG and tumour volume, and 47% for COV.

COV proved the best parameter for assessing early response, with a sensitivity of 68% and a specificity of 88%. A decrease of COV during

and after therapy indicated histo-pathologic response. In fact, it was the only parameter to show a statis-tically significant predictive capabil-ity when changes in PET/CT images acquired before and two weeks after treatment were analysed. COV also had the highest area under the curve for late response assessment, with a sensitivity of 79% and a specificity of 88%. TLG, skewness, kurtosis and SUVmax were also statistically signifi-cant parameters.

In their analysis of parameters that may identify patients with a high risk of disease progression, Bundschuh and colleagues determined that COV also had the best predictive capabil-ity early in the course of therapy.

The authors suggested that one reason for the correlation between a strong decrease in tumour het-erogeneity during therapy and good therapy response and prognosis is the hypothesis that high heterogene-ity may correspond to high levels of

neovascularization, a characteristic of more aggressive tumours. They noted that a decrease in tumour het-erogeneity could be an indicator of reduced vascularization and necro-sis. Consistent legion heterogeneity during therapy could indicate the presence of a tumour cell clone that does not respond to therapy.

The researchers note that COV is easy to calculate if the mean uptake and standard deviation within the tumour volume are known. These parameters can be assessed with commercially available PET analysis software and could be used today in clinical routines. They recommend that assessment of COV should be included in routine 18F-FDG PET/CT scans to identify patients responding to therapy, as well as patients with a high risk of disease progression.

Cynthia E Keen is a freelance journalist specializing in medicine and healthcare-related innovations.

US start-up Eden Radioisotopes has licensed a Sandia National Laborato-ries technology for making molyb-denum (Mo)-99, the precursor for the medical imaging radioisotope technetium-99m. Mo-99 it is made using a limited number of aging nuclear reactors (none in the US), and concerns about future shortages have been in the news for years. The company hopes to build the first US reactor for making the isotope and become a global supplier.

“One of the pressing reasons for starting this company is the Mo-99 shortages that are imminent in the next few years,” said Eden’s chief operating officer Chris Wagner. “We really feel this is a critical time period to enter the market and sup-ply replacement capacity for what is going offline.”

Based on technology developed in Sandia’s medical isotope production program in the 1990s, the Eden team created a new reactor concept. “This reactor is very small, less than two megawatts in power, about a foot-and-a-half in diameter and about the same height, but very efficient,” said Dick Coats, Eden’s chief technol-ogy officer and a retired Sandia Labs researcher who helped develop the Mo-99 reactor concept.

The reactor sits in a pool of cool-ing water 28 to 30 feet deep and has an all-target core of low-enriched uranium - less than 20% U-235 - fuel elements. “The targets are irradi-ated and every one can be pulled out and processed for Mo-99. The entire core is available for Mo-99 production,” explained Coats. “The reactor’s only purpose is medical iso-tope production. This is what is new and unique. Nobody thought about

approaching it that way.”Sandia’s Ed Parma, who was on the

original team, says that the world demand for Mo-99 can be met with a small, all-target reactor processed every week. Larger reactors aren’t cost effective because they use so much power to drive the targets, he added. “They’re using 150 mega-watts to drive a 1 megawatt system. When you add in fuel costs, opera-tions, maintenance, it’s hard to make

money.” He noted that there has never before been a reactor system designed just to make Mo-99. “Our design is scaled down just for the production of Mo-99. The reactor is only the size you need. It’s more effi-cient and economically viable.”

Eden hopes to be in production in about four years. “It’s very excit-ing to be part of a project that could be commercialized,” Parma said. “I think this is the future.”

The superior image quality that time-of-f light (TOF) PET provides over traditional PET is undisputed. However, to date, clinical studies have been limited to assessments of lesion detectability, rather than quantitative measurements of radio-tracer uptake.

In a new study, researchers in the US have performed the first system-atic assessment of TOF PET accuracy and precision in clinical radioisotope distributions, reporting increases in lesion uptake of up to 50% and decreases in lesion variability of up to 30% over non-TOF PET. With many commercial PET scanners now routinely using TOF data in the reconstruction of images, the study has important implications for clini-cal practise and clinical trials ( J. Nucl. Med. 55 602).

“These findings will increase the physician’s confidence that a meas-urement of activity uptake is both accurate and reliable,” said first author Margaret Daube-Wither-spoon, from the University of Penn-sylvania in Philadelphia. “This is important because PET images are used for quantitative assessment of uptake, especially in oncology, not just lesion detection by visual inspection.”

In collaboration with Philips Healthcare, the researchers com-pared measurements of a lesion of known uptake in images of six nor-mal volunteers reconstructed with and without TOF data. The syn-thetic lesions were 10-mm diameter spheres, scanned in air and merged into the list mode data of the volun-teer’s scans. Filled with known activ-ities of fluorine-18 FDG, six spheres were merged into the imaged lungs of the volunteers and a further six were incorporated into the liver.

“We created a condition with all of the physiological variations in activ-ity and attenuation distributions of clinical studies, but where we now know the true uptake of the spheres, so we can assess accuracy and pre-cision of the measurement,” said Daube-Witherspoon.

The researchers compared TOF and non-TOF measurements of sphere uptake using a normalized uptake value (NUV) – the uptake of the sphere normalized by uptake averaged over the whole body, cal-culated using the equivalent ratio of counts for the same volumes. Sphere counts were measured using a volume-of-interest with the same diameter as the sphere. To generate a larger image database for analysis, the researchers used “bootstrap-ping” to resample each volunteer’s scan. By allowing individual anni-hilation events to be sampled more than once, they created 60 datasets with the same number of events as the original scan.

Incorporating the TOF data into image reconstruction resulted in higher measured uptakes. Averaged over all volunteers and spheres, TOF produced mean NUV that were 50% and 20% higher in the lungs and the liver, respectively, compared to equivalent the non-TOF images. Quantified by coefficients of varia-tion, precision in uptake measure-ments also improved with TOF data.

The authors note that the superior performance they observed with the 375-ps TOF resolution scanner that they used will not be observed clinically, as commercial scanners typically have a TOF resolution of between 500 and 600 ps. However, in the future they plan to repeat the study for a more representative 500-ps system.

New design: Eden Radioisotopes’ Dick Coats (right) talks to Sandia nuclear engineer John Ford at the Annular Core Research Reactor, where they helped develop the Mo-99 reactor concept in the 1990s.

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11focus on: nuclear medicine

PET tracers are stable during therapyIn the drive towards more custom-ized radiotherapy, dose painting guided by PET is under investigation as a way to boost dose to the most radioresistant regions of a tumour, while limiting dose to surrounding healthy tissue to acceptable levels. However, before the potential of this approach can be explored fully, the stability of PET tracers in the tumour over the course of treatment must be established to ensure that the correct regions are targeted.

In new work, researchers in the US have compared PET scans acquired before and early on in courses of intensity-modulated radiotherapy in canine patients with sinona-sal tumours (14 carcinoma and 8 sarcoma). They found that spatial distributions of 61Cu-ATSM and 18F-f luorothymidine (FLT), surro-gates for hypoxia and cell prolifera-tion respectively, were very similar before and after the start of treatment (Int. J. Radiat. Onc. Biol. Phys. 89 399).

“This has significant practical implications, as one would not need to scan multiple times, which has been one of the major concerns for dose painting in general,” said Robert Jeraj, senior author of the study and head of the Image Guided Therapy group at the University of Wisconsin

in Madison.Dose painting is not yet in routine

clinical use in radiotherapy depart-ments. Clinical trials are under way, mostly using the common PET tracer 18F-FDG, but Jeraj argues that mul-tiparametric investigations includ-ing Cu-ATSM and FLT tracers are needed to identify the most effective dose painting strategy. Confl icting studies on the stability of hypoxic

tumour subvolumes during treat-ment prompted the group to inves-tigate Cu-ATSM, while variability in FLT is of interest as a potential indica-tor of treatment response.

“Changes in proliferation maps during therapy, particularly those measured with FLT PET, have a lot of potential in radiation oncology,” said Jeraj. “They’ve been shown to respond rapidly to different treat-

ments, and we are really in the beginning stages of understanding how these changes relate to tumour response. This work is a step in that direction.”

The researchers acquired PET/CT scans of the 22 dogs for each tracer between one and three days before the start of their 10-fraction treat-ment courses. The FLT scan was repeated after two fractions and the Cu-ATSM scan after three fractions. For each tracer, the mid-treatment scans were matched to the pre-treat-ment scans using deformable regis-tration. This enabled voxel-by-voxel comparison of the uptake in the tumour, using standardized uptake values (SUV) that were derived from the voxel counts.

Spearman rank correlation coef-ficients for both tracers revealed strong correlations between the pre-treatment distributions and those detected during treatment. Averaged over all subjects, coeffi cients of 0.88 (standard deviation 0.07) and 0.79 (standard deviation 0.13) were cal-culated for Cu-ATSM and FLT respec-tively, indicating that the parts of the tumours that were most hypoxic and proliferative before treatment largely remained so after the second and third fractions.

“If Cu-ATSM PET were to be used as a target in a dose painting clini-cal trial, the Cu-ATSM target would likely be spatially stable early during therapy,” said Jeraj. “This is also true, although to lesser degree, for FLT PET.”

While the average FLT correlation coefficient was significantly lower than those for Cu-ATSM in each sub-ject and showed more inter-subject variation, the researchers were still surprised at how stable the FLT dis-tributions were. Tumour stability quantifi ed by the correlation coef-ficients is one of several potential biomarkers of treatment resistance under investigation by the group.

“We are investigating if any imag-ing biomarkers that quantify FLT and Cu-ATSM uptake, for example SUV, predict clinical outcome following therapy … and if tumour regions with high FLT or Cu-ATSM uptake correspond to regions that are more likely to have recurrence following therapy,” Tyler Bradshaw, PhD can-didate and fi rst author of the study, told medicalphysicsweb.

Once the strongest biomarkers have been identifi ed, the group plan to build on the research by perform-ing a prospective dose painting study.

PET scan: an anaesthetised dog undergoing IMRT to treat a sinonasal tumour is imaged with PET before and during its treatment course.

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12 focus on: radiotherapy

Ultrasound tracks motion during treatmentHypofractionated radiotherapy of prostate cancer requires accurate knowledge of prostate motion dur-ing treatment delivery, to reduce target volume margins compared to those used in conventional therapy and limit toxicity in nearby healthy tissue. In a new study, UK researchers have compared motion detection by 3D ultrasound (3D-US) with X-ray imaging of fiducial markers, con-cluding that 3D-US could be used in both hypofractionated and conven-tional treatments (Phys. Med. Biol. 59 1701).

“ With current mechanically swept 3D-US transducer technol-ogy, 3D-US based soft-tissue motion tracking could effectively track intra-fraction motion and reduce superior–inferior and anterior–pos-terior prostate treatment margins,” said Tuathan O’Shea, first author and physicist at the Institute of Can-cer Research and the Royal Marsden NHS Foundation Trust in London.

Ultrasound does not require implanted fiducial markers nor does it expose the patient to ionizing radiation. Another key advantage over commonly used X-ray-based techniques is its potential for signifi-cantly higher temporal resolution, with the most sophisticated scan-

ners reaching frame rates of hun-dreds of frames per second. “This makes ultrasound an ideal candidate for image-guided radiotherapy with state-of-the-art delivery systems,” said co-author Phil Evans, from the University of Surrey in Guildford.

The researchers used a moving phantom to compare the accuracy of a 3D 7.5 MHz ultrasound probe and scanner with the Cyberknife X-ray imaging system. The gel phantom, which contained cellulose particles to provide acoustic backscatter and fiducial markers for X-ray tracking, was placed on a motion platform. Five motion traces measured in vivo

using the Calypso tracking system were used to drive the platform. The traces included persistent prostate excursions of several millimetres and a large transient excursion over 10 mm.

Assuming a supine patient and mimicking a transperineal scan-ning approach, the ultrasound probe was pointed superiorly along the treatment couch and swept mechanically in the left-right direc-tion. The tracking algorithm detects motion by comparing the speckle pattern produced by scatterers in a reference region in a given image frame with patterns in subsequent

frames. A normalized cross cor-relation similarity measure locates the most similar pattern in the later frame, calculating the associated displacement.

3D-US tracking accuracy, using an optimum volume rate of 1.7 Hz, varied with motion direction and was comparable with X-ray fiducial tracking in the superior–inferior and anterior–posterior directions. For these directions, the root mean square error (RMSE) was less than 0.81 mm for all five traces, com-pared with 0.74 mm for X-ray track-ing. Sub-millimetre accuracy was also demonstrated when 3D-US was used to detect prostate motion up to a threshold displacement, making gated treatments, where the therapy beam is paused while the prostate is outside the threshold, a future possibility.

However, 3D-US tracking in the left–right direction was less accu-rate. While sub-millimetre accura-cies were measured in four of the five motion traces, the transient trace produced an RMSE of 4.13 mm, which was subsequently reduced to below 2 mm with modifications to the tracking algorithm. The researchers argue that larger left–right errors are less critical for accu-

rate treatments, with an analysis of 480 motion traces from 22 patients (from which the five tested traces were taken) revealing that significant left–right motion was rare.

Based on their findings, the researchers are planning a feasibility study to assess the potential of either a 2D or 2D/3D hybrid ultrasound approach. “2D imaging would allow 2D tracking of anterior–posterior and superior–inferior prostate motion at high frame rates, while computational methods could be used to identify potential out-of-plane displacements or rotations, triggering 3D imaging only when needed,” said O’Shea. Other plans include an in vivo human study and refinements to increase the speed of the tracking algorithm, which is currently an offline post-processing technique.

Further into the future, senior author Jeff Bamber predicts that left–right tracking accuracy will match anterior–posterior accuracy, and that volume imaging rates hundreds of times per second will increase the overall tracking accuracy and preci-sion. “Trends in ultrasound technol-ogy development are likely to solve the limitations we observed,” he told medicalphysicsweb.

Targeted alpha-particle therapy is a promising treatment for killing dis-seminated tumour cells and small metastatic clusters. Alpha particles have a short range and a high lin-ear energy transfer (LET), enabling delivery of a powerful, highly local-ized radiation dose to tumours while sparing surrounding normal tissues.

The most promising alpha-emit-ting radionuclide is astatine-211 (211At), which decays either into 207Bi, via emission of a 5.87 MeV alpha particle, or into the ultrashort-lived alpha emitter 211gPo. The alpha par-ticles produced by such decays have a range of less than 70 µm in water and a high LET of 100–130 keV/µm. Importantly, 211At has a half-life of 7.2 h – enough time for it to be pro-duced, radiolabelled, transported and administered to the patient.

Astatine-211 can be produced by bombarding bismuth targets with cyclotron-accelerated alpha particles. Currently, however, it is only routinely made by a few cyclo-trons – and this limited availability is impeding progress in its clinical application.

One severe constraint associated with 211At production is the fact that if the bombarding particles are too energetic, the reaction can lead to 210At instead. The radioisotope 210At decays (with a half-life of 8.3 h) into 210Po, an extremely dangerous alpha-emitter that damages the liver, bone

surfaces and bone marrow.It’s vital, therefore, to maximize

211At production while minimizing 210At contamination. With this goal, and aiming to help exploit the prom-ise of 211At for targeted radiotherapy, researchers at the Korea Institute of Radiological and Medical Sciences (KIRAMS) have published details of an optimized production technique (Phys. Med. Biol. 59 2849).

The KIRAMS team studied the pro-duction of 211At using a Scanditronix MC-50 cyclotron, which can generate a 45 MeV beam of alpha particles. The nuclear reaction required to create 211At from bismuth has a threshold energy of around 21 MeV and reaches a maximum cross-section at 30 MeV. However, as the threshold for creat-ing 210At is about 29 MeV, they lim-ited the incident beam energy to near or below this value.

Instead of directly extracting 29 MeV alpha particles, which could result in a low-intensity beam, the researchers extracted the beam with an initial energy of 45 MeV and atten-uated it with an aluminium degrader. To calculate the optimal aluminium thickness, they simulated energy spectra for alpha particle beams passing through degraders of 0.3–0.42 mm in thickness. Degraders of 0.42, 0.41, 0.39, 0.35 and 0.30 mm produced beams with average ener-gies of 33.96, 31.81, 30.07, 29.17 and 28.71 MeV, respectively.

Moving onto physical experi-ments, the researchers prepared targets by heating bismuth metal powder. They irradiated each target

for 30 min, using the 45 MeV alpha particle beam degraded by the five different thicknesses of aluminium. Approximately 50 min after the end of bombardment, they performed activity measurements on the irradi-ated targets with a γ-spectrometer. All spectra showed the presence of 211At/211gPo but, as expected, only minute amounts of 210At were seen after 28.71 MeV irradiation. Much larger amounts of 210At resulted from irradiation at 30.07 MeV and above.

The researchers also used the measured γ-spectra to calculate the thick target yields (TTYs) of 211At and 210At from the different bom-bardments. For 28.71 MeV irradia-tion, the TTY of 211At was 17.2±0.32 MBq/µAh. Moving to 29.17 MeV improved this value by approxi-mately 85%. Increasing the energy further increased the TTY again but also increased the TTY of 210At.

The ratio of 210At to 211At activ-ity was 0.0072% for 28.71 MeV and 0.0883% at 29.17 MeV. These very low levels of 210At are accept-able according to recommendations from the International Commission on Radiation Protection (ICRP), the US Nuclear Regulatory Commission and US Environmental Protection Agency. The resulting small quanti-ties of 210Po generated were not con-sidered a significant impurity in the final 211At-radiopharmaceutical.

The researchers concluded that an alpha particle beam energy of up to about 29.17 MeV should be used to maximize 211At yield and minimize 210At production.

Real-time kilovoltage (kV) imaging is a valuable option for intra-frac-tional tumour tracking. Its clinical adoption, however, is impeded by concern over the excess radiation dose delivered to the patient when imaging in continuous fluoroscopic mode. Zachary Grelewicz and Rod-ney Wiersma from the University of Chicago are working to solve this problem by using convex optimi-zation tools to optimally integrate the excess kV imaging dose into the megavoltage (MV) therapeutic dose.

For 10 previously treated lung-cancer patients, they used BEAMnrc to model the 6 MV treatment beam and a kV on-board-imaging beam of a commercial linac. They then modified the IMRT dose optimiza-tion problem to include additional

constraints for real-time kV intra-fractional tracking (Phys. Med. Biol. 59 1607).

The combined MV and kV optimi-zation allowed patient-specific quan-tification of the dosimetric effect of real-time imaging. The researchers found that incorporating the kV imaging into the MV treatment dose offers the potential to substantially lower the kV skin dose compared with standard IMRT with kV track-ing. Importantly, it does this without lowering the overall quality of the treatment plan. The researchers note that the benefits of this combined optimization were most relevant in situations that would previously have resulted in high kV dose, such as large apertures and high mAs or frame rate settings.

ICR authors: (left to right) Emma Harris, Jeff Bamber and Tuathan O’Shea.


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MV/kV planning cuts excess dose

Dose distributions: doses from combined MV + kV optimization (a, c) and from standard IMRT (b, d). The target volume is outlined in black.

13focus on: radiotherapy

Shimming enables imaging on MRI-linacMagnetic field inhomogeneities induced by the close proximity of linac components pose a challenge to the handful of groups developing hybrid MRI-linac systems for cancer treatment. The associated image dis-tortions must be minimized if the full image-guidance potential of the technology is to be realized.

In a new study, researchers in the Netherlands have demonstrated that images acquired with their pro-totype system, which was upgraded with a ring-based gantry, are suffi-ciently accurate for treatment guid-ance when the gantry is static. Based at the University Medical Center Utrecht, Sjoerd Crijns and Bas Raay-makers used measurements of field inhomogeneities to calculate the minimum gradient strength that limits image distortions to less than a millimetre (Phys. Med. Biol. 59 3241).

“Although there is a clear influence of that structure on the magnetic field homogeneity inside the scanner, the image quality in terms of geometric fidelity is not degraded, provided that the right imaging parameters are used and the gantry is kept static during imaging,” explained Crijns.

In conventional stand-alone MRI scanners, inhomogeneities caused by nearby ferromagnetic materials,

such as iron reinforcements in the floor, are corrected using ferromag-netic plates positioned inside the bore of the scanner – a form of pas-sive shimming.

For MRI-linacs, active shimming is also required to compensate for vari-ations in inhomogeneity that occur at different gantry angles. The vari-ations result from the movement of magnetic linac components, includ-ing those found in the magnetron

and RF circulator and are corrected by the scanner gradient coils during the preparation phase of a sequence.

Rotating the gantry while imaging, as would be the case for continuously monitored volumetric-modulated arc therapy (VMAT), adds a further layer of variability to the scanner’s magnetic field. In this case, dynamic adaptation of the scanner’s mag-netic field – dynamic shimming – and advanced image reconstruc-

tion methods are two ways in which image distortions can be minimized.

Crijns and Raaymakers mapped field inhomogeneities over 72 static gantry positions using a dual gradi-ent echo sequence applied to a disc-shaped phantom. They acquired data for both shimmed and unshimmed magnetic fields. Repeated measure-ments at each gantry angle showed the optimal settings chosen by the scanner produced reproducible magnetic field maps.

Based on the inhomogeneities measured in the field maps, the researchers mapped the minimum read-out gradient strength that limited geometric distortions to less than a millimetre. The thresh-old gradient was calculated as the measured deviation in the magnetic field divided by the maximum image distortion.

The researchers demonstrated that submillimetre image distortions were achievable without shimming with a minimum gradient strength of 15 mTm-1, but this dropped to 10 mTm-1 for the shimmed case, cor-responding to higher signal-to-noise ratios. “Stronger imaging gradients are one solution to field inhomoge-neity, however, the stronger the gra-dients, the more noise in the images,”

explained Crijns.In a separate experiment, Cri-

jns and Raaymakers investigated the effect of gantry rotation dur-ing imaging with a bottle-shaped phantom, testing the MRI-linac for a range of gantry speeds and imag-ing parameters. The optimal active shim settings from the previous experiment were used. The resulting images were severely distorted, with the distortions increasing as gantry speed and the sequence echo time increased, highlighting the need for dynamic shimming or advanced image reconstruction techniques that mitigate them.

The data acquired by the research-ers applies only to their pre-clinical MRI-linac prototype and the new clinical system under construction at UMC Utrecht is expected to suffer less from gantry position depend-ent field inhomogeneities. Based on their findings, the researchers are working on the dynamic shimming and advanced image reconstruction techniques needed to reduce the dis-tortion of images acquired while the gantry is moving. Crijns told medi-calphysicsweb that VMAT with con-tinuous MRI monitoring is on the wish-list of clinical techniques for the hybrid treatment system.

Combining intensity-modulated radiotherapy (IMRT) with oncolytic adenovirus-mediated cytotoxic gene therapy (OAMCGT) improves the outcome for patients with interme-diate-risk prostate cancer, without affecting quality-of-life. That’s the conclusion of a trial from Henry Ford Hospital and Johns Hopkins School of Medicine.

The phase II trial randomized 44 patients with intermediate-risk prostate cancer to receive either gene therapy plus IMRT or IMRT alone, with all participants receiving IMRT to a dose of 80 Gy in 2.0 Gy fractions over eight weeks (Int. J. Radiat. Oncol. Biol. Phys. 89 268).

There was no significant differ-ence in acute gastrointestinal or gen-itourinary toxicity between the two arms, though men in the OAMCGT arm exhibited a greater incidence of low-grade flu-like symptoms. Two years after treatment, 84% of patients underwent prostate biopsy, which is prognostic of long-term results.

In the OAMCGT arm, 33% of men were biopsy-positive, versus 58% in the other arm, representing a 42% relative reduction for the investi-gational group. At the time of the study’s findings, one patient in each arm had exhibited biochemical failure, no patients had developed hormone-refractory or metastatic disease and none had died from pros-tate cancer.

Cerenkoscopy – the monitoring of radiation therapy using Cerenkov radiation – has been tested on a human patient for the first time by scientists in the US. The technique, which involves capturing the flashes of Cerenkov light produced as radia-tion penetrates tissue, could improve the success of radiotherapy by visu-alizing radiation dose distributions in real time (Int. J. Radiat. Oncol. Biol. Phys. 89 615).

Side effects of radiation therapy can only be minimized by carefully regu-lating radiation doses, but knowing exactly how much radiation enters a body is not easy to assess. Normally, treatment is planned according to computer simulations generated by CT scans, and, at select points during a course of treatment, a patient can also have a detector inserted into them to estimate the amount of inci-dent radiation. Such methods are not foolproof, however: a patient could lose weight, for instance, leading to a relatively high dose.

One new approach to measuring radiation dose is to make use of Cer-enkov radiation, which is emitted when electrons and other charged particles travel through a dielectric medium faster than light would travel. Cerenkov radiation is poten-tially visible as flashes of light during radiation therapy as the radiation penetrates the tissue, and is in most cases proportional to the dose.

Earlier this year, Brian Pogue at Dartmouth College in Hanover, NH, and others successfully dem-onstrated that Cerenkov radiation could be used to estimate the radia-tion being received during therapy on a live dog that was suffering from an oral sarcoma tumour – the first time that Cerenkoscopy was tested successfully on a live animal. In these tests, the researchers found that they could not only measure the Ceren-kov radiation, but that the frame rate

was fast enough to capture changes in the beam shape over time.

Now Pogue’s group has gone one step further by testing Cerenkos-copy on a human patient who was suffering from a breast tumour. The researchers employed the same apparatus, incorporating a gated CCTV camera located about five metres from the patient that con-tinuously acquired Cerenkov images (at 2.8 frames/s) whenever radiation pulses were delivered.

By also capturing the total light when the radiation pulses were not being delivered, the system could subtract the ambient light and leave for inspection only the bursts of Cerenkov radiation. The research-ers captured the Cerenkov radiation emitted by the patient’s breast tis-sue 10 times for each of 10 different whole-breast radiotherapy sessions.

Pogue and colleagues found that they could see the radiation beam incident on the breast tissue clearly, with shape and intensity related to the dose. The images were repeat-able, they say, indicating that the imaging is stable and reliable. But the real benefit of the technique was that changes in the shape of the radiation beam could be imaged in real time – a feature that makes Cerenkoscopy stand out from other dosimetry methods.

“The strongest benefits might be in the ability for real-time feedback,” says Pogue. “As far as we are aware, this is the only way to directly visu-alize radiation dose incident upon tissue, and would allow radiation therapists to actually see what they are doing when they press the button to deliver radiation dose.”

Pogue says that the team has now finished imaging 12 further patients participating in a pilot study. The researchers will be publishing those results soon. “All these results were reported on one subject, so need confirmation,” he adds.

Jon Cartwright is a freelance journalist based in Bristol, UK.

Imaging tests: Sjoerd Crijns works on UMC Utrecht’s MRI-linac prototype.

Dose tracking: Cerenkov emission generated from a 6 MV (left column) or 10 MV (right column) radiation beam, entering (top row) or exiting (bottom row) breast tissue. In the pseudocolour images, white indicates the highest doses and black the lowest; asterisks show blood vessels.

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15


focus�on:�radiation�safety

Safety in radiotherapy: help or hindrance?Is the strong focus on radiation pro-tection and safety hampering the introduction of new radiotherapy technologies and treatment strate-gies? That was the question under discussion during a lively debate at this year’s ESTRO 33 meeting in Vienna, Austria.

The session examined whether too cautious an approach to safety issues has slowed the implementation of advanced radiotherapy techniques such as intensity-modulated radio-therapy (IMRT) into wider clinical practice, thereby delaying the roll-out of potential benefits to patients. Speaking for the motion was Håkan Nyström, chief physicist at the Skan-dion Clinic in Sweden, while Robin Garcia, physicist and head of depart-ment at Institut Sainte Catherine in France presented the case against.

A show-of-hands vote taken at the start of the session revealed that the majority of the assembled delegates disagreed with the proposed motion. Nyström spoke first, tasked with convincing the audience otherwise.

He described how radiotherapy has always been technology-driven, with constant developments over the decades improving outcomes for millions of cancer patients. But while advances in treatment delivery offer the potential to reduce errors, they may also introduce new types of errors. As such, the introduction of new techniques and modalities must be performed with caution.

Nyström cited a study examin-ing the introduction of IMRT and comparing reported delivery errors (deviations from the intended treat-ment) with those seen for the less complex techniques of 3D confor-mal and conventional radiotherapy. The study found 155 errors in radio-therapy delivery among 241,546 fractions, with different types of error seen for the different modali-ties. Interestingly, IMRT was associ-ated with the lowest error rate of the three.

“This is 155 errors too many,” he said. “But errors happen, and con-sidering that they were looking at a quarter of a million fractions, we could say that they only found 155 errors. In addition, none of these were clinically significant. Radio-therapy is a safe procedure.”

Though IMRT was introduced over a decade ago, uptake has been slower than ideal, with some cancer centres still not implementing this advanced technique even today. “A lot of patients who could have ben-efited from IMRT don’t get it, because it took time to introduce,” said Nyström. So why was there a gap of some 10 years between early and late implementation of IMRT?

Nyström attributes the delay to issues surrounding safety and the public’s sensitivity regarding the use of ionizing radiation. He gave some examples of recent media coverage heavily publicizing radiotherapy

accidents, as well as TV reports inflating the risks of radiation and further increasing public anxiety.

He compared the situation to that in the aviation industry, where many people are scared of f lying and think it is dangerous, whereas in reality – just like radiotherapy – flying is safe. “The reason for being afraid to fly is not rational, it’s emo-tional,” he said. “There is a high risk for cancer patients – the main risk is not being cured. The second risk is being harmed by the side effects of treatment.”

Nyström emphasized that poorly supported information misrepre-senting radiation risks must not be allowed to prevent medical physi-cists from continuing to optimize radiotherapy modalities. “Maybe the most important mission that we have as medical physicists is the introduction of new technology,” he said. “Of course it should be safe, but never forget that we need new tech-nologies to increase the probability of cure and reduce side effects.”

Such research must then be trans-ferred into the clinic as efficiently as possible. This requires equally strong emphasis on all the key steps: cutting-edge research, translational research, technology improvement and clinical implementation.

“If you’re afraid of f lying, stay at home or take the train. If you’re afraid of radiation, fine, avoid expo-sure. But if you are a cancer patient in need of radiotherapy, you don’t have as many options – you should be offered the best treatment using the best modalities that we can offer,” Nyström concluded.

Next to take the stage, Garcia began by discussing exactly what is involved in the introduction of a new radiotherapy technique, emphasiz-ing that it’s “not just about installa-tion”. The process is a long chain: the equipment is chosen; instal-lation and commissioning takes place, followed by testing and qual-ity assurance; procedures must be established and staff trained; and finally, treatments can begin, with ongoing assessment of results.

One of the key links in this chain is the training process. Medical physi-cists are tasked with supporting the technical implementation of new treatment techniques. But with rapid technology evolution, and increas-ing system and software complex-ity, it ’s vital that users become experts before a new technology is used on patients. This could be achieved via transfer of experience from colleagues, industry training, knowledge transfer from existing specialists or training workshops.

Economic constraints, however, can impede the availability of such training, leaving physicists and cli-nicians to work on new equipment without sufficient expertise. Garcia described a discussion that he had with a colleague at a small treatment centre that was installing a new sys-tem. The colleague requested a work-shop to learn how to use the device, but his boss replied that there was no money available, and he’d just have to be taught by the vendor.

Insufficient training, however, along with other examples of “non-safety” such as unsuitable measure-ment equipment, lack of human

resources and machine access, and no external help, can result in seri-ous accidents.

Garcia presented a stark exam-ple of a recent incident in France in which lack of resources, equipment and competences led to many patient injuries and several fatalities six years ago. In this case, incorrect cali-bration during installation of new radiotherapy machines, insufficient training of technicians in use of the new systems, as well as errors in dose calculations led to patients receiving radiation overdoses.

In an ensuing court case, two doc-tors and a physicist were given prison terms. Garcia noted that the hospital administrators were acquitted of any charges against them. “I agree with need for new technology, but at the same time, I have a colleague who will go to jail,” he said.

He concluded by emphasizing that the continual introduction of new technologies will increase the risks – for patients, but also for the physicists. The only safe option is to obtain sufficient resources such that insertion of new technologies can be performed everywhere with higher quality and greater safety.

“Safety improves the introduction of new technologies,” Garcia con-cluded. “Every time that we intro-duce a new technology, we should start with a safety phase.”

The debate was then thrown open to the audience. Pedro Andreo from Stockholm University in Sweden agreed that people are overly afraid of X-rays, but pointed out that there is proof that new technology can be harmful and result in radiotherapy accidents. “I can’t believe that safety is delaying the introduction of new technologies, that’s like saying traf-fic rules are hampering the traffic,” he said. “If you introduce a new technique and have no idea of the potential consequences, you have to be sure that the patient won’t be harmed.”

Philip Mayles from the UK’s Clat-terbridge Cancer Centre pointed out that older technologies are not neces-sarily safer than newer approaches. “If you ask whether RapidArc is more dangerous that using wedges [to modify the beam], I can think of two examples of accidents with wedges,” he said.

“You can never make a process totally fail-proof,” added Dirk Verel-len from Vrije Universiteit Brussel in Belgium. “Yes we need safety, but at some point you must decide how much risk you are willing to take.”

The session concluded with a sec-ond show-of-hands vote. As pre-viously, the majority of attendees disagreed with the motion – believ-ing that safety issues do not neces-sarily hamper the introduction of new technologies. It seems for this audience at least, it’s a case of “safety first” when it comes to radiotherapy evolution.

Debating the options: Håkan Nyström (left) spoke for the motion while Robin Garcia (right) presented the case against. A show-of-hands poll (lower image) allowed the attending delegated to share their opinions.

A round up of recent international patent applications.

Device keeps track of radiation doseSiemens has developed a device that measures radiation dose delivered to a patient, during both diagnostic imaging and radiotherapy (WO/2014/033112). The dose measurement field contains a number of pixels, preferably connected in a matrix shape, which can be switched to adapt the measurement area to the patient. The measurement area is read out in real time, enabling adjustment of the radiation source to avoid any potential overdose in the patient, even during the measuring procedure. The device is suitable for use with any electromagnetic radiation, in particular, high-energy radiation such as gamma rays or X-rays.

Compensating for target motion Varian Medical Systems has introduced a multi-axis dynamic tracking system that can adapt a radiotherapy beam to compensate for any target motion during treatment delivery (WO/2014/043172). The beam can be adjusted, for example, using controls for setting the beam shape and beam intensity. The target is supported on a surface that can also be adjusted using controls for setting the surface position and the speed of surface movement. The tracking system selects these different controls to adjust the beam and the surface cooperatively and compensate for motion.

Perfusion imaging tailors planningPhilips has come up with a method for imaging tumour perfusion during radiotherapy, either in real-time or between fractions, thereby providing a measure of the therapy’s effectiveness (WO/2014/001961). The proposed system includes an imaging device that collects information such as blood flow or oxygen saturation from the target area and determines perfusion levels based on these data. A planning module correlates the perfusion levels with the treatment (radiotherapy with or without chemotherapy) to provide an adapted plan, with the treatment adjusted based upon the perfusion levels in the target area.

Taking the inertia out of radiotherapyElekta has devised an improved means for dealing with inertia in a radiotherapy system, which arises when rotating the radiation source support, for example, or moving MLC leaves. The idea is to account for inertia in advance, either by incorporating inertia factors into the output from the delivery control system, which adapts the treatment plan accordingly, or by including the inertia factors as a constraint in the treatment planning process. Therefore, instead of instructing the machine to make movements that assume perfect inertia-less behaviour and then compensating for this afterwards, the instructions delivered to the system will reflect their inertia behaviour and can thus be followed closely (WO/2014/090336).

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17focus on: radiotherapy


Biological data personalize treatmentRadiation therapy is a highly per-sonalized modality, with treatment plans tailored according to a patient’s individual anatomy, tumour size and location. Could biological individu-alization help to improve results further?

That was the question posed by Michael Baumann, speaking at the ICTR-PHE meeting held earlier this year in Geneva, Switzerland. Bau-mann, from Technische Universität and OncoRay in Dresden, Germany, examined the potential of integrat-ing biological information into a patient’s treatment strategy.

He began by introducing the con-cept of cancer stem cells (CSCs), which are thought to be responsible for tumour formation, metastasis and recurrence – and also may show increased radiation resistance. To achieve permanent local tumour control, all CSCs need to be killed during irradiation. If radiotherapy is delivered at too low a dose, some CSCs may survive and lead to cancer recurrence.

In vitro studies have shown that the tumour control dose is also propor-tional to tumour volume, implying that volume may serve as a surrogate for the number of CSCs. Baumann explained that introducing tumour

volume data into the treatment plan-ning process can alter the resulting dose prescription. “Our idea is to introduce this concept and test it on a large number of patients,” he said.

But even when irradiating tumours of identical volume using identical plans, it’s not unusual to observe considerably different responses between patients. This heterogene-ous dose-response can be attributed to factors such as the density of CSCs within a tumour and their cellular radiosensitivity. “We don’t know whether a specific patient falls into the radiosensitive or the radioresist-ant group,” said Baumann. If this knowledge was available, treatment could be personalized. As it stands, clinicians have to work with average dose-response curves.

So is it possible to determine the level of CSCs within an individual tumour? Baumann noted that CSC biomarkers are available that can, if not specifically identify CSCs, at least be indicative of radiotherapy outcome in some tumours. “This research direction looks very con-vincing; we should put effort into this area,” he said.

The radiosensitivity of a tumour is also influenced by its level of hypoxia. Baumann described a study looking

at a series of head-and-neck squa-mous cell carcinomas to investigate the relationship between hypoxia and local tumour control after irradiation.

Results showed that hypoxia levels prior to treatment were weakly cor-related to outcome, but that the prog-nostic value was not strong enough to use for dose prescription. The study did, however, reveal a stronger corre-lation between local tumour control and hypoxia levels during radiother-apy (after 10 fractions).

Following these findings, Baumann and colleagues examined the prog-nostic value of PET/CT imaging with the hypoxia-specific tracer F-MISO,

before and during radio-chemother-apy. Results from 25 patients with locally advanced head-and-neck can-cer showed that F-MISO PET/CT one or two weeks into treatment carries strong prognostic value for tumour control. This could provide a means to select patients that would benefit from dose-escalated treatment.

In parallel, they evaluated the dis-tribution of hypoxia during treat-ment, observing heterogeneous distributions with large variation between tumours. This begs the question of whether the presence of hypoxia indicates a resistant phe-notype (thus requiring increased irradiation of the entire tumour),

or whether radioresistance arises from hypoxic subvolumes (requir-ing targeted dose boosts to hypoxic areas). To investigate these options, the team is now embarking on a translational intervention trial. The plan is to use F-MISO PET two weeks into radiotherapy to identify patients with poor prognosis. Such patients can then receive dose escalation to the hypoxic volume and the gross tumour volume.

Finally, Baumann discussed the use of molecular targeting in radio-therapy. For example, the expression of epidermal growth factor receptor (EGFR) in tumours is related to treat-ment outcome, with highly express-ing tumours more radioresistant. He described an EGFR-based theragnos-tic approach in which external-beam radiotherapy is combined with a radiolabelled antibody (Y-90 bound to the anti-EGFR antibody cetuxi-mab) to help treat non-responding tumours. Initial results showed that this approach can improve perma-nent local tumour control compared to radiotherapy alone.

“Radiotherapy is already highly individualized, and I’m sure that biology-driven approaches offer sig-nificant potential for further person-alization,” Bauman concluded.

Personal take: Michael Baumann (right) and session chair Jean Bourhis.

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19focus�on:�non-cancer�therapy

Radiation therapy is a mainstay treatment for a wide range of can-cers. But, according to research pre-sented at the 2014 AAPM Annual Meeting in Austin, TX, radiotherapy could also prove promising for treat-ing conditions such as atrial fibrilla-tion or hypertension.

Speaking at the meeting’s John R Cameron Young Investigator Symposium, Svenja Ipsen from the University of Luebeck in Germany described the use of radiation to treat atrial fibrillation (AFib), a con-dition in which the electrical signals controlling the heartbeat become chaotic and cause the heart to beat irregularly. AFib, which increases the risk of suffering stroke, is usu-ally treated using catheter ablation, but this is an invasive approach.

“Ablative doses of ionizing radia-tion are used to treat cancer, so why not use this to treat AFib non-inva-sively,” said Ipsen, who conducted the research at the University of Syd-ney in Australia. Radiosurgery of the pulmonary veins has been proposed as a treatment for AFib, and previ-ous studies have demonstrated that a dose of about 30 Gy is needed to ablate the target. The idea is to create non-conducting scar tissue that will block the AFib signals before they

enter the heart.One big challenge for this

approach, however, is to image a beating heart accurately enough to direct radiation to the small, ring-like target without damaging nearby critical structures. “Our approach is to use entirely non-invasive tracking using an MRI-linac,” said Ipsen.

To test the feasibility of MRI-guided treatment, Ipsen and col-leagues quantified target motion ranges by imaging four volunteers with real-time cardiac MRI, under free breathing conditions. They found that the mean respiratory-induced target motion was largest in the superior-inferior direction (10.2

mm). Overall, results indicated that real-time MRI tracking of the pul-monary veins appears feasible.

The researchers then performed a radiotherapy planning study, with the treatment target defined as an ablation line at each pulmonary vein antrum, and safety margins ranging from 0 mm (perfect tracking) to 8 mm (untracked motion). Increas-ing the margins to encompass untracked motion resulted in exces-sive heart dose in all plans, implying that the reduced margins enabled by MRI tracking are essential. Monte Carlo simulations revealed that a 1T magnetic field had little impact on the dose distribution.

“We hope to expand the horizons of radiosurgery beyond conven-tional use in cancer treatment,” said Ipsen. “We hope to provide an alter-native treatment for heart rhythm disorders.”

Bringing the pressure downHypertension, or high blood pres-sure, is a common condition that puts sufferers at risk for heart dis-ease, stroke and kidney disease. For those with refractory hypertension, in whom standard treatments do not work, radiation therapy may provide another option. In a study chosen as one of AAPM’s “Best in Physics” presentations, Peter Maxim from Stanford University described his latest work in this area.

Blood pressure is regulated by nerve signals between the brain, heart, blood vessels and kidneys. By ablating the nerves surround-ing the main arteries to the kidney with radiation, it may be possible to disrupt these signals and inter-rupt the feedback loop that causes hypertension.

“We have the tools to focus radia-tion so precisely, that we can target the nerves responsible while spar-ing nearby healthy structures such as the spine and kidneys,” explained

Maxim. “It’s non-invasive and could be done in a single treatment.”

Maxim presented a study assess-ing the safety and efficacy of ste-reotactic radiotherapy for treating refractory hypertension in a swine model. Twelve hypertensive pigs received 40 Gy radiation in a single fraction delivered to the renal nerves under image guidance. All animals survived to the six-month follow-up point with no adverse events. Micro-scopic evaluation 4–6 weeks after treatment showed evidence of dam-age to the nerves around the treated renal arteries

The animals’ plasma norepineph-rine levels (measured as a surrogate for renal denervation) decreased by 63% on average during follow-up. Pathologic examination after the follow-up period revealed moderate damage to the nerves and minimal damage to nearby critical organs, highlighting the targeting accuracy.Maxim says that the first human trial will start in the Autumn of this year, in which 10–15 patients will be eval-uated to demonstrate the safety of this approach. This will be followed by a larger trial to demonstrate effi-cacy. “If this works, it dwarfs any-thing that we’re doing with cancer,” he told medicalphysicsweb.

The speakers: Svenja Ipsen from the University of Luebeck (left) and Stanford University’s Peter Maxim (right) by his “Best in Physics” poster.

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21focus�on:�new�products

The 2014 AAPM Annual Meeting in Austin, TX, saw over 100 companies showcasing new and improved prod-ucts and software on the trade show floor. Here’s just a few of the innova-tions that caught our eye.

All-in-one QAIBA unveiled myQA, a global quality assurance (QA) platform that inte-grates all of a radiotherapy depart-ment’s QA needs into a single software system. The platform is based around myQACockpit, which delivers an instant update showing the status of all plan verification, machine QA and com-missioning tests within a clinic.

The myQACockpit component can be accessed from anywhere in the clinic via devices including smart-phones and tablets. According to IBA’s Suzanne Shankle, “myQA is one central tool that can solve a lot of dif-ferent problems for physicists”.

From myQACockpit users can access a series of modules. For treatment plan verification, myQAPatients enables users to input a treatment plan, perform a measurement with the MatriXX ion chamber array and compare results with the expected plan. The myQAMa-

chines module, meanwhile, offers com-plete machine QA and is pre-installed with TG-142 specifications. It can also be customized by moderating tolerances or adding tests, for exam-ple, and can import water phantom data for reference. Finally, for com-missioning and annual linac checks, there’s myQAAccept. This module can

also be used to compare the perfor-mance of different machines, or track a system’s performance over time.

Data are stored on a local data-base, or users can use the myQACLOUD option. “If you publish your data in the cloud, you are also allowed to receive benchmarks from the cloud,” said IBA’s Andreas Strempf l. He explained that this allows a centre to compare its systems with other cen-tre’s machines, noting that data are anonymized and only the machine type and test results are shared.

“It’s all-in-one, all connected, all secure,” Strempfl added. “It can also be customized to anyone’s needs.” The full version of myQA will be released at the end of this year, with more modules added in the future.

Planning for multiple metsBrainlab announced the release of ELEMENTS Automatic Brain

Metastases Planning software, for planning stereotactic radiosurgery of metastatic brain tumours. Brain metastases are traditionally treated with whole brain radiotherapy, but this can lead to side effects due to irradiation of healthy brain tissue. Radiosurgery, on the other hand, can deliver targeted radiation to each lesion. But as the number of metas-tases increases, treatment becomes increasingly complex and time consuming.

According to Brainlab’s David Brett, the new software was devel-oped to meet a growing need as cli-nicians weigh up whether to treat brain metastases with radiosurgery or whole-brain irradiation. “Over the last couple of years, we’ve tried to identify clinical areas where we expect an influx of patients looking to get radiosurgery,” he explained. “If there are no longer technical

limitations, then a clinical choice is available.”

The metastases software simpli-fies the planning process and rapidly generates radiosurgery plans for effi-cient treatment of multiple metasta-ses. Once patient images are loaded, the Atlas Segmentation software automatically contours and labels all structures in the brain for user review and editing.

Contouring of the lesions is per-formed by the user, using the Smart-Brush computer-assisted tumour outlining tool. The user then selects the required dose prescription, and the algorithm generates an opti-mized volumetric conformal radio-surgery plan, for up to 10 metastases, in about two minutes. Treatment plans are based on a single isocentre approach using up to five arcs with up to two passes each.

The ELEMENTS Automatic Brain Metastases Planning software is CE marked and has been submitted for FDA approval. “We are now doing clinical tests in Europe and we’ve had very positive feedback from this,” said Brett. “We hope that this will revolutionize the way that people treat multiple metastases.”

Keeping patients in placeOrfit Industries showcased its Sagit-tilt Prone Breast Solution – an immo-bilization system that accurately sets-up and reproduces the prone position of a breast patient during radiotherapy simulation and treat-

ment delivery.According to Jeff Life, Radiation

Oncology Product Specialist at Orfit Industries America, the challenge when setting up a patient for breast radiotherapy is to ensure that the patient is comfortable, but also that they are placed in exactly the same position each day. “What makes Sag-ittilt unique,” he explained, “is that it has multiple comfort adjustments that can be easily documented and easily set, regardless of the height or size of the patient.”

Another unique feature of Orfit’s system is that once a patient is posi-tioned, they can be accurately rotated by up to 10° in each direction. This allows the ipsi-lateral breast to fall deeper into the cutout and further away from organs-at-risk such as heart and lung. This rotation can be used to bring the body out of the beam path, thereby sparing more healthy tissue.

Orfit was also demonstrating its SBRT Solution, for patient position-ing during stereotactic body radio-therapy. When treating abdominal and lung tumours, it’s essential to minimize breathing motion. This is achieved using an abdominal pressure arch with a quick release mechanism for after treatment or if necessary earlier. Other components include the base plate, feet and knee cushions, and an arm positioning system. “Because the margin of error is very strict for SBRT, you need very precise positioning,” added Life.

On show: Orfit’s Jeff Life with the Sagittilt Prone Breast Solution.

AAPM Annual Meeting: product update13

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22 focus on: nanomedicine


Tracking nanoparticle temperatureWhat’s the best shape for a nanoparticle?The shape of a nanoparticle is impor-tant for how easily it can penetrate into a tumour, with both cubic nanocages and nanorods enter-ing more readily than disk-like and spherical shaped structures. This new result, from researchers at Georgia Tech and Washington Uni-versity Medical School, could help better engineer nanostructures for more effective cancer diagnosis and therapy (ACS Nano 8 4385).

Nanostructures can be used to deliver drugs inside tumour cells. However, how effi cient they are at this task depends on a variety of fac-tors, and one of the most critical of these is the shape of the structure. It is therefore important to under-stand which shapes are best, but until now such studies have been diffi cult because it is difficult to track the movement of nanostructures in vivo.

A team of researchers led by You-nan Xia from Georgia Tech and Yongjian Liu of Washington Univer-sity has now successfully prepared gold nanostructures containing radioactive Au-198 in their crystal lattices. The nanostructures were made in four distinct shapes (disks, rods, spheres and cubic cages) but were all roughly the same size (between 50 and 100 nm across). By measuring the gamma radiation as the Au-198 decays, the researchers were able to follow how the nano-structures distributed themselves in mice with tumours.

The gold nanodisks are 2D circles 7 nm thick and 100 nm in diameter. The nanorods are 1D structures that

are 10 nm wide and 50 nm across. The nanospheres are round with a diameter of around 50 nm. Finally, the nanocages are cubic hollow nanostructures with pores in their walls. Their edge length is around 50 nm and their walls are approxi-mately 5 nm thick.

The researchers also found that the nanorods did not accumulate in the tumour sites as readily as the other shapes. However, because the nanorods were less than 50 nm in diameter, they were able to leak out through the pores in the mircovas-culature of a tumour and penetrate into its core. In contrast, the nano-spheres and nanodisks were only able to reside on the surface of the

tumours, said Xia. “Interestingly, we found that the cubic nanocages accumulated inside the core of the tumour too – a phenomenon that we believe comes about thanks to their hollow structure and relatively low density.”

The team will now focus on reduc-ing the size of the nanostructures so that they can stay in the bloodstream for longer periods and better pen-etrate cancer cells at the same time. “We also plan to test these radioac-tive nanostructures on other tumour models, such as orthotopic mouse breast-cancer cells,” said Xia.

Belle Dumé is contributing editor at nanotechweb.org.

Magnetic nanoparticles (MNPs) are employed for various thermal cancer therapies, with applied mag-netic fi elds used to heat the MNPs in situ. Such thermal therapies require accurate monitoring of nanoparti-cle temperature to ensure safe treat-ments and optimal outcomes, a task that can prove challenging.

One way to determine nanopar-ticles’ temperature is by measuring their Brownian relaxation time, a metric that depends directly on the temperature. This can be achieved via magnetic spectroscopy of nano-particle Brownian motion (MSB), a technique that uses an oscillating magnetic fi eld to excite particles and simultaneously measures how they react. Their behaviour indicates the conditions of their environment and thus properties like temperature can be inferred. The exciting possibility is that the oscillating magnetic fi eld can be used both to heat tissue in thera-pies like hyperthermia and monitor temperature rises using MSB.

In a previously reported MSB method, measurements were cali-brated by varying the amplitude of the applied magnetic fi eld. Now, researchers from Dartmouth College have come up with a new approach: varying the frequency of the applied fi eld to measure the relaxation time. They show that this “frequency sweep” method is more accurate than the “amplitude sweep” approach at higher frequencies (Phys. Med. Biol. 59 1109). “We had a method of measur-ing the temperature at low frequen-cies, but it is important to measure the temperature for applications that use higher frequencies, and we showed it could be done,” said senior author John Weaver.

The MSB method exploits the fact that MNP magnetization is depend-ent upon the product of oscilla-tion frequency and relaxation time. The relaxation time can therefore be determined experimentally by measuring the nanoparticle mag-netization induced by an alternat-ing magnetic fi eld applied at various frequencies. The method could be implemented clinically using appa-ratus similar to, but less complex than, the scanners current employed for magnetic particle imaging.

For this study, research associate Irina Perreard and colleagues applied oscillating fi elds with frequencies of 290, 510, 755, 1050, 1270, 1890 and

2110 Hz to the MNPs and measured the changes in nanoparticle magneti-zation using a solenoid pickup coil. They recorded MNP spectra at tem-peratures from 21.5–50 °C.

The researchers generated a cali-bration curve using measurements (the ratio of the 5th to the 3rd har-monic) of reference MNPs at 37 °C. To determine an unknown tempera-ture, measured data can be shifted back onto this calibration curve by a scaling factor, which represents the change in relaxation time. Compari-sons of relaxation times calculated from measured ratios with those computed using Einstein’s theo-retical formulation for Brownian relaxation time showed a mean dis-crepancy of 2.53%.

The team then used the calculated relaxation times to estimate sample temperatures. Comparing MSB tem-perature estimates with thermom-eter readouts revealed a mean error of 1.15% (an accuracy of 0.42 °C).

To assess the potential advantages of the frequency sweep approach, the researchers compared the above results with data recorded using the amplitude sweep method. For meas-ured amplitude sweeps, mean error values increased with frequency, from 1.847% at 290 Hz to 3.501% at 2100 Hz. In contrast, dividing the fre-quency sweep data into lower (290–1050 Hz) and higher (1050–2110 Hz) frequency ranges revealed that the mean error for the higher range (0.876%) was roughly half that of the lower range (1.721%).

Finally, the researchers performed simulations to validate the two methods further. For the amplitude-based method, they considered a low range of field values (1–2 mT) and frequency values of 20, 100, 200 and 1000 Hz. They observed a signifi-cant increase in mean error in tem-perature estimate with increasing frequency, from 0.128% at 20 Hz to 435% at 1000 Hz.

For the frequency sweep method, they examined four frequency inter-vals (0.29–2.1, 2.1–3, 3–4 and 4–5 kHz) using an applied fi eld amplitude of 50 mT. The method gained accu-racy with an increase in frequency range, with mean error decreasing from 0.093% in the lowest interval to 0.016% for the highest. These results are potentially important for moni-toring MNP-based thermal thera-pies, which use kHz frequencies.

Shape up: in vivo luminescence imaging reveals the uptake of variousnanostructures 1 h (left panel) and 24 h (right panel) after injection with nanospheres (a), nanodisks (b), nanorods (c) and cubic nanocages (d).

Dartmouth researchers: (left to right) Daniel Reeves, Xiaojuan Zhang, John Weaver, Yipeng Shi, Irina Perreard, Esra Kuehlert and Ben Fiering.

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