Ions for Non Malignancies

7/29/2019 Ions for Non Malignancies

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Particle therapy for noncancer diseases

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

Rita Engenhart-CabillicPhilipps-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, 64289Darmstadt, 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, specifically

because it is unclear whether the putative clinical advantages justify the high additional costs.

However, particle therapy can find 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/benefit ratio of the accelerator facilities.Future challenges in this field 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

fibrillation and renal denervation) or stereotactic radiation therapy (trigeminal neuralgia, epilepsy,

and macular degeneration). Particle body radiosurgery could be a future key application of

accelerator-based particle therapy facilities in 10 years from today. VC 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 parti-

cle therapy currently planned, proposed, or under construc-

tion, the debate on the cost/benefit ratio is now going beyondthe radiotherapy community and involving the general pub-

lic, with several reports in the press. Therapy with acceler-

ated charged particles exploits protons or heavier ions

(typically carbon) produced by accelerators.15 Current clini-

cal results support the predictions that charged particles are

effective in tumor killing with greater sparing of the normaltissue, including a reduced risk of secondary cancers, which

makes it particularly important for pediatric cancers.6,7 How-

ever, direct clinical trials comparing x- or c-rays to protons

or carbon ions are still lacking,8 and this fuels the contro-

versy on the cost/benefit ratio of ion therapy.

Since the first patient treatments in the Lawrence Berke-

ley 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 pro-

tons, with eight centers currently in operation. Many new

centers have been proposed, but at the moment, only a hand-

ful 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: so-

phisticated model-based economic evaluations, including in

silico clinical trials, are necessary to provide sensible advi-

ces for medical decision-making.11 Independent evidence-

based studies on the cost-effectiveness of the particle therapy

have indeed concluded that the current lack of evidence forbenefit of protons should provide a stimulus for continued

research.12 In this paper, we provide some new research

topics that can potentially boost the benefits of the particle

therapy centers.

One factor that is generally not considered in planning

particle facilities is the possibility of applications in non-

cancer diseases. The charged particle depth-dose distribution

is completely different from x-rays, c-rays, electrons, or neu-

trons. 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 Mis the particle mass,p the momentum and b v/c the relative velocity.5 As a con-

sequence, the Bragg peak can become more and more nar-

row 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

1716 Med. Phys. 39 (4), April 2012 0094-2405/2012/39(4)/1716/12/$30.00 VC 2012 Am. Assoc. Phys. Med. 1716


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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 peakcould be used more successfully for these and other non-

cancer disorders. The number of noncancer diseases eligible

for particle radiosurgery can be drastically increased if mov-

ing organs are considered. Management of organ motion is

indeed a problem both for x-ray14 and particle15 radiother-apy, but recent progress in the field suggest that, in the com-

ing 10 years, the problem may be tackled with sufficient

precision (see Sec. II D).

II. CURRENT STATE OF THE ART

II.A. Ion therapy in oncology

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/benefit ratio compared to conven-

tional x-ray therapy,12 it is currently used even in the ab-

sence 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 differentbiological 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 fractio-

nation scheme and LET.17 In addition to the large set of clin-

ical data already acquired at NIRS (Japan) with C-ions,4

more clinical results on different cancers treated with pro-

tons and carbon ions are coming from the new Heidelberg

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 heav-

ier ions facilities is therefore becoming easier and should

allow tests in noncancer diseases.

II.B. Stereotactic particle radiotherapy andradiosurgery

Considering the favorable dose-depth distribution com-pared to photons, particle therapy in oncology is often eval-

uated 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 Gamma-

knife19 at the Karolinska Institute in Sweden. Latest versions

include the use of special LINACs for pencil beam radiosur-

gery (Cyberknife) and intensity modulated radiation therapy

delivery (Tomotherapy).20 SRS is generally delivered in sin-

gle fractions, while SRT is used for fractionated intracranialtreatments. Energetic charged particles have been used since

many years in the treatment of AVM, but so far, very fewother skull or body lesions have been treated with protons or

heavier ions.

II.B.1. Treatment of AVM

The potential of stereotactic particle radiosurgery (SpRS)

or stereotactic particle radiotherapy (SpRT) was soon recog-nized in neurosurgery. For deep, inoperable AVM, SpRS/T

represents an interesting alternative: when hemodynamic

flow in AVM is different from normal vessels, focal beam

irradiation of the shunting vessels leads to thrombosis andhemostasis, with eventual complete obliteration of the

AVM. Treatment of AVM with protons has been one of the

first noncancer applications of charged particle therapy21 and

is indeed currently performed in several proton therapy cen-

ters.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 fixed 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 isocen-

tric gantry can be used if more angles are needed in the treat-

ment 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, pro-

tons are used for large and irregularly shaped lesions,24

which are very difficult to treat with photons but whoseprognosis is worse than for small AVM. Broadly speaking,

protons seem to be comparable to photons and a better alter-

native for large, irregular lesions. The experience at the pro-

ton 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

(25 ml)

FIG. 1. Depth-dose distribution for high-energy x-rays, protons, and C-ionsat two different energies in tissue. For charged particles, most of the dose isdeposited in the distal region (the Bragg peak), and the beam penetrationdepth can be modified by changing the beam energy (particle velocity). TheBragg peak is broadened both in depth and in the plane for protons com-

pared to carbons, because of their lower mass (courtesy of Dr. Uli Weber,Phillips University Marburg, Germany).

1717 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1717

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


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lesions.27 A recent analysis of 64 patients treated with hypo-

fractionated (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 noncancerdiseases

X- orc-ray SRS or SRT is currently under study for treat-

ing several noncancer diseases in the skull including trigemi-

nal 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 ortic douloureux) has an inci-

dence of 1 in 15 000 people, while macular degenerationaffects 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 Gamma-knife or Cyberknife are generally considered positive,

although randomized clinical trials are generally lacking.33

Trigeminal neuralgia, which is characterized by a tempo-

rary paroxysmal lancinating facial pain, can be treated with

drugs (anticonvulsant or antidepressant) or alternatively with

microvascular decompression, a craniotomy where the sur-

geon 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 trigeminalnerve. 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 surgical-

refractory trigeminal neuralgia. In many cases, SRS is per-formed 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 Gamma-

knife 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 50% of the patients lost >2 lines of vision. Improvements

can be expected if different ions and energies can provide

additional benefit, 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-rayscombined to antiangiogenic drugs in cultures representative

of the target tissue. Cultures of choroid endothelial cells mayrepresent an interesting in vitro model, and survival and pro-

liferation of these cells after exposure to protons has been

recently measured.44

II.C. Stereotactic body radiation therapy

Stereotactic body radiation therapy (SBRT) and stereotac-

tic 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 abdo-

men (e.g., hepatocellular carcinoma47,48), using hypofractio-

nation. 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. Dif-

ferent body immobilization systems are necessary, includingthe 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 defined targets with large dose fractiona-

tion, 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 finally 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 fibrillation. 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 per-

formed 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 dedicateddefinition of the planning target volume to incorporate range

changes caused by organ motion. For scanned particle ther-

apy,15

where the lesion is irradiated in the narrow particleBragg peak of small diameter, the problem is even more

acute due to interference effects of scanned beam and mov-

ing 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 canchange 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 interfieldmotion in intensity modulated particle therapy (IMPT), the

other due to interference between scanning motion and intra-

fractional (or intrafield) organ motion, which is often called

interplay and typically results into underdosage and overdos-

age 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 pas-

sive scattering (e.g., MGH or Loma Linda in USA) or active

scanning (e.g. PSI, Switzerland or HIT, Germany) are used. Inscattered beam treatments, the use of margins is sufficient to

ensure dose coverage of the clinical target volume (CTV) if

the range influence is addressed. For prostate treatments (as

an example for interfractional motion51) as well as lung can-

cer treatments (as an example for intrafractionally moving

organs52), the use of margins is the dominant technique, sup-

plemented by gating in case of large respiratory motion ampli-

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 sup-

pressed by dedicated immobilization, i.e., controlled rectum

and bladder filling by drinking schemes, enemas, or rectal bal-

loons.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 ex-

amination55,56). These changes aim of replacing low-density

lung tissue by high-density tumor tissue to ensure proper tar-

get coverage in all states of the respiratory cycle. For patient

positioning, several centers use fluoroscopy to check consis-

tency 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 sizeof the aperture is large enough and positioning is accu rate to

ensure that the tumor moves within the irradiation field.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

FIG. 2. 4D treatment plan (scanned carbon beam, single field, and absorbeddose) to the GTV of a lung tumor. (a) Planned dose in the reference phase ofthe 4DCT without motion influence. (b) Dose distribution in the presence ofmotion with margins (internal target volume, ITV) as only motion mitiga-tion technique. Interplay of beam scanning and organ motion deteriorateshomogeneity and conformation. (c) Irradiation by beam gating covers the

target as planned. Data were calculated with the 4D version of GSIs plan-ning code TRiP (Ref. 15).




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moving tumors with a scanned beam using apnea under intu-

bation and anesthesia.60 Several groups are working on mitiga-

tion 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 feasi-

ble61,62 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 fixed alternated gradient

field 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 facilitiesworldwide is going to increase rapidly: the reduced cost of

the accelerator may lead to a reduction in the investmentcost 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 benefit (in terms of cure rate

and/or reduction in overall treatment time) compared to con-

ventional radiotherapy units. Since high-energy charged par-

ticles 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 effective-

ness 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 tis-

sues is known for photons, this is not the case for heavier

ions. Moreover, the RBE for the target volume can be differ-

ent from the RBE for the normal tissue surrounding it. This

problem is the major source of uncertainty in heavy-ion can-

cer therapy,5 and dedicated research studies are neededbefore extension to new (noncancerous) diseases.

Apart from these upcoming developments with respect to

particle type, also an increase in particle energy (non-

Bragg-peak or plateau particle radiosurgery65) is foreseen

with applications mainly in SpRS/T. This treatment option

will not only benefit from reduced lateral beam size but alsoallow online proton radiography exploiting the same thera-

peutic beam crossing the patient. The combination of both

physical effects leads to a high precision image-guided ste-

reotactic particle radiosurgery (IGSpRS).

III.A.1. New energies

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 treat-

ment of the lesion on the Bragg peak, but radiosurgery will

still be possible in the plateau region of the Bragg curve

(Fig. 1), as done with Gammaknife or Cyberknife where the

depth-dose deposition pattern is opposite to charged par-

ticles. 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 lat-

eral scattering is indeed largely reduced compared to Bragg-

peak protons when relativistic protons are used (Fig. 3). Of

course, the beam has to be directed from different angles,

cross-firing the target. As yet, only one facility has used

1 GeV protons for therapy: the Petersburg Nuclear Physics

Institute (PNPI) synchrocyclotron in S. Petersburg (Rus-

sia).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, endo-

crine ophthalmopathy, and epilepsy.

SRS with relativistic protons (non-Bragg-peak or plateau

radiosurgery) may be an interesting approach for reducingthe 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 mar-

gins in the PTV. Although 1 GeV protons have a very low-

LET ($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 (evapora-

tion recoils). These nuclear reactions should be carefully

considered in the treatment plan, as they can significantly

modify the physical dose and the biological effectiveness of

the beam.68 Kick-off protons also broaden the lateral dosedistribution 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 flux,71 but very few

FIG. 3. Simulation using the SRIM2011 code of the spatial distribution ofproton beams (directed to the center) passing through 15 cm of water. Eachdot represents the position of a single proton (scales are in centimeter).Clearly, 1 GeV protons (in plateau) have a much higher spatial resolutionthan beams normally used in therapy (on the Bragg peak).




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studies are available in radiotherapy regime (high dose, bio-

logical 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 ra-

diography.72 Proton73 and heavy ion74 radiography in medi-

cine had been proposed many years ago, but the idea wasdropped with the rapid improvements of CT and imaging.

However, proton radiography is nowadays seriously consid-ered as a sensitive tool for online monitoring in proton ther-

apy of lung tumors.75 Detection devices include CMOS

active pixel sensors76 and time-resolved proton range tele-

scopes.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 im-

plosion tests (hydrotest).78 A project for the construction of a

proton microscope (PRIOR) in the new Facility for Antipro-

tons 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 combina-

tion of high-precision radiosurgery with high-resolution radi-

ography 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 aim-

and-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 par-

ticle 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 neural-

gia, 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 imagineclinical centers; however, trials can be started at several ac-

celerator facilities already in operation where proton radiog-

raphy is also implemented, such as FAIR in Darmstadt

(Germany) and ITEP in Moscow (Russia), or other accelera-

tor 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 first withtrials 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

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

FIG. 4. Calculations of the beam shapes FWHM for a monoenergetic inci-dent proton beam in water using Molieres formula or simulated by theMonte Carlo code GEANT4. The Moliere theory is an approximation oftenused to calculate the lateral spread of proton beams used in Bragg peak ther-apy (Ref. 5). The FWHM spread is calculated for beams accelerated at60 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 (plannedfor proton radiography in the future FAIR facility in Germany). Calculationscourtesy by Dr. Marie Vanstalle (GSI, Germany).

FIG. 5. Lateral dose distribution of a 1 GeV proton beam passing through a30 mm Al target. The beam was accelerated at the NASA Space RadiationLaboratory (Brookhaven National Laboratory, Upton, NY) and the dosemeasured at different distances from the beam axis using an ionizationchamber (Ref. 68). FWHM of the beam extracted in air was 18 mm. Meas-urements were performed in air at 10 mm from the Al target. Simulations bythe Monte Carlo code PHITS courtesy of Dr. Davide Mancusi (CEA Saclay,France).




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spread-out Bragg-peak (SOBP) to ensure increased RBE and

reduced oxygen enhancement factor (OER) in the target tu-

mor. 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 he-

lium 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 histo-

grams in treatment of AVM, using a binomial model for

the number of crucial blood vessels in AVM, Andishehet al.81 concluded that particle radiosurgery generates bet-

ter 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 flexibility of

choosing among different ions sources will greatlyimprove 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 scatter-

ing 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 prepar-ing dedicated treatment rooms. A treatment room completely

dedicated to radiosurgery has been installed in the newGunma University Heavy Ion Medical Center in Japan,83

where carbon ions will be used to treat different venous mal-

formations 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 benefit 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, andimage guidance, SBpRT may also represent a major break-through in radiotherapy of noncancerous lesions in the next

decade. In the following, we describe the potential of SBpRT

on the example of atrial fibrillation 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 (preva-

lence 0.4%1% in the general population with an increase

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 poten-

tial cure by destroying the arrhythmogenic substrate. Abla-

tion is normally performed by microwaves produced by a

flexible catheter introduced fluoroscopy 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-Par-

kinson-White syndrome or the atrial flutter, for atrial fibrilla-

tion, 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 sus-

ceptible to ablation. SBRT, as noninvasive method, could

provide significant 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 significant decreased voltage at the pul-monary 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 fibrillation? 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 ionsfor the target cells can be high and may overcome resistance

induced by atrial remodeling and reduce the latency timeobserved with photons. Particle body radiosurgery has there-

fore the potential of providing an alternative, noninvasive

management to atrial fibrillation. This hypothesis is under

study in Japan and Germany (Fig. 6). Nontransmural myo-

cardial infarction was induced in rabbits by microsphere

injection into the coronary arteries, and the heart was irradi-

ated with 15 Gy C-ions 2 weeks after the infarction.89 High-

energy heavy ions induce upregulation of connexin43

(Cx43) expression in association with an improvement of

conduction, a decrease of the spatial inhomogeneity of repo-

larization, a reduction of vulnerability to ventricular arrhyth-

mias 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 experimentalstudies 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 equiv-

alent ion dose.91 Ion treatment of fibrillations is therefore

very promising.




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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 denervationIn 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, resist-

ant 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 hyper-

tension 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 recentclinical 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 interest-

ing alternative. Some patients are not eligible for catheter

ablation, based on the anatomy of the kidney arteries (exam-

ined 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 onthe 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 treat-

ment. The tolerance dose is about 60 Gy, but it is markedly

reduced by hypofractionation,96 suggesting that hypofractio-

nated 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 bodyradiotherapy

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 parti-cle beam therapy including the vision for the next years have

previously been addressed with respect to cancer ther-

apy.15,98 Treatment of patients with respiration influences

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

FIG. 6. IMRT plan for treatment of atrial fibrillation by photon beam therapy produced within a feasibility planning study. (a) and (b) show each seven copla-nar 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 figure contains isodose lines for 9 Gy (light blue), 15 Gy (magenta), and 25 Gy (yellow) and the contours of various organs at risk [OAR, bron-chial 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 providedin (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 shownin (d) for IMRT (~) and 3D conformal (n) treatment delivery options. Images courtesy of Dr. O. Blanck (UKSH Lubeck, Germany).




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treat tumors with rescanning (in combination with gating atNIRS) in the next years.

The techniques used for treatment of moving tumors will

also be appropriate to treat noncancerous lesions like renaldenervation. In this specific example, the most natural way

to irradiate the kidney, especially for a low number of beam

positions as required for ablation treatment of renal denerva-

tion, 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 ratherthan 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 surro-

gate to suppress the impact of respiratory motion. Patientpositioning is performed via fluoroscopy 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 classified 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 treat-

ment options that can cope with respiratory motion, includ-

ing 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 pre-ferred. 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 car-

diac as well as respiratory motion. However, specific

improvements are needed to address the 5D treatment work-flow. Changes are not only required in the treatment delivery

modules but also toward imaging, treatment planning,

patient positioning, and quality assurance. Details will oncemore depend on the specific site and the facility used for

treatment delivery. For atrial fibrillation 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 degrada-

tion 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 4DCTwith the appropriate deformation maps and 4D (cardiac)

treatment planning for beam tracking resulting in transfor-

mation parameters for each beam position with respect to the

cardiac reference phase.103,104 Motion surrogates for beamdelivery 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 assur-

ance 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 verification 105107 but also 4DPET

can be an option for proton as well as carbon beams. Initial

phantom studies were successful,108 and translation to clini-

cal routine is currently performed for treatment of hepatocel-

lular cancer patients at HIT.

IV. CONCLUSIONS

In the coming 10 years, particle therapy centers should beable 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) pro-

tons, also very promising for their potential in simultaneous

radiography (image-guided stereotactic particle radiosurgery).

FIG. 7. The combined 5D motion of heart beat and res-piration requires different treatment concepts. In princi-ple, for each of the two motion dimensions, one of themotion mitigation techniques that were proposed for re-

spiratory motion (margins, rescanning, gating, beamtracking) has to be used. Depending on the chosencombination treatment efficiency and target volumeconformation will change.




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Particle body radiosurgery may have breakthrough applica-

tions where currently invasive catheter ablation techniques

are needed, e.g., atrial fibrillation or renal sympathetic dener-

vation. 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/benefit ratio

currently ongoing about the construction of new accelerator-

based therapy facilities. In silico trials (including Bragg-peak

protons, plateau protons, heavier ions with 2 Z 8, and of

course x-rays orc-rays) should be pursued for these different

diseases to highlight possible cases where charged particles

may provide a clear clinical advantage. Preclinical radiobiol-

ogy studies should then corroborate the treatment plan predic-

tions, and finally 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.

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Ions for Non Malignancies

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