Particle therapy for noncancer diseases

Christoph Bert
GSI Helmholtzzentrum fur Schwerionenforschung, Biophysics Department, Planckstrae 1, 64291 Darmstadt, Germany

Rita Engenhart-Cabillic
Philipps-University Marburg, Center for Radiology, Department of Radiation Therapy, Baldinger Strasse, 35043 Marburg, Germany

Marco Durantea)
GSI Helmholtzzentrum fur Schwerionenforschung, Biophysics Department, Planckstrae 1, 64291 Darmstadt, Germany; Technische Universitat Darmstadt, Institut fur Festkorperphysik, Hochschulstrae 3, 64289 Darmstadt, Germany; and Frankfurt Institute for Advanced Studies, Johann Wolfgang Goethe University, Ruth-Moufang-Str. 1, 60438 Frankfurt am Main, Germany

(Received 3 August 2011; revised 3 January 2012; accepted for publication 13 February 2012; published 8 March 2012) Radiation therapy using high-energy charged particles is generally acknowledged as a powerful new technique in cancer treatment. However, particle therapy in oncology is still controversial, specically because it is unclear whether the putative clinical advantages justify the high additional costs. However, particle therapy can nd important applications in the management of noncancer diseases, especially in radiosurgery. Extension to other diseases and targets (both cranial and extracranial) may widen the applications of the technique and decrease the cost/benet ratio of the accelerator facilities. Future challenges in this eld include the use of different particles and energies, motion management in particle body radiotherapy and extension to new targets currently treated by catheter ablation (atrial brillation and renal denervation) or stereotactic radiation therapy (trigeminal neuralgia, epilepsy, and macular degeneration). Particle body radiosurgery could be a future key application of C accelerator-based particle therapy facilities in 10 years from today. V 2012 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.3691903] I. BACKGROUND AND INTRODUCTION With the increasing number of accelerator facilities for particle therapy currently planned, proposed, or under construction, the debate on the cost/benet ratio is now going beyond the radiotherapy community and involving the general public, with several reports in the press. Therapy with accelerated charged particles exploits protons or heavier ions (typically carbon) produced by accelerators.15 Current clinical results support the predictions that charged particles are effective in tumor killing with greater sparing of the normal tissue, including a reduced risk of secondary cancers, which makes it particularly important for pediatric cancers.6,7 However, direct clinical trials comparing x- or c-rays to protons or carbon ions are still lacking,8 and this fuels the controversy on the cost/benet ratio of ion therapy. Since the rst patient treatments in the Lawrence Berkeley Laboratory (USA) and Uppsala (Sweden) at the end of the 1950s,9 almost 100 000 patients have been treated with energetic ions all over the world for different cancers. Over 80% of these patients were treated with protons.10 The cost of particle therapy is dominated by the construction cost, which currently ranges from $35 M$ (for a single room, proton therapy commercial machine) up to $350 M$ (for a heavy ion center including radiodiagnostic and conventional x-ray therapy accelerators such as the one in construction in Shanghai, China). In the United States, where heavy ion therapy started in Berkeley, particle therapy is limited to protons, with eight centers currently in operation. Many new
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centers have been proposed, but at the moment, only a handful of facilities have the capability of treating patients with different ions (see Sec. II A and Ref. 10). The main problem is that the cost of particle therapy is more than two times higher than the most advanced x-ray methods.8 Of course, cost-effectiveness is more than just looking at the costs: sophisticated model-based economic evaluations, including in silico clinical trials, are necessary to provide sensible advices for medical decision-making.11 Independent evidencebased studies on the cost-effectiveness of the particle therapy have indeed concluded that the current lack of evidence for benet of protons should provide a stimulus for continued research.12 In this paper, we provide some new research topics that can potentially boost the benets of the particle therapy centers. One factor that is generally not considered in planning particle facilities is the possibility of applications in noncancer diseases. The charged particle depth-dose distribution is completely different from x-rays, c-rays, electrons, or neutrons. Most of the energy is released in a narrow volume at the end of the particle path in the body, the Bragg peak (Fig. 1). The relative straggling is proportional to $M1/2, and the lateral beam spread to $1/bpc, where M is the particle mass, p the momentum and b v/c the relative velocity.5 As a consequence, the Bragg peak can become more and more narrow using heavy ions (i.e., increasing Mcompare protons to C-ion Bragg peaks at the same range in Fig. 1) and increasing the particle energy (i.e., increasing b). Eventually, the Bragg peak can be used as a remote scalpel for
C V 2012 Am. Assoc. Phys. Med.

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facility (HIT) (Refs. 16 and 17) in Germany. The new center in Italy (CNAO) started treatments in 2011 and will treat patients with both H- and C-ions. Several new facilities with capabilities to deliver both H- and C-ions are currently under construction in Europe and Asia.10 Access to proton or heavier ions facilities is therefore becoming easier and should allow tests in noncancer diseases.
II.B. Stereotactic particle radiotherapy and radiosurgery

FIG. 1. Depth-dose distribution for high-energy x-rays, protons, and C-ions at two different energies in tissue. For charged particles, most of the dose is deposited in the distal region (the Bragg peak), and the beam penetration depth can be modied by changing the beam energy (particle velocity). The Bragg peak is broadened both in depth and in the plane for protons compared to carbons, because of their lower mass (courtesy of Dr. Uli Weber, Phillips University Marburg, Germany).

radiosurgery. Stereotactic radiosurgery (SRS) or stereotactic radiation therapy (SRT) (Ref. 13) are successfully performed in many clinical centers using x- or c-rays (e.g., Cyberknife and Gammaknife) for several noncancer disorders such as trigeminal neuralgia, arterial aneurism, and arteriovenous malformations (AVM). In principle, the narrow Bragg peak could be used more successfully for these and other noncancer disorders. The number of noncancer diseases eligible for particle radiosurgery can be drastically increased if moving organs are considered. Management of organ motion is indeed a problem both for x-ray14 and particle15 radiotherapy, but recent progress in the eld suggest that, in the coming 10 years, the problem may be tackled with sufcient precision (see Sec. II D). II. CURRENT STATE OF THE ART
II.A. Ion therapy in oncology

Considering the favorable dose-depth distribution compared to photons, particle therapy in oncology is often evaluated in competition to stereotactic x-ray therapy. The word stereotactic refers to the use of a 3D coordinates system to locate small targets in the patient. Radiosurgery was indeed initially performed with protons18 and then with the Gammaknife19 at the Karolinska Institute in Sweden. Latest versions include the use of special LINACs for pencil beam radiosurgery (Cyberknife) and intensity modulated radiation therapy delivery (Tomotherapy).20 SRS is generally delivered in single fractions, while SRT is used for fractionated intracranial treatments. Energetic charged particles have been used since many years in the treatment of AVM, but so far, very few other skull or body lesions have been treated with protons or heavier ions.
II.B.1. Treatment of AVM

The current status of particle therapy in oncology has been reviewed several times in the past few years, including the Vision 20/20 series on this Journal.2,3 For this review, it is enough to remark that proton therapy is now a widely adopted conformal radiotherapy method, and despite the controversy on the cost/benet ratio compared to conventional x-ray therapy,12 it is currently used even in the absence of phase III clinical trials.16 For heavy-ion therapy, the experience is more limited, but the advantages compared to x-rays are potentially much greater, thanks to the different biological effects in the Bragg peak region.1 Clinical trials comparing heavy ions to protons or photons are complicated by the relative paucity of patients and differences in fractionation scheme and LET.17 In addition to the large set of clinical data already acquired at NIRS (Japan) with C-ions,4 more clinical results on different cancers treated with protons and carbon ions are coming from the new Heidelberg
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The potential of stereotactic particle radiosurgery (SpRS) or stereotactic particle radiotherapy (SpRT) was soon recognized in neurosurgery. For deep, inoperable AVM, SpRS/T represents an interesting alternative: when hemodynamic ow in AVM is different from normal vessels, focal beam irradiation of the shunting vessels leads to thrombosis and hemostasis, with eventual complete obliteration of the AVM. Treatment of AVM with protons has been one of the rst noncancer applications of charged particle therapy21 and is indeed currently performed in several proton therapy centers.22,23 At MGH-Francis H. Burr Proton Therapy Center (USA), the patient is placed in an immobilizing head frame on a couch that can be rotated around a xed proton beam line. Using 3 linear and 2 rotational degrees of freedom, this system (known as the STAR device) is able to accurately position the brain lesions at the beam isocenter.24 An isocentric gantry can be used if more angles are needed in the treatment plan. Apart from protons, helium ions were used in the 1950s at the Lawrence Berkeley National Laboratory.25 A detailed comparison of protons vs x-rays for AVM treatment is complicated by the fact that, in most cases, protons are used for large and irregularly shaped lesions,24 which are very difcult to treat with photons but whose prognosis is worse than for small AVM. Broadly speaking, protons seem to be comparable to photons and a better alternative for large, irregular lesions. The experience at the proton center in Uppsala (Sweden) shows that protons provide an advantage for lesions >10 ml.26 Results from Berkeley with He-ions demonstrated complete obliteration for small (<4 ml) lesions and 70% success rate for large (>25 ml)

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lesions.27 A recent analysis of 64 patients treated with hypofractionated (23 fractions) protons at iThemba in South Africa28 shows obliteration in 67% of the patients with lesions smaller than 14 ml and 43% obliteration in patients with larger AVM volumes. Grade IV acute complications were observed in 3% of the patients.
II.B.2. Stereotactic radiotherapy in other noncancer diseases

X- or c-ray SRS or SRT is currently under study for treating several noncancer diseases in the skull including trigeminal neuralgia,29 epilepsy,30 intracranial aneurysm,31 and macular degeneration.32 These treatments may greatly expand the spectrum of skull lesions where external beam radiation therapy can replace surgery. In fact, trigeminal neuralgia (Fothergills disease or tic douloureux) has an incidence of 1 in 15 000 people, while macular degeneration affects from 10% to 30% of the population older than 65 years, representing the major cause of visual impairment in elderly. Results of SRS or SRT treatments using Gammaknife or Cyberknife are generally considered positive, although randomized clinical trials are generally lacking.33 Trigeminal neuralgia, which is characterized by a temporary paroxysmal lancinating facial pain, can be treated with drugs (anticonvulsant or antidepressant) or alternatively with microvascular decompression, a craniotomy where the surgeon has to locate and separate veins and arteries in contact with the trigeminal nerve.34 In fact, the pain is often caused by a blood vessel compressing or pulsating on the trigeminal nerve. In addition to external beam therapy, a further option is radiofrequency gangliotomy. SRS has been proven to be safe and effective in patients with medical- and surgicalrefractory trigeminal neuralgia. In many cases, SRS is performed with a shot size around 5 mm, a maximum point dose of 8090 Gy and about 40 Gy prescribed at the 50% isodose line.35 If the patient is nonresponsive or the pain returns, SRS can be repeated, and up to 4 repeated Gammaknife treatments have been reported in a few patients. The main treatment-related complication is facial numbness. The complication rate depends on the total dose and could be increased by repeated treatments.36 For epilepsy patients nonresponsive to anticonvulsants, SRS is an alternative to resective surgery.37 Hypothalamic hamartomas and mesial temporal lobe epilepsy are small enough (50% isodose volume <7.5 ml) to be treated by SRS. The dose is generally 2024 Gy and is limited by the nearby brainstem, optic nerves, and chiasm. Although minimally invasive compared to surgery, Gammaknife radiosurgery has a relatively long latency (up to 2 years) from treatment to seizure remission and can induce various brain lesions, including multilobar edema and midline shifts, resulting in high rates of headaches that require steroid treatment and even surgery in a few cases.38 Macular degeneration is a relatively common disease in the elderly and the leading cause of blindness in adults over 50 years. The standard treatment is based on antivascular endothelial growth factor (anti-VEGF) drugs.39 Anti-VEGF
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drugs target the subfoveal choroidal neovascularization, which invade the subretinal space and whose leaking or rupture impairs the photoreceptor layer, eventually leading to blindness. Anti-VEGF treatment requires monthly intraocular injections and is only effective in only about 1/3 of the patients. There is, therefore, a need for a durable treatment modality to reduce the cost and burden of treatment, while maintaining or improving vision. Radiation is certainly a candidate, since the target are the rapidly cycling neovascular cells, more radiosensitive than the quiescent surrounding cells in the eye.40 Clinical trials using epimacular brachytherapy and SRS are ongoing to determine whether radiotherapy combined to anti-VEGF drugs is more effective than pharmaceutical treatment alone. The IRay system (Oraya Therapeutics, Newark, CA) uses low-energy [100 kV(peak)] x-rays and delivers three elds in a 4 mm disc target centered in the fovea. The average accuracy of the IRay system is about 0.6 mm and the precision (reproducibility) about 0.4 mm.41 Total doses between 16 and 24 Gy are currently used in ongoing clinical trials. Protons have been used for treatment of macular degeneration for several years. A clinical trial with protons in Harvard comparing 16 to 24 cobalt-gray-equivalent (CGE) gave similar results between the two dose groups.42 After 2 years, >50% of the patients lost >2 lines of vision. Improvements can be expected if different ions and energies can provide additional benet, in terms of increased relative biological effectiveness (RBE) (see Sec. III A 2) or increased precision (see Sec. III A 1). Moreover, in the treatment of macular degeneration, ionizing radiation will be always associated to anti-VEGF drugs, and synergistic effects are possible.43 In vitro studies are necessary to compare protons and x-rays combined to antiangiogenic drugs in cultures representative of the target tissue. Cultures of choroid endothelial cells may represent an interesting in vitro model, and survival and proliferation of these cells after exposure to protons has been recently measured.44
II.C. Stereotactic body radiation therapy

Stereotactic body radiation therapy (SBRT) and stereotactic body particle radiation therapy (SBpRT) are generally used for treating small extracranial targets primarily in thorax [e.g., nonsmall cell lung cancers (NSCLC)]33,45,46 and abdomen (e.g., hepatocellular carcinoma47,48), using hypofractionation. Different instrumentations are currently used in clinical practice including Cyberknife, Clinac (Novalis Shaped Beam), Tomotherapy, the Synergy System (Elekta, Stockholm, Sweden), and scattered particle beams. From 1 to 12 radiation beams are used, generally in 15 fractions. Different body immobilization systems are necessary, including the Alpha Cradle and the Stereotactic Body Frame. No direct comparative studies have been reported so far comparing SBRT to conformal fractionated radiotherapy, because they are used for different conditions: SBRT requires small well dened targets with large dose fractionation, and conformal fractionated therapy is typically used for larger targets with standard fractionation. For stage I

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peripheral NSCLC treatment using C-ions, NIRS in Japan is performing an interesting phase I/II dose escalation study for several fractionation schemes: from 16 fractions in 6 weeks already in 1994, down to 4 fractions in 1 week since 2001, and nally a single fraction since 2004, i.e., stereotactic body particle radiosurgery (SBpRS).49 Apart from tumor treatments, an interesting noncancer application of SBRT has been recently proposed: treatment of atrial brillation. This treatment has not yet reached the clinic and will be discussed in Sec. III B 1.
II.D. Management of organ motion in SBRT

Radiosurgery of extracranial lesions can only be performed taking into account the organ motion, as organ movement is already a severe hindrance in the fractionated high-dose regime.14 In particle beam therapy with a scattered beam, most centers use beam gating along with dedicated denition of the planning target volume to incorporate range changes caused by organ motion. For scanned particle therapy,15 where the lesion is irradiated in the narrow particle Bragg peak of small diameter, the problem is even more acute due to interference effects of scanned beam and moving target. From a geometrical point of view, the impact of organ motion in particle therapy is comparable to the impact in 3D conformal photon beam therapy, i.e., target motion results in blurring of the dose gradients from target volume to normal tissue.14 In addition to these geometrical effects, the motion of organs in the target area and within the beams path can change the radiological pathlength and thus the distribution of the deposited dose.50 These changes are independent of the delivery technique. For beam scanning, there are two additional interference options: one is due to intereld motion in intensity modulated particle therapy (IMPT), the other due to interference between scanning motion and intrafractional (or intraeld) organ motion, which is often called interplay and typically results into underdosage and overdosage within the target volume (Fig. 2).15 As we will discuss below, options for SBpRS heavily rely on management of organ motion, in particular if used in combination with a scanned beam that provides best conformation. Especially for treatment of cardiac lesions, new techniques will be required since the heart is not only beating but also moving due to respiration. Current management of inter- and intrafractional motion in charged particle beam therapy is widely based on the methods established for x-ray therapy.15 A distinction should be made with respect to the beam delivery method, i.e., whether passive scattering (e.g., MGH or Loma Linda in USA) or active scanning (e.g. PSI, Switzerland or HIT, Germany) are used. In scattered beam treatments, the use of margins is sufcient to ensure dose coverage of the clinical target volume (CTV) if the range inuence is addressed. For prostate treatments (as an example for interfractional motion51) as well as lung cancer treatments (as an example for intrafractionally moving organs52), the use of margins is the dominant technique, supplemented by gating in case of large respiratory motion ampliMedical Physics, Vol. 39, No. 4, April 2012

FIG. 2. 4D treatment plan (scanned carbon beam, single eld, and absorbed dose) to the GTV of a lung tumor. (a) Planned dose in the reference phase of the 4DCT without motion inuence. (b) Dose distribution in the presence of motion with margins (internal target volume, ITV) as only motion mitigation technique. Interplay of beam scanning and organ motion deteriorates homogeneity and conformation. (c) Irradiation by beam gating covers the target as planned. Data were calculated with the 4D version of GSIs planning code TRiP (Ref. 15).

tudes.53 Gating is the method used at NIRS in Japan for the SBpRS of NSCLC (see Sec. II C). For prostate treatments, the potential intrafractional motion components are often suppressed by dedicated immobilization, i.e., controlled rectum and bladder lling by drinking schemes, enemas, or rectal balloons.54 Range uncertainties can be addressed by compensator smearing and/or manual changes of the underlying planning CT scan (which typically is a free-breathing or a gated CT examination55,56). These changes aim of replacing low-density lung tissue by high-density tumor tissue to ensure proper target coverage in all states of the respiratory cycle. For patient positioning, several centers use uoroscopy to check consistency to the motion state (e.g., exhale) that is being used in the treatment planning and (gated) delivery. Fluoroscopy is further often used to check the motion range such that the size of the aperture is large enough and positioning is accurate to ensure that the tumor moves within the irradiation eld.57 In case of scanned beam delivery, the presence of organ motion requires more complex mitigation procedures. Scanned beam delivery interferes with target motion typically leading to underdosage of the CTV even if margins are used.58,59 Therefore, currently, only one center treats intrafractionally

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moving tumors with a scanned beam using apnea under intubation and anesthesia.60 Several groups are working on mitigation techniques that will allow reliable coverage of the CTV also for scanned beams.15 Gating and rescanning will be soon translated to clinical usage. Beam tracking is technically feasible61,62 but will require robust planning to cover for potential changes of the underlying 4DCT data between planning and delivery. III. DEVELOPMENTS IN THE NEXT DECADE
III.A. Technical developments

The cost of particle treatment facilities will decrease in the future, both as a result of the interest of large commercial companies and of technical developments in the construction of compact accelerators, such as xed alternated gradient eld syncrocyclotrons,63 ultracompact synchrotrons, and laser-driven or dielectric-wall accelerators.64 In the next 10 years, the number of proton and heavy ion therapy facilities worldwide is going to increase rapidly: the reduced cost of the accelerator may lead to a reduction in the investment cost of a factor of 2, but the overall cost of the treatment will remain higher than x-ray therapy. The new centers should therefore prove an increased benet (in terms of cure rate and/or reduction in overall treatment time) compared to conventional radiotherapy units. Since high-energy charged particles have improved physical characteristics compared to x-rays for radiosurgery, all of the current applications of SRS or SRT (see Sec. II B) could be gradually tested with protons or heavier ions as well. An increase in RBE for the therapy-related endpoint might further increase the effectiveness for heavier ions compared to photons or protons, as it happens in oncology for radioresistant tumors.1 One basic problem using heavy ions is the RBE of the particles in the different tissues. While the tolerance dose for the various tissues is known for photons, this is not the case for heavier ions. Moreover, the RBE for the target volume can be different from the RBE for the normal tissue surrounding it. This problem is the major source of uncertainty in heavy-ion cancer therapy,5 and dedicated research studies are needed before extension to new (noncancerous) diseases. Apart from these upcoming developments with respect to particle type, also an increase in particle energy (nonBragg-peak or plateau particle radiosurgery65) is foreseen with applications mainly in SpRS/T. This treatment option will not only benet from reduced lateral beam size but also allow online proton radiography exploiting the same therapeutic beam crossing the patient. The combination of both physical effects leads to a high precision image-guided stereotactic particle radiosurgery (IGSpRS).
III.A.1. New energies

(Fig. 1), as done with Gammaknife or Cyberknife where the depth-dose deposition pattern is opposite to charged particles. The rational for using very high-energy protons is linked to the reduction in proton scattering.66 Scattering causes blurs in the proton treatment plan, which are normally less sharp than those obtained with heavier ions. However, using protons in the Giga-electron-volt region (b > 0.87), it is possible to produce a narrow beam with very sharp edges, ideal for ablation of small structures such as AVM. The lateral scattering is indeed largely reduced compared to Braggpeak protons when relativistic protons are used (Fig. 3). Of course, the beam has to be directed from different angles, cross-ring the target. As yet, only one facility has used 1 GeV protons for therapy: the Petersburg Nuclear Physics Institute (PNPI) synchrocyclotron in S. Petersburg (Russia).67 Since 1975, a total of 1362 patients were treated at PNPI for pituitary adenoma, breast and prostate cancer, and skull noncancer lesions including AVM, aneurysm, endocrine ophthalmopathy, and epilepsy. SRS with relativistic protons (non-Bragg-peak or plateau radiosurgery) may be an interesting approach for reducing the target margins and escalating the target dose. At high energy, the beam FWHM will be very narrow (Fig. 4), thus ensuring very sharp dose gradients and reduction of the margins in the PTV. Although 1 GeV protons have a very lowLET ($0.2 keV/lm), they induce several nuclear reactions and can produce many neutrons and secondary protons, both at high-energy (kick-off protons) and low-energy (evaporation recoils). These nuclear reactions should be carefully considered in the treatment plan, as they can signicantly modify the physical dose and the biological effectiveness of the beam.68 Kick-off protons also broaden the lateral dose distribution of the beam (Fig. 5), and Monte Carlo codes have to be used for accurate predictions (see Figs 4 and 5). Relativistic protons have been extensively studied for space radiation protection,69,70 because they represent the major component of the galactic cosmic ray ux,71 but very few

Proton beam energies used generally in oncology range from 60 MeV for uveal melanoma up to 250 MeV for deep solid tumors. Higher energies ($GeV) would not allow treatment of the lesion on the Bragg peak, but radiosurgery will still be possible in the plateau region of the Bragg curve
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FIG. 3. Simulation using the SRIM2011 code of the spatial distribution of proton beams (directed to the center) passing through 15 cm of water. Each dot represents the position of a single proton (scales are in centimeter). Clearly, 1 GeV protons (in plateau) have a much higher spatial resolution than beams normally used in therapy (on the Bragg peak).

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FIG. 4. Calculations of the beam shapes FWHM for a monoenergetic incident proton beam in water using Molieres formula or simulated by the ` Monte Carlo code GEANT4. The Moliere theory is an approximation often ` used to calculate the lateral spread of proton beams used in Bragg peak therapy (Ref. 5). The FWHM spread is calculated for beams accelerated at 60 MeV (used in eyes therapy), 200 MeV (deep protontherapy), 1 GeV (available in several high-energy accelerators, such as the Brookhaven National Laboratory in USA and GSI in Germany), 2 and 4.5 GeV (planned for proton radiography in the future FAIR facility in Germany). Calculations courtesy by Dr. Marie Vanstalle (GSI, Germany).

studies are available in radiotherapy regime (high dose, biological tissues as targets) to be used for in silico trials of treatment plans. A further advantage of using relativistic protons is that the particles traversing the patient can be used for proton radiography.72 Proton73 and heavy ion74 radiography in medicine had been proposed many years ago, but the idea was dropped with the rapid improvements of CT and imaging. However, proton radiography is nowadays seriously considered as a sensitive tool for online monitoring in proton therapy of lung tumors.75 Detection devices include CMOS active pixel sensors76 and time-resolved proton range telescopes.77 Relativistic protons could be used for all kinds of lesions in the body, and they have superior spatial and tem-

poral resolution. About 15 years ago, at Los Alamos National Laboratory, it was shown that 800 MeV protons could provide improved imaging compared to x-rays of implosion tests (hydrotest).78 A project for the construction of a proton microscope (PRIOR) in the new Facility for Antiprotons and Ion Research (FAIR) in Darmstadt is planning to use a 4.5 GeV proton beam able to achieve a resolution below 10 lm with a time resolution of 10 ns.79 A combination of high-precision radiosurgery with high-resolution radiography using protons in the Giga-electron-volt energy range may represent a new powerful tool for treating several types of lesions in the next 10 years. In fact, IGSpRS may allow a reduction of target margins and a potential for dose escalation. Online imaging opens the possibility of an aimand-shoot technique, and with relativistic protons, the imaging reaches unprecedented resolution. The different diseases described in the Sec. II B 2 may be excellent candidates for SpRS, and especially IGSpRS if online radiography is used. As noted in the Sec. II B 2, SRS is always considered an attractive alternative to surgery for patients nonresponsive to pharmacological treatments, because it is noninvasive and can be repeated especially if the dose to OARs is kept low as it would be the case for particle beams especially in the Giga-electron-volt regime. One of the main problems is the clear delineation of the target, especially for epilepsy, and the sparing of structures very close to the target, like veins or arteries in trigeminal neuralgia, brainstem in epilepsy, and optical nerve and retina in macular degeneration. In all these cases, IGSpRS may be superior to photon-SRS: using relativistic protons and online radiography, the accuracy can go below that achievable in SRS, and the target visualization was improved. The cost of the high-energy proton facilities is of course very high, and at the moment, it is not realistic to imagine clinical centers; however, trials can be started at several accelerator facilities already in operation where proton radiography is also implemented, such as FAIR in Darmstadt (Germany) and ITEP in Moscow (Russia), or other accelerator centers with these capabilities such as the Brookhaven National Laboratory in USA and CERN in Switzerland. It should be noted that particle therapy always started rst with trials in existing nuclear physics facilities, and only in later stages, the construction of dedicated centers was planned and eventually completed. Moreover, some proton facilities using synchrotrons and those using carbon ions (up to 400 MeV/n) are potentially able to accelerate protons close to 1 GeV and could then quickly translate in patient treatments in the preclinical tests. In silico trials are needed to demonstrate that relativistic protons can have an impact in IGRT.
III.A.2. New ions

FIG. 5. Lateral dose distribution of a 1 GeV proton beam passing through a 30 mm Al target. The beam was accelerated at the NASA Space Radiation Laboratory (Brookhaven National Laboratory, Upton, NY) and the dose measured at different distances from the beam axis using an ionization chamber (Ref. 68). FWHM of the beam extracted in air was 18 mm. Measurements were performed in air at 10 mm from the Al target. Simulations by the Monte Carlo code PHITS courtesy of Dr. Davide Mancusi (CEA Saclay, France). Medical Physics, Vol. 39, No. 4, April 2012

The issue of which particle is optimal for radiotherapy is often debated in oncology. Protons are considered safe because their RBE is similar to x-rays (a value of 1.1 is used in cancer therapy).80 Carbon ions present an optimal plateau/ peak ratio, with a low-LET in the entrance channel to spare the normal tissue, and a relatively high-LET in the

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spread-out Bragg-peak (SOBP) to ensure increased RBE and reduced oxygen enhancement factor (OER) in the target tumor. The use of ions with 2 Z 5 can be interesting since they have reduced lateral scattering compared to protons but lower LET than C-ions. Currently, the Heidelberg Ion Beam Therapy Center (HIT) is preparing the installation of a helium source to allow clinical studies with a helium beam. Ions heavier than carbon can be used for very hypoxic tumors, when the OER should be reduced more. The current investigations toward other projectiles than protons and carbon ions in cancer treatment will also apply to the choice of optimal ions in noncancer diseases. As noted above, He-ions were already used in Berkeley for AVM.25,27 In a recent meta-analysis of dose-volume histograms in treatment of AVM, using a binomial model for the number of crucial blood vessels in AVM, Andisheh et al.81 concluded that particle radiosurgery generates better dose gradients than x-rays and that for large AVM (> 10 ml) ions heavier than helium should provide higher obliteration rates than light ions. Having the exibility of choosing among different ions sources will greatly improve the degrees of freedom of the medical physicists in selecting the best possible treatment: lighter ions cover the dose more uniformly avoiding any possible cold spot in the target, but heavier ions have reduced lateral scattering and improved radiobiological properties on the Bragg peak.82
III.B. SBpRT

With the exception of AVM, only in very few cases that charged particles have been used for treating noncancer lesions (Sec. II B 1). The new particle therapy centers are, however, already considering these pathologies and preparing dedicated treatment rooms. A treatment room completely dedicated to radiosurgery has been installed in the new Gunma University Heavy Ion Medical Center in Japan,83 where carbon ions will be used to treat different venous malformations and macular degeneration in the coming 10 years. As noted above, the favorable depth-dose distribution for Bragg-peak radiosurgery and the margin reduction expected with non-Bragg-peak proton radiosurgery (IGSpRS) may provide substantial benet in several clinical cases. In silico trials should be pursued to isolate cases where advantages are clear. As SBpRT has become a reality in cancer treatment, thanks to 4D imaging, improved treatment planning, and image guidance, SBpRT may also represent a major breakthrough in radiotherapy of noncancerous lesions in the next decade. In the following, we describe the potential of SBpRT on the example of atrial brillation and renal denervation. Since both are subject to organ motion, a dedicated section on motion management will follow that is especially required for scanned beams that provide maximal conformation.
III.B.1. Atrial fibrillation

Cardiac arrhythmia is a common heart disease (prevalence 0.4%1% in the general population with an increase
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by age, leading to 4.5 million patients in the EU),84 which can predispose to life-threatening stroke and embolism. The treatment of many cardiac arrhythmias is moving from a strategy of suppression by antiarrhythmic drugs, which does not improve the situation for many patients, to one of potential cure by destroying the arrhythmogenic substrate. Ablation is normally performed by microwaves produced by a exible catheter introduced uoroscopy guided in a large blood vessel and moved in direct contact with the heart (catheter ablation).85 While the success rate is >90% for some diseases causing arrhythmias, such as the Wolff-Parkinson-White syndrome or the atrial utter, for atrial brillation, the success rate of a single catheter ablation drops below 30%, requiring multiple invasive interventions.86 This seems to be caused by atrial remodeling, especially in patients over 50 years old, which makes the heart poorly susceptible to ablation. SBRT, as noninvasive method, could provide signicant advantages.87 A recent experimental study in a swine model has proven that Cyberknife (there called Cyberheart) can produce cavotricuspid isthmus block, AV nodal block, and signicant decreased voltage at the pulmonary veinleft atrial junction with no early pathological changes in the surrounding tissue.88 However, cavotricuspid isthmus block was achieved only in two out of eight animals, and the electrophysiological endpoint was delayed and may not be clinically relevant. These results form the basis for clinical studies on the treatment of cardiac arrhythmias with radiotherapy. Can charged particles provide better results than the Cyberheart in control of atrial brillation? Heavy ions may allow a large increase in the dose delivered to a small area with sparing of the normal tissue. The biological effectiveness of heavy ions for the target cells can be high and may overcome resistance induced by atrial remodeling and reduce the latency time observed with photons. Particle body radiosurgery has therefore the potential of providing an alternative, noninvasive management to atrial brillation. This hypothesis is under study in Japan and Germany (Fig. 6). Nontransmural myocardial infarction was induced in rabbits by microsphere injection into the coronary arteries, and the heart was irradiated with 15 Gy C-ions 2 weeks after the infarction.89 Highenergy heavy ions induce upregulation of connexin43 (Cx43) expression in association with an improvement of conduction, a decrease of the spatial inhomogeneity of repolarization, a reduction of vulnerability to ventricular arrhythmias after myocardial infarction, and no late radiation injury up to 1 year after the treatment.90 These results are striking because gap junction remodeling creates arrhythmogenic substrates by modulating the propagation of excitation, and gap junctions in the human heart are mostly made with Cx43. Radiation-induced Cx43 upregulation in hearts after myocardial infarction can therefore represent an approach in the treatment of arrhythmias. A number of experimental studies should be completed on the response of cardiac cells to high-LET radiation to fully exploit the potential of heavy ions and to propose treatment plans using a biological equivalent ion dose.91 Ion treatment of brillations is therefore very promising.

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FIG. 6. IMRT plan for treatment of atrial brillation by photon beam therapy produced within a feasibility planning study. (a) and (b) show each seven coplanar beams that are used to treat the left pulmonary vein (LPV) and the right pulmonary vein (RPV), respectively. Apart from the beam portals and the target contour each gure contains isodose lines for 9 Gy (light blue), 15 Gy (magenta), and 25 Gy (yellow) and the contours of various organs at risk [OAR, bronchial tree in blue, esophagus in green, spinal cord in light blue, left coronary artery (LCA) in magenta]. A 3D overview of the irradiation geometry is provided in (c) with both target volumes indicated in red, the 25 Gy isodose in yellow, and in OARs in the colors indicated above. Dose-volume histograms are shown in (d) for IMRT (~) and 3D conformal (n) treatment delivery options. Images courtesy of Dr. O. Blanck (UKSH Lubeck, Germany).

However, for cardiac ablation, it will be necessary to reach a 5D treatment, i.e., compensation is necessary for both patients breathing and heartbeat: three spatial coordinates two time coordinates. This problem will be discussed in the Sec. III B 3.

III.B.2. Renal denervation

In principle, with the treatment of extracranial lesions, SBpRT may be competitive to catheter ablation in different applications. Another example is renal denervation in patients with treatment-resistant hypertension. Severe, resistant hypertension that is uncontrolled despite patients taking antihypertensive medications is a big unmet clinical need, with those affected being at increased risk of stroke and renal failure. Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension and lie within and immediately adjacent to the wall of the renal artery. The concept of denervation of the renal sympathetic nerve to try to reduce blood pressure is old and was attempted by surgery some years ago but abandoned because of perioperative and long-term side effects. Recently, however, it has been shown that renal sympathetic nerves can be accessed by a catheter inserted in the femoral artery and the nerves ablated by radiofrequency.92 A recent clinical trial has shown that 84% of the patients had a >10 mm Hg drop in systolic pressure, compared to 34% in the control group.93 Kidney function was not altered, and the blood pressure reduction is sustained over 2 years from the treatment.94 Despite the success of the method, there is a 16% of nonresponders, without clinical predictors for the success. Also, in this case, SBpRT may represent an interestMedical Physics, Vol. 39, No. 4, April 2012

ing alternative. Some patients are not eligible for catheter ablation, based on the anatomy of the kidney arteries (examined by angiography). Transcatheters target 45 sites at each renal sympathetic nerve, which would be the targets for radiosurgery. The dose necessary for the radiotherapeutical denervation is unknown. The experience with stereotactic radiotherapy in trigeminal neuralgia (Sec. II B 2) can be translated to the sympathetic nerve. Further indications on the peripheral nerve tolerance doses can be obtained by the incidence of brachial plexopathy95 following radiotherapy, especially for breast cancer. Plexopathy is generally a late effect, which is observed after a few months from the treatment. The tolerance dose is about 60 Gy, but it is markedly reduced by hypofractionation,96 suggesting that hypofractionated SBpRT can be exquisitely effective in denervation. Treatment of the kidney requires careful management of the respiratory motion: motion amplitudes up to 40 mm have been reported.97 Detailed thoughts are given in Sec. III B 3.

III.B.3. 4D- and 5D-treatment plans for particle body radiotherapy

The predominant cause of motion in SBpRT is respiration that affects both of the chosen example sites, i.e., heart and kidney. Management of respiratory motion in scanned particle beam therapy including the vision for the next years have previously been addressed with respect to cancer therapy.15,98 Treatment of patients with respiration inuences tumors has already been started for proton as well as carbon beam therapy using abdominal compression (HIT, Germany) and apnea (RPTC Munich).60 Treatment with gating at HIT can be expected by early 2012 and NIRS as well as PSI will

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FIG. 7. The combined 5D motion of heart beat and respiration requires different treatment concepts. In principle, for each of the two motion dimensions, one of the motion mitigation techniques that were proposed for respiratory motion (margins, rescanning, gating, beam tracking) has to be used. Depending on the chosen combination treatment efciency and target volume conformation will change.

treat tumors with rescanning (in combination with gating at NIRS) in the next years. The techniques used for treatment of moving tumors will also be appropriate to treat noncancerous lesions like renal denervation. In this specic example, the most natural way to irradiate the kidney, especially for a low number of beam positions as required for ablation treatment of renal denervation, should be a gated irradiation as shown in Fig. 2 for a lung tumor.99 Motion monitoring could either be achieved by one of the established motion detection systems (e.g., ANZAI belt, VARIAN RPM, and Cyberknife Synchrony correlation model) but kidney motion is also detectable via ultrasound,97 which would provide internal motion rather than a surrogate. NIRS in Japan performs treatment of renal cell carcinoma with a passively scattered carbon beam since 1997.100 They use gating based on the skin motion as surrogate to suppress the impact of respiratory motion. Patient positioning is performed via uoroscopy using implanted iridium needles. For other sites rescanning, beam tracking or combinations motion mitigation techniques will be appropriate. In general, also for noncancer lesions, the concluding remarks of Rietzel and Bert98 are valid, i.e., patients will be classied according to their motion characteristics and treated with a single or combinations of the established motion mitigation techniques. For treatment of cardiac lesions, respiration and heart beat have to be compensated. In the Cyberheart study in swines,88 beam tracking was used to compensate respiratory motion. Heart motion was incorporated by margins. This mode of operation is in principle available today for all treatment options that can cope with respiratory motion, including heavy-ion therapy that is indeed used to treat cardiac angiosarcomas.101 In order to exploit the full potential of SBpRT, more conformal treatment options would be preferred. This is possible by considering the motion of heart and respiration independently (Fig. 7) resulting into a 5D treatment scheme. For each of the two motions, one of the previously mentioned techniques can be used resulting in treatment combinations such as respiratory gating combined with cardiac gating or double beam tracking based on cardiac as well as respiratory motion. However, specic
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improvements are needed to address the 5D treatment workow. Changes are not only required in the treatment delivery modules but also toward imaging, treatment planning, patient positioning, and quality assurance. Details will once more depend on the specic site and the facility used for treatment delivery. For atrial brillation as the example, catheter ablation requires a few hundred ablation points, which should correspond to one Bragg-peak position each. In cyclotron based treatments with passive energy degradation like at PSI, scanning of 100 points would take less than 10 s even if each point requires a different energy since energy changes are feasibly in 80 ms.102 Treatments could then be delivered based on a respiratory gated cardiac 4DCT with the appropriate deformation maps and 4D (cardiac) treatment planning for beam tracking resulting in transformation parameters for each beam position with respect to the cardiac reference phase.103,104 Motion surrogates for beam delivery would be identical to CT imaging, e.g., chest wall motion plus ECG triggering. These systems could also be used for cardiac respiratory gated setup using orthogonal x-ray imaging of a potentially clipped target. Quality assurance will be an important but challenging topic. But also the results and methods that are currently translated into clinical use for 4D therapy of respiratory moving tumors can be used. For example, various groups develop motion phantoms that can be used for plan verication 105107 but also 4DPET can be an option for proton as well as carbon beams. Initial phantom studies were successful,108 and translation to clinical routine is currently performed for treatment of hepatocellular cancer patients at HIT. IV. CONCLUSIONS In the coming 10 years, particle therapy centers should be able to treat several noncancer diseases and to provide an effective stereotactic radiosurgery, provided that research studies ongoing and planned will give positive results. Research accelerator facilities should be used for testing the applications of new ions and very high-energy ($GeV) protons, also very promising for their potential in simultaneous radiography (image-guided stereotactic particle radiosurgery).

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Particle body radiosurgery may have breakthrough applications where currently invasive catheter ablation techniques are needed, e.g., atrial brillation or renal sympathetic denervation. A 5D treatment planning system should be developed and tested in animal models. The RBE of the charged particles must be studied in the tissue of interest at high doses. Options for Bragg-peak or relativistic plateau proton-radiosurgery should be considered in the debate about cost/benet ratio currently ongoing about the construction of new acceleratorbased therapy facilities. In silico trials (including Bragg-peak protons, plateau protons, heavier ions with 2 Z 8, and of course x-rays or c-rays) should be pursued for these different diseases to highlight possible cases where charged particles may provide a clear clinical advantage. Preclinical radiobiology studies should then corroborate the treatment plan predictions, and nally clinical trials can be planned.

ACKNOWLEDGMENT Research on particle therapy at GSI is partly supported by SIEMENS AG and EU FP7 project ULICE and ENVISION.
a)

Electronic address: m.durante@gsi.de M. Durante and J. S. Loefer, Charged particles in radiation oncology, Nat. Rev. Clin. Oncol. 7, 3743 (2010). 2 A. R. Smith, Vision 20/20: proton therapy, Med. Phys. 36, 556568 (2009). 3 O. Jakel, C. P. Karger, and J. Debus, The future of heavy ion radio therapy, Med. Phys. 35, 56535663 (2008). 4 D. Schulz-Ertner and H. Tsujii, Particle radiation therapy using proton and heavier ion beams, J. Clin. Oncol. 25, 953964 (2007). 5 D. Schardt, T. Elsasser, and D. Schulz-Ertner, Heavy-ion tumor therapy: Physical and radiobiological benets, Rev. Mod. Phys. 82, 383425 (2010). 6 T. E. Merchant, Proton beam therapy in pediatric oncology, Cancer J. 15, 298305 (2009). 7 W. D. Newhauser, and M. Durante, Assessing the risk of second malignancies after modern radiotherapy, Nat. Rev. Cancer 11, 438448 (2011). 8 T. Terasawa, T. Dvorak, S. Ip, G. Raman, J. Lau, and T. A. Trikalinos, Systematic review: Charged particle therapy for cancer, Ann. Intern. Med. 151, 556565 (2009). 9 E. C. Halperin, Particle therapy and treatment of cancer, Lancet Oncol. 7, 676685 (2006). 10 Particle Therapy Co-Operative group homepage. http://ptcog.web.psi.ch 11 P. Pommier, Y. Lievens, F. Feschet, J. M. Borras, M. H. Baron, A. Shtiliyanova, and M. Pijls-Johannesma, Simulating demand for innovative radiotherapies: An illustrative model based on carbon ion and proton radiotherapy, Radiother. Oncol. 96, 243249 (2010). 12 M. Brada, M. Pijls-Johannesma, and D. De Ruysscher, Current clinical evidence for proton therapy, Cancer J. 15, 319324 (2009). 13 D. Benedict, F. J. Bova, B. Clark, S. J. Goetsch, W. H. Hinson, D. D. Leavitt, D. J. Schlesinger, and K. M. Yenice, Anniversary paper: The role of medical physicists in developing stereotactic radiation therapy, Med. Phys. 35, 42624277 (2008). 14 S. Dietrich, K. Cleary, W. DSouza, M. Murphy, K. H. Wong, and P. Keall, Locating and targeting moving tumors with radiation beams, Med. Phys. 35, 56845691 (2008). 15 C. Bert, and M. Durante, Motion in radiotherapy: particle therapy, Phys. Med. Biol. 56, R113R144 (2011). 16 H. Suit, H. Krooy, A. Tromov, J. Farr, J. Munzenrider, T. DeLaney, J. S. Loefer, B. Clasie, S. Safai, and H. Paganetti, Should positive phase III clinical trial data be required before proton beam therapy is more widely adopted? No, Radiother. Oncol. 86, 148153 (2008). 17 H. Suit, T. DeLaney, S. Goldberg, H. Paganetti, B. Clasie, L. Germeck, A. Niemerko, E. Hall, J. Flanz, J. Hallman, and A. Tromov, Proton vs.
1

carbon ion beams in the denitive radiation treatment of cancer patients, Radiother. Oncol. 95, 322 (2010). 18 B. Larsson, L. Leksell, B. Rexed, P. Sourander, W. Mair, and B. Andersson, The high-energy proton beam as a neurosurgical tool, Nature 182, 12221223 (1958). 19 L. Leksell, Radiosurgery, Neurosurgery 24, 297298 (1989). 20 J. D. Fenwick, W. A. Tome, E. T. Soisson, M. P. Mehta, and T. Rock Mackie, Tomotherapy and other innovative IMRT delivery systems, Semin. Radiat. Oncol. 16, 199208 (2006). 21 R. N. Kjellberg, T. Hanamura, K. R. Davis, S. L. Lyons, and R. D. Adams, Bragg-peak proton-beam therapy for arteriovenous malformations of the brain, N. Engl. J. Med. 30, 269274 (1983). 22 V. Seifert, D. Stolke, H. M. Mehdorn, and B. Hoffmann, Clinical and radiological evaluation of long-term results of stereotactic proton beam radiosurgery in patients with cerebral arteriovenous malformations, J. Neurosurg. 81, 683689 (1994). 23 F. G. Barker II, W. E. Butler, S. Lyons, E. Cascio, C. S. Ogilvy, J. S. Loefer, and P. H. Chapman, Dose-volume prediction of radiation-related complications after proton beam radiosurgery for cerebral arteriovenous malformations, J. Neurosurg. 99, 254263 (2003). 24 C. C. Chen, P. Chapman, J. Petit, and J. S. Loefer, Proton radiosurgery in neurosurgery, Neurosurg. Focus 23, E5 (2007). 25 R. P. Levy, J. I. Fabrikant, K. A. Frankel, M. H. Phillips, and J. T. Lyman, Stereotactic heavy-charged-particle Bragg peak radiosurgery for the treatment of intracranial arteriovenous malformations in childhood and adolescence, Neurosurgery 24, 841852 (1989). 26 H. Silander, L. Pellettieri, P. Enblad, A. Montelius, E. Grusell, C. Vallhagen-Dahlgren, U. Isacsson, G. Nyberg, U. Mostrom, A. Lilja, G. Gal, and E. Blomquist, Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations, Acta Neurol. Scand. 109, 8590 (2004). 27 G. K. Steinberg, J. I. Fabrikant, M. P. Marks, R. P. Levy, K. A. Frankel, M. H. Phillips, L. M. Shuer, and G. D. Silverberg, Stereotactic heavycharged-particle Bragg-peak radiation for intracranial arteriovenous malformations, N. Engl. J. Med. 323, 96101 (1990). 28 F. J. A. I. Vernimmen, J. P. Slabbert, J. A. Wilson, S. Fredericks, and R. Melvill, Stereotactic proton beam therapy for intracranial arterovenous malformations, Int. J. Radiat. Oncol., Biol., Phys. 62, 4452 (2005). 29 B. C. Lopez, P. J. Hamlyn, and J. M. Zakrzewska, Stereotactic radiosurgery for primary trigeminal neuralgia: State of the evidence and recommendations for future reports, J. Neurol. Neurosurg. Psychiatry 75, 10191024 (2004). 30 M. Quigg and N. M. Barbaro, Stereotactic radiosurgery for treatment of epilepsy, Arch Neurol. 65, 177183 (2008). 31 B. W. Chong, Current issues in endovascular surgical neuroradiology, Semin. Neurol. 27, 385392 (2007). 32 J. Hanlon, C. Lee, E. Chell, M. Gertner, S. Hansen, R. W. Howell, and W. E. Bolch, Kilovoltage stereotactic radiosurgery for age-related macular degeneration: Assessment of optic nerve dose and patient effective dose, Med. Phys. 36, 36713681 (2009). 33 K. Tipton, J. H. Launders, R. Inamdar, C. Miyamoto, and K. Schoelles, Stereotactic body radiation therapy: Scope of the literature, Ann. Intern. Med. 154, 737745 (2011). 34 J. M. Zakrzewska and M. E. Linskey, Trigeminal neuralgia, Clin. Evid. 12, 1207 (2009). 35 G. C. Jones, A. L. Elaimy, J. J. Demakas, H. Jiang, W. T. Lamoreaux, R. K. Fairbanks, A. R. Mackay, B. S. Cooke, and C. M. Lee, Feasibility of multiple repeat gamma knife radiosurgeries for trigeminal neuralgia: A case report and review of the literature, Case Report Med. 2011, 258910 (2011). 36 A. C. Aubuchon, M. D. Chan, J. F. Lovato, C. J. Balamucki, T. L. Ellis, S. B. Tatter, K. P. McMullen, M. T. Munley, A. F. Deguzman, K. E. Ekstrand, J. D. Bourland, and E. G. Shaw, Repeat gamma knife radiosurgery for trigeminal neuralgia, Int. J. Radiat. Oncol., Biol., Phys. 81, 10591065 (2011). 37 T. H. Schwarz, Predicting the unpredictable: Stereotactic radiosurgery and temporal lobe epilepsy, Epilepsy Curr. 10, 150152 (2010). 38 E. F. Chang, M. Quigg, M. C. Oh, W. P. Dillon, M. M. Ward, K. D. Laxer, D. K. Broshek, and N. M. Barbaro; Epilepsy Radiosurgery Study Group, Predictors of efcacy after stereotactic radiosurgery for medial temporal lobe epilepsy, Neurology 74, 165172 (2010).

Medical Physics, Vol. 39, No. 4, April 2012

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Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer diseases

60

1726

A. Yuan and P. K. Kaiser, Emerging therapies for the treatment of neovascular age related macular degeneration, Semin. Ophthalmol. 26, 149155 (2011). 40 R. Petrarca and T. L. Jackson, Radiation therapy for neovascular agerelated macular degeneration, Clin. Ophthalmol. 5, 5763 (2011). 41 M. Gertner, E. Chell, K. H. Pan, S. Hansen, P. K. Kaiser, and D. M. Moshfeghi, Stereotactic targeting and dose verication for age-related macular degeneration, Med. Phys. 37, 600606 (2010). 42 H. J. Zambarakji, A. M. Lane, E. Ezra, D. Gauthier, M. Goitein, J. A. Adams, J. E. Munzenrider, J. W. Miller, and E. S. Gragoudas, Proton beam irradiation for neovascular age-related macular degeneration, Ophthalmology 113, 20122019 (2006). 43 S. M. Hahn and A. Maity, General principles of radiation and chemoradiation, Retina 29, S30S31 (2009). 44 K. V. Chalam, S. Balaiya, R. S. Malyappa, W. Hsi, V. S. Brar, and R. K. Murthy, Evaluation of choroidal endothelial cell proliferation after exposure to varying doses of proton beam radiation, Retina 31, 169176 (2011) 45 T. Miyamoto, M. Baba, T. Sugane, M. Nakajima, T. Yashiro, K. Kagei, N. Hirasawa, T. Sugawara, N. Yamamoto, M. Koto, H. Ezawa, K. Kadono, H. Tsujii, J. E. Mizoe, K. Yoshikawa, S. Kandatsu, and T. Fujisawa; Working Group for Lung Cancer, Carbon ion radiotherapy for stage I non-small cell lung cancer using a regimen of four fractions during 1 week, J. Thorac. Oncol. 2, 916926 (2007). 46 Z. Liao, S. H. Lin, and J. D. Cox, Status of particle therapy for lung cancer, Acta Oncol. 50, 745756 (2011). 47 T. Chiba, K. Tokuuye, Y. Matsuzaki, S. Sugahara, Y. Chuganji, K. Kagei, J. Shoda, M. Hata, M. Abei, H. Igaki, N. Tanaka, and Y. Akine, Proton beam therapy for hepatocellular carcinoma: A retrospective review of 162 patients, Clin. Cancer Res. 11, 37993805 (2005). 48 H. Kato, H. Tsujii, T. Miyamoto, J. E. Mizoe, T. Kamada, H. Tsuji, S. Yamada, S. Kandatsu, K. Yoshikawa, T. Obata, H. Ezawa, S. Morita, M. Tomizawa, N. Morimoto, J. Fujita, and M. Ohto; Liver Cancer Working Group, Results of the rst prospective study of carbon ion radiotherapy for hepatocellular carcinoma with liver cirrhosis, Int. J. Radiat. Oncol., Biol., Phys. 59, 14681476 (2004). 49 T. Okada, T. Kamada, H. Tsuji, J. E. Mizoe, M. Baba, S. Kato, S. Yamada, S. Sugahara, S. Yasuda, N. Yamamoto, R. Imai, A. Hasegawa, H. Imada, H. Kiyohara, K. Jingu, M. Shinoto, and H. Tsujii, Carbon ion radiotherapy: Clinical experiences at National Institute of Radiological Science (NIRS), J. Radiat. Res. 51, 355364 (2010). 50 S. Mori, G. T. Chen, and M. Endo, Effects of intrafractional motion on water equivalent path length in respiratory gated heavy charged particle beam radiotherapy, Int. J. Radiat. Oncol., Biol., Phys. 69, 308317 (2007). 51 H. Tsuji, T. Yanagi, H. Ishikawa, T. Kamada, J. E. Mizoe, T. Kanai, S. Morita, and H. Tsujii; Working Group for Genitourinary Tumors, Hypofractionated radiotherapy with carbon ion beams for prostate cancer, Int. J. Radiat. Oncol., Biol., Phys. 63, 11531160 (2005). 52 D. A. Bush, J. D. Slater, B. B. Shin, G. Cheek, D. W. Miller, and J. M. Slater, Hypofractionated proton beam radiotherapy for stage I lung cancer, Chest 126, 11981203 (2004). 53 T. Miyamoto, N. Yamamoto, H. Nishimura, M. Koto, H. Tsujii, J. E. Mizoe, T. Kamada, H. Kato, S. Yamada, S. Morita, K. Yoshikawa, S. Kandatsu, and T. Fujisawa, Carbon ion radiotherapy for stage I nonsmall cell lung cancer, Radiother. Oncol. 66, 127140 (2003). 54 R. J. Smeenk, B. S. Teh, E. B. Butler, E. N. van Lin, and J. H. Kaanders, Is there a role for endorectal balloons in prostate radiotherapy? A systematic review, Radiother. Oncol. 95, 277282 (2010). 55 M. Urie, M. Goitein, and M. Wagner, Compensating for heterogeneities in proton radiation therapy, Phys. Med. Biol. 29, 553566 (1984). 56 M. Koto, T. Miyamoto, N. Yamamoto, H. Nishimura, S. Yamada, and H. Tsujii, Local control and recurrence of stage I non-small cell lung cancer after carbon ion radiotherapy, Radiother. Oncol. 71, 147156 (2004). 57 S. Minohara, T. Kanai, M. Endo, K. Noda, and M. Kanazawa, Respiratory gated irradiation system for heavy-ion radiotherapy, Int. J. Radiat. Oncol., Biol., Phys. 47, 10971103 (2000). 58 M. H. Phillips, E. Pedroni, H. Blattmann, T. Boehringer, A. Coray, and S. Scheib, Effects of respiratory motion on dose uniformity with a charged particle scanning method, Phys. Med. Biol. 37, 223233 (1992). 59 C. Bert, S. O. Grozinger, and E. Rietzel, Quantication of interplay effects of scanned particle beams and moving targets, Phys. Med. Biol. 53, 22532265 (2008). Medical Physics, Vol. 39, No. 4, April 2012

M. Eckermann, Scanning proton beam radiotherapy under functional apnea, PTCOG 50 2011 (presentation and abstract). 61 C. Bert, A. Gemmel, N. Saito, N. Chaudhri, D. Schardt, M. Durante, G. Kraft, and E. Rietzel, Dosimetric precision of an ion beam tracking system, Radiat. Oncol. 5, 61 (2010). 62 N. Saito, C. Bert, N. Chaudhri, A. Gemmel, D. Schardt, M. Durante, and E. Rietzel, Speed and accuracy of a beam tracking system for treatment of moving targets with scanned ion beams, Phys. Med. Biol. 54, 48494862 (2009). 63 D. Clery, The next big beam?, Science 327, 142143 (2010). 64 G. Kraft and S. D. Kraft, Research needed for improving heavy-ion therapy, New J. Phys. 11, 025001 (2009). 65 S. M. Vatnitsky, D. W. Miller, M. F. Moyers, R. P. Levy, R. W. Schulte, J. D. Slater, and J. M. Slater, Dosimetry techniques for narrow proton beam radiosurgery, Phys. Med. Biol. 44, 27892801 (1999). 66 J. M. Schippers and A. J. Lomax, Emerging technologies in proton therapy, Acta Oncol. 50, 838850 (2011). 67 N. K. Abrosimov, Y. A. Gavrikov, E. M. Ivanov, D. L. Karlin, A. V. Khanzadeev, N. N. Yalynych, G. A. Riabov, D. M. Seliverstov, and V. M. Vinogradov, 1000 MeV proton therapy facility at Petersburg Nuclear Physics Institute Synchrocyclotron, J. Phys. 41, 424432 (2006). 68 A. Bertucci, M. Durante, G. Gialanella, G. F. Grossi, L. Manti, M. Pugliese, P. Scampoli, D. Mancusi, L. Sihver, and A. Rusek A., Shielding of relativistic protons, Radiat. Environ. Biophys. 46, 107111 (2007). 69 H. Yang, N. Magpayo, and K. D. Held, Targeted and non-targeted effects from combination of low doses of energetic protons and iron ions in human broblasts, Int. J. Radiat. Biol. 87, 311319 (2011). 70 M. Durante and F. A. Cucinotta, Heavy ion carcinogenesis and human space exploration, Nat. Rev. Cancer 8, 465472 (2008). 71 M. Durante and F. A. Cucinotta, Physical basis of radiation protection in space travel, Rev. Mod. Phys. 83, 12451281 (2011). 72 A. Niranjan and J. C. Flickinger, Radiobiology, principle and technique of radiosurgery, Prog. Neurol. Surg. 21, 3242 (2008). 73 A. M. Koehler, Proton radiography, Science 160, 303 (1968). 74 C. A. Tobias, The future of heavy-ion science in biology and medicine, Radiat. Res. 103, 133 (1985). 75 N. Depauw and J. Seco, Sensitivity study of proton radiography and comparison with kV and MV x-ray imaging using GEANT4 Monte Carlo simulations, Phys. Med. Biol. 56, 24072421 (2011). 76 J. Seco and N. Depauw, Proof of principle study of the use of a CMOS active pixel sensor for proton radiography, Med. Phys. 38, 622623 (2011). 77 B. Han, X. G. Xu, and G. T. Chen, Proton radiography and uoroscopy of lung tumors: A Monte Carlo study using patient-specic 4DCT phantoms, Med. Phys. 38, 19031911 (2011). 78 P. A. Rigg, C. L. Schwartz, R. S. Hixson, G. E. Hogan, K. K. Kwiatkowski, F. G. Mariam, M. Marr-Lyon, F. E. Merrill, C. L. Morris, P. Rightly, A. Saunders, and D. Tupa, Proton radiography and accurate density measurements: A window into shock wave processes, Phys. Rev. B 77, 220101 (2008). 79 F. E. Merrill, A. A. Golubev, F. G. Mariam, V. I. Turtikov, and D. Varentsov, Proton microscopy at FAIR, AIP Conf. Proc. 1195, 667670 (2009). 80 H. Paganetti, Interpretation of proton relative biological effectiveness using lesion induction, lesion repair, and cellular dose distribution, Med. Phys. 32, 25482556 (2005). 81 B. Andisheh, A. Brahme, M. A. Bitaraf, P. Mavroidis, and B. K. Lind, Clinical and radiobiological advantages of single-dose stereotactic lightion radiation therapy for large intracranial arteriovenous malformations. Technical note, J. Neurosurg. 111, 919926 (2009). 82 A. Brahme, Recent advances in light ion therapy, Int. J. Radiat. Oncol. Biol. Phys. 58, 203216 (2004). 83 Gunma University Heavy Ion Medical Center webpage. http://heavy-ion. showa.gunma-u.ac.jp/en/index.html 84 V. Fuster, L. E. Ryden, D. S. Cannom, H. J. Crijns, A. B. Curtis, K. A. Ellenbogen, J. L. Halperin, J. Y. Le Heuzey, G. N. Kay, J. E. Lowe, S. B. Olsson, E. N. Prystowsky, J. L. Tamargo, S. Wann, S. C. Smith, Jr., A. K. Jacobs, C. D. Adams, J. L. Anderson, E. M. Antman, J. L. Halperin, S. A. Hunt, R. Nishimura, J. P. Ornato, R. L. Page, B. Riegel, S. G. Priori, J. J. Blanc, A. Budaj, A. J. Camm, V. Dean, J. W. Deckers, C. Despres, K. Dickstein, J. Lekakis, K. McGregor, M. Metra, J. Morais, A. Osterspey, J. L. Tamargo, and J. L. Zamorano; American College of Cardiology, American Heart Association Task Force, European Society of Cardiology

1727

Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer diseases

94

1727

Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines for the management of patients with atrial brillation: full text: A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 guidelines for the management of patients with atrial brillation) developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society, Europace 8, 651745 (2006). 85 T. Terasawa, E. M. Balk, M. Chung, A. C. Garlitski, A. A. Alsheikh-Ali, J. Lau, and S. Ip, Systematic review: Comparative effectiveness of radiofrequency catheter ablation for atrial brillation, Ann. Intern. Med. 151,191202 (2009). 86 A. Cheema, C. R. Vasamreddy, D. Dalal, J. E. Marine, J. Dong, C. A. Henrikson, D. Spragg, A. Cheng, S. Nazarian, S. Sinha, H. Halperin, R. Berger, and H. Calkins, Long-term single procedure efcacy of catheter ablation of atrial brillation, J. Interv. Card. Electrophysiol. 15, 145155 (2006). 87 R. M. Sullivan and A. Mazur, Stereotactic robotic radiosurgery (CyberHeart): A cyber revolution in cardiac ablation?, Heart Rhythm. 7, 811812 (2010). 88 A. Sharma, D. Wong, G. Weidlich, T. Fogarty, A. Jack, T. Sumanaweera, and P. Maguire, Noninvasive stereotactic radiosurgery (CyberHeart) for creation of ablation lesions in the atrium, Heart Rhythm. 7, 802810 (2010). 89 M. Amino, K. Yoshioka, T. Tanabe, E. Tanaka, H. Mori, Y. Furusawa, W. Zareba, M. Yamazaki, H. Nakagawa, H. Honjo, K. Yasui, K. Kamiya, and I. Kodama, Heavy ion radition up-regulates Cx43 and ameliorates arrhythmogenic substrates in hearts after myocardial infarction, Cardiovasc. Res. 72, 412421 (2006). 90 M. Amino, K. Yoshioka, D. Fujibayashi, T. Hashida, Y. Furusawa, W. Zareba, Y. Ikari, E. Tanaka, H. Mori, S. Inokuchi, I. Kodama, and T. Tanabe, Year-long upregulation of connexin43 in rabbit hearts by heavy ion irradiation, Am. J. Physiol. Heart. Circ. Physiol. 298, H1014H1021 (2010). 91 T. Elsasser, W. Kraft-Weyrather, T. Friedrich, M. Durante, G. Iancu, M. Kramer, G. Kragl, S. Brons, M. Winter, K. J. Weber, and M. Scholz, Quantication of the relative biological effectiveness for ion beam radiotherapy: Direct experimental comparison of proton and carbon ion beams and a novel approach for treatment planning, Int. J. Radiat. Oncol., Biol., Phys. 78, 11771183 (2010). 92 L. Paulis and T. Unger, Novel therapeutic targets for hypertension, Nat. Rev. Cardiol. 7, 431441 (2010). 93 Symplicity HTN-2 Investigators, Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial, Lancet 376, 19031909 (2010).

Symplicity HTN-1 Investigators, Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months, Hypertension 57, 911917 (2011). 95 E. J. Dropcho, Neurotoxicity of radiation therapy, Neurol. Clin. 28, 217234 (2010). 96 S. Fridberg and B. I. Ruden, Hypofractionation in radiotherapy. An investigation of injured Swedish women, treated for cancer of the breast, Acta Oncol. 48, 822831 (2009). 97 I. Suramo, M. Paivansalo, and V. Myllyla, Cranio-caudal movements of the liver, pancreas and kidneys in respiration, Acta Radiol. Diagn. 25, 129131 (1984). 98 E. Rietzel and C. Bert, Respiratory motion management in particle therapy, Med. Phys. 37, 449460 (2010). 99 C. Bert, A. Gemmel, N. Saito, N. Chaudhri, D. Schardt, M. Durante, G. Kraft, and E. Rietzel, Dosimetric precision of an ion beam tracking system, Radiat Oncol. 5, 61 (2010). 100 T. Nomiya, H. Tsuji, N. Hirasawa, H. Kato, T. Kamada, J. Mizoe, H. Kishi, K. Kamura, H. Wada, K. Nemoto, and H. Tsujii, Carbon ion radiation therapy for primary renal cell carcinoma: initial clinical experience, Int. J. Radiat. Oncol., Biol., Phys. 72, 828833 (2008). 101 Y. Aoka, T. Kamada, M. Kawana, Y. Yamada, T. Nishikawa, H. Kasanuki, and H. Tsujii, Primary cardiac angiosarcoma treated with carbonion radiotherapy, Lancet Oncol. 5, 636638 (2004). 102 S. M. Zenklusen, E. Pedroni, and D. A. Meer, Study on repainting strategies for treating moderately moving targets with proton pencil beam scanning at the new Gantry 2 at PSI, Phys. Med. Biol. 55, 51035121 (2010). 103 C. Bert and E. Rietzel, 4D treatment planning for scanned ion beams, Radiat. Oncol. 2, 24 (2007). 104 R. Luchtenborg, N. Saito, M. Durante, and C. Bert, Experimental verication of a real-time compensation functionality for dose changes due to target motion in scanned particle therapy, Med Phys. 38, 54485458 (2011). 105 Y. Y. Vinogradskiy, P. Balter, D. S. Followill, P. E. Alvarez, R. A. White, and G. Starkschall, Verication of four-dimensional photon dose calculations, Med. Phys. 36, 34383447 (2009). 106 D. S. Followill, D. R. Evans, C. Cherry, A. Molineu, G. Fisher, W. F. Hanson, and G. S. Ibbott, Design, development, and implementation of the radiological physics centers pelvis and thorax anthropomorphic quality assurance phantoms, Med. Phys. 34, 20702076 (2007). 107 J. Biederer and M. Heller, Articial thorax for MR imaging studies in porcine heart-lung preparations, Radiology 226, 250255 (2003). 108 K. Parodi, N. Saito, N. Chaudhri, C. Richter, M. Durante, W. Enghardt, E. Rietzel, and C. Bert, 4D in-beam positron emission tomography for verication of motion-compensated ion beam therapy, Med. Phys. 36, 42304243 (2009).

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