7/29/2019 Ions for Non Malignancies
1/12
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
7/29/2019 Ions for Non Malignancies
2/12
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
7/29/2019 Ions for Non Malignancies
3/12
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
1718 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1718
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
4/12
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).
1719 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1719
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
5/12
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).
1720 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1720
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
6/12
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).
1721 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1721
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
7/12
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.
1722 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1722
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
8/12
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).
1723 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1723
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
9/12
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.
1724 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1724
Medical Physics, Vol. 39, No. 4, April 2012
7/29/2019 Ions for Non Malignancies
10/12
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.
a)Electronic address: [email protected]. Durante and J. S. Loeffler, Charged particles in radiation oncology,
Nat. Rev. Clin. Oncol. 7, 3743 (2010).2A. R. Smith, Vision 20/20: proton therapy, Med. Phys. 36, 556568
(2009).3O. Jakel, C. P. Karger, and J. Debus, The future of heavy ion radio-
therapy, Med. Phys. 35, 56535663 (2008).4D. Schulz-Ertner and H. Tsujii, Particle radiation therapy using proton
and heavier ion beams, J. Clin. Oncol. 25, 953964 (2007).5D. Schardt, T. Elsasser, and D. Schulz-Ertner, Heavy-ion tumor therapy:
Physical and radiobiological benefits, Rev. Mod. Phys. 82, 383425(2010).
6
T. E. Merchant, Proton beam therapy in pediatric oncology, Cancer J.15, 298305 (2009).7W. D. Newhauser, and M. Durante, Assessing the risk of second malig-
nancies after modern radiotherapy, Nat. Rev. Cancer 11, 438448(2011).
8T. 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).
9E. C. Halperin, Particle therapy and treatment of cancer, Lancet Oncol.7, 676685 (2006).
10Particle Therapy Co-Operative group homepage. http://ptcog.web.psi.ch11P. Pommier, Y. Lievens, F. Feschet, J. M. Borras, M. H. Baron, A. Shti-
liyanova, and M. Pijls-Johannesma, Simulating demand for innovativeradiotherapies: An illustrative model based on carbon ion and protonradiotherapy, Radiother. Oncol. 96, 243249 (2010).
12M. Brada, M. Pijls-Johannesma, and D. De Ruysscher, Current clinical
evidence for proton therapy, Cancer J.15
, 319324 (2009).13D. Benedict, F. J. Bova, B. Clark, S. J. Goetsch, W. H. Hinson, D. D.Leavitt, D. J. Schlesinger, and K. M. Yenice, Anniversary paper: Therole of medical physicists in developing stereotactic radiation therapy,Med. Phys. 35, 42624277 (2008).
14S. 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).
15C. Bert, and M. Durante, Motion in radiotherapy: particle therapy,Phys. Med. Biol. 56, R113R144 (2011).
16H. Suit, H. Krooy, A. Trofimov, J. Farr, J. Munzenrider, T. DeLaney,J. S. Loeffler, B. Clasie, S. Safai, and H. Paganetti, Should positivephase III clinical trial data be required before proton beam therapy ismore widely adopted? No, Radiother. Oncol. 86, 148153 (2008).
17H. Suit, T. DeLaney, S. Goldberg, H. Paganetti, B. Clasie, L. Germeck,A. Niemerko, E. Hall, J. Flanz, J. Hallman, and A. Trofimov, Proton vs.
carbon ion beams in the definitive radiation treatment of cancer patients,Radiother. Oncol. 95, 322 (2010).
18B. Larsson, L. Leksell, B. Rexed, P. Sourander, W. Mair, and B. Ander-sson, The high-energy proton beam as a neurosurgical tool, Nature 182,12221223 (1958).
19L. Leksell, Radiosurgery, Neurosurgery 24, 297298 (1989).20J. 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).
21R. N. Kjellberg, T. Hanamura, K. R. Davis, S. L. Lyons, and R. D.Adams, Bragg-peak proton-beam therapy for arteriovenous malforma-tions of the brain, N. Engl. J. Med. 30, 269274 (1983).
22V. Seifert, D. Stolke, H. M. Mehdorn, and B. Hoffmann, Clinical and ra-diological evaluation of long-term results of stereotactic proton beamradiosurgery in patients with cerebral arteriovenous malformations,J. Neurosurg. 81, 683689 (1994).
23F. G. Barker II, W. E. Butler, S. Lyons, E. Cascio, C. S. Ogilvy,J. S. Loeffler, and P. H. Chapman, Dose-volume prediction ofradiation-related complications after proton beam radiosurgery forcerebral arteriovenous malformations, J. Neurosurg. 99, 254263(2003).
24C. C. Chen, P. Chapman, J. Petit, and J. S. Loeffler, Proton radiosurgeryin neurosurgery, Neurosurg. Focus 23, E5 (2007).
25R. P. Levy, J. I. Fabrikant, K. A. Frankel, M. H. Phillips, and J. T.Lyman, Stereotactic heavy-charged-particle Bragg peak radiosurgery forthe treatment of intracranial arteriovenous malformations in childhoodand adolescence, Neurosurgery 24, 841852 (1989).
26H. 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 treatmentof cerebral arteriovenous malformations, Acta Neurol. Scand. 109,8590 (2004).
27G. 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 heavy-charged-particle Bragg-peak radiation for intracranial arteriovenousmalformations, N. Engl. J. Med. 323, 96101 (1990).
28F. J. A. I. Vernimmen, J. P. Slabbert, J. A. Wilson, S. Fredericks, andR. Melvill, Stereotactic proton beam therapy for intracranial arterove-nous malformations, Int. J. Radiat. Oncol., Biol., Phys. 62, 4452(2005).
29B. C. Lopez, P. J. Hamlyn, and J. M. Zakrzewska, Stereotactic radiosur-gery for primary trigeminal neuralgia: State of the evidence and recom-mendations for future reports, J. Neurol. Neurosurg. Psychiatry 75,10191024 (2004).
30M. Quigg and N. M. Barbaro, Stereotactic radiosurgery for treatment ofepilepsy, Arch Neurol. 65, 177183 (2008).
31B. W. Chong, Current issues in endovascular surgical neuroradiology,Semin. Neurol. 27, 385392 (2007).
32J. Hanlon, C. Lee, E. Chell, M. Gertner, S. Hansen, R. W. Howell, andW. E. Bolch, Kilovoltage stereotactic radiosurgery for age-related macu-lar degeneration: Assessment of optic nerve dose and patient effectivedose, Med. Phys. 36, 36713681 (2009).
33K. Tipton, J. H. Launders, R. Inamdar, C. Miyamoto, and K. Schoelles,Stereotactic body radiation therapy: Scope of the literature, Ann. In-tern. Med. 154, 737745 (2011).
34J. M. Zakrzewska and M. E. Linskey, Trigeminal neuralgia, Clin. Evid.12, 1207 (2009).
35G. 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 ofmultiple repeat gamma knife radiosurgeries for trigeminal neuralgia: Acase report and review of the literature, Case Report Med. 2011, 258910(2011).
36A. 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 radio-surgery for trigeminal neuralgia, Int. J. Radiat. Oncol., Biol., Phys. 81,10591065 (2011).
37T. H. Schwarz, Predicting the unpredictable: Stereotactic radiosurgeryand temporal lobe epilepsy, Epilepsy Curr. 10, 150152 (2010).
38E. 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 StudyGroup, Predictors of efficacy after stereotactic radiosurgery for medialtemporal lobe epilepsy, Neurology 74, 165172 (2010).
1725 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1725
Medical Physics, Vol. 39, No. 4, April 2012
http://dx.doi.org/10.1038/nrclinonc.2009.183http://dx.doi.org/10.1118/1.3058485http://dx.doi.org/10.1118/1.3002307http://dx.doi.org/10.1200/JCO.2006.09.7816http://dx.doi.org/10.1103/RevModPhys.82.383http://dx.doi.org/10.1097/PPO.0b013e3181b6d4b7http://dx.doi.org/10.1038/nrc3069http://dx.doi.org/10.1016/S1470-2045(06)70795-1http://ptcog.web.psi.ch/http://dx.doi.org/10.1016/j.radonc.2010.04.010http://dx.doi.org/10.1097/PPO.0b013e3181b6127chttp://dx.doi.org/10.1118/1.2969268http://dx.doi.org/10.1118/1.3020593http://dx.doi.org/10.1088/0031-9155/56/16/R01http://dx.doi.org/10.1016/j.radonc.2007.12.024http://dx.doi.org/10.1016/j.radonc.2010.01.015http://dx.doi.org/10.1038/1821222a0http://dx.doi.org/10.1097/00006123-198902000-00026http://dx.doi.org/10.1016/j.semradonc.2006.04.002http://dx.doi.org/10.1056/NEJM198308043090503http://dx.doi.org/10.3171/jns.1994.81.5.0683http://dx.doi.org/10.3171/jns.2003.99.2.0254http://dx.doi.org/10.3171/FOC-07/10/EIntrohttp://dx.doi.org/10.1227/00006123-198906000-00009http://dx.doi.org/10.1046/j.1600-0404.2003.00154.xhttp://dx.doi.org/10.1056/NEJM199007123230205http://dx.doi.org/10.1016/j.ijrobp.2004.09.008http://dx.doi.org/10.1136/jnnp.2003.018564http://dx.doi.org/10.1001/archneurol.2007.40http://dx.doi.org/10.1055/s-2007-985339http://dx.doi.org/10.1118/1.3168554http://dx.doi.org/10.1016/j.ijrobp.2010.07.010http://dx.doi.org/10.1111/epc.2010.10.issue-6http://dx.doi.org/10.1212/WNL.0b013e3181c9185dhttp://dx.doi.org/10.1212/WNL.0b013e3181c9185dhttp://dx.doi.org/10.1111/epc.2010.10.issue-6http://dx.doi.org/10.1016/j.ijrobp.2010.07.010http://dx.doi.org/10.1118/1.3168554http://dx.doi.org/10.1055/s-2007-985339http://dx.doi.org/10.1001/archneurol.2007.40http://dx.doi.org/10.1136/jnnp.2003.018564http://dx.doi.org/10.1016/j.ijrobp.2004.09.008http://dx.doi.org/10.1056/NEJM199007123230205http://dx.doi.org/10.1046/j.1600-0404.2003.00154.xhttp://dx.doi.org/10.1227/00006123-198906000-00009http://dx.doi.org/10.3171/FOC-07/10/EIntrohttp://dx.doi.org/10.3171/jns.2003.99.2.0254http://dx.doi.org/10.3171/jns.1994.81.5.0683http://dx.doi.org/10.1056/NEJM198308043090503http://dx.doi.org/10.1016/j.semradonc.2006.04.002http://dx.doi.org/10.1097/00006123-198902000-00026http://dx.doi.org/10.1038/1821222a0http://dx.doi.org/10.1016/j.radonc.2010.01.015http://dx.doi.org/10.1016/j.radonc.2007.12.024http://dx.doi.org/10.1088/0031-9155/56/16/R01http://dx.doi.org/10.1118/1.3020593http://dx.doi.org/10.1118/1.2969268http://dx.doi.org/10.1097/PPO.0b013e3181b6127chttp://dx.doi.org/10.1016/j.radonc.2010.04.010http://ptcog.web.psi.ch/http://dx.doi.org/10.1016/S1470-2045(06)70795-1http://dx.doi.org/10.1038/nrc3069http://dx.doi.org/10.1097/PPO.0b013e3181b6d4b7http://dx.doi.org/10.1103/RevModPhys.82.383http://dx.doi.org/10.1200/JCO.2006.09.7816http://dx.doi.org/10.1118/1.3002307http://dx.doi.org/10.1118/1.3058485http://dx.doi.org/10.1038/nrclinonc.2009.1837/29/2019 Ions for Non Malignancies
11/12
39A. Yuan and P. K. Kaiser, Emerging therapies for the treatment of neo-vascular age related macular degeneration, Semin. Ophthalmol. 26,149155 (2011).
40R. Petrarca and T. L. Jackson, Radiation therapy for neovascular age-related macular degeneration, Clin. Ophthalmol. 5, 5763 (2011).
41M. Gertner, E. Chell, K. H. Pan, S. Hansen, P. K. Kaiser, and D. M.Moshfeghi, Stereotactic targeting and dose verification for age-relatedmacular degeneration, Med. Phys. 37, 600606 (2010).
42H. J. Zambarakji, A. M. Lane, E. Ezra, D. Gauthier, M. Goitein, J. A.Adams, J. E. Munzenrider, J. W. Miller, and E. S. Gragoudas, Protonbeam irradiation for neovascular age-related macular degeneration, Oph-thalmology 113, 20122019 (2006).
43S. M. Hahn and A. Maity, General principles of radiation and chemo-radiation, Retina 29, S30S31 (2009).
44K. V. Chalam, S. Balaiya, R. S. Malyappa, W. Hsi, V. S. Brar, and R. K.Murthy, Evaluation of choroidal endothelial cell proliferation after ex-posure to varying doses of proton beam radiation, Retina 31, 169176(2011)
45T. 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. Fuji-sawa; Working Group for Lung Cancer, Carbon ion radiotherapy forstage I non-small cell lung cancer using a regimen of four fractions dur-ing 1 week, J. Thorac. Oncol. 2, 916926 (2007).
46Z. Liao, S. H. Lin, and J. D. Cox, Status of particle therapy for lung can-cer, Acta Oncol. 50, 745756 (2011).
47T. Chiba, K. Tokuuye, Y. Matsuzaki, S. Sugahara, Y. Chuganji, K. Kagei,J. Shoda, M. Hata, M. Abei, H. Igaki, N. Tanaka, and Y. Akine, Protonbeam therapy for hepatocellular carcinoma: A retrospective review of162 patients, Clin. Cancer Res. 11, 37993805 (2005).
48H. 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 WorkingGroup, Results of the first prospective study of carbon ion radiotherapyfor hepatocellular carcinoma with liver cirrhosis, Int. J. Radiat. Oncol.,Biol., Phys. 59, 14681476 (2004).
49T. 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 ionradiotherapy: Clinical experiences at National Institute of RadiologicalScience (NIRS), J. Radiat. Res. 51, 355364 (2010).
50S. Mori, G. T. Chen, and M. Endo, Effects of intrafractional motion onwater equivalent path length in respiratory gated heavy charged particlebeam radiotherapy, Int. J. Radiat. Oncol., Biol., Phys. 69, 308317(2007).
51H. 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 can-cer, Int. J. Radiat. Oncol., Biol., Phys. 63, 11531160 (2005).
52D. 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 can-cer, Chest 126, 11981203 (2004).
53T. 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 non-small cell lung cancer, Radiother. Oncol. 66, 127140 (2003).
54R. 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 sys-tematic review, Radiother. Oncol. 95, 277282 (2010).
55M. Urie, M. Goitein, and M. Wagner, Compensating for heterogeneitiesin proton radiation therapy, Phys. Med. Biol. 29, 553566 (1984).
56M. Koto, T. Miyamoto, N. Yamamoto, H. Nishimura, S. Yamada, and H.Tsujii, Local control and recurrence of stage I non-small cell lung cancerafter carbon ion radiotherapy, Radiother. Oncol. 71, 147156 (2004).
57S. 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).
58M. H. Phillips, E. Pedroni, H. Blattmann, T. Boehringer, A. Coray, and S.Scheib, Effects of respiratory motion on dose uniformity with a chargedparticle scanning method, Phys. Med. Biol. 37, 223233 (1992).
59C. Bert, S. O. Grozinger, and E. Rietzel, Quantification of interplayeffects of scanned particle beams and moving targets, Phys. Med. Biol.53, 22532265 (2008).
60M. Eckermann, Scanning proton beam radiotherapy under functionalapnea, PTCOG 50 2011 (presentation and abstract).
61C. Bert, A. Gemmel, N. Saito, N. Chaudhri, D. Schardt, M. Durante, G.Kraft, and E. Rietzel, Dosimetric precision of an ion beam trackingsystem, Radiat. Oncol. 5, 61 (2010).
62N. Saito, C. Bert, N. Chaudhri, A. Gemmel, D. Schardt, M. Durante, andE. Rietzel, Speed and accuracy of a beam tracking system for treatmentof moving targets with scanned ion beams, Phys. Med. Biol. 54,48494862 (2009).
63D. Clery, The next big beam?, Science 327, 142143 (2010).64G. Kraft and S. D. Kraft, Research needed for improving heavy-ion
therapy, New J. Phys. 11, 025001 (2009).65S. 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 protonbeam radiosurgery, Phys. Med. Biol. 44, 27892801 (1999).
66J. M. Schippers and A. J. Lomax, Emerging technologies in protontherapy, Acta Oncol. 50, 838850 (2011).
67N. 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 NuclearPhysics Institute Synchrocyclotron, J. Phys. 41, 424432 (2006).
68A. Bertucci, M. Durante, G. Gialanella, G. F. Grossi, L. Manti, M. Pugli-ese, P. Scampoli, D. Mancusi, L. Sihver, and A. Rusek A., Shielding ofrelativistic protons, Radiat. Environ. Biophys. 46, 107111 (2007).
69H. Yang, N. Magpayo, and K. D. Held, Targeted and non-targetedeffects from combination of low doses of energetic protons and iron ionsin human fibroblasts, Int. J. Radiat. Biol. 87, 311319 (2011).
70M. Durante and F. A. Cucinotta, Heavy ion carcinogenesis and humanspace exploration, Nat. Rev. Cancer8, 465472 (2008).
71M. Durante and F. A. Cucinotta, Physical basis of radiation protection inspace travel, Rev. Mod. Phys. 83, 12451281 (2011).
72A. Niranjan and J. C. Flickinger, Radiobiology, principle and techniqueof radiosurgery, Prog. Neurol. Surg. 21, 3242 (2008).
73A. M. Koehler, Proton radiography, Science 160, 303 (1968).74C. A. Tobias, The future of heavy-ion science in biology and medicine,
Radiat. Res. 103, 133 (1985).75N. Depauw and J. Seco, Sensitivity study of proton radiography and
comparison with kV and MV x-ray imaging using GEANT4 Monte Carlosimulations, Phys. Med. Biol. 56, 24072421 (2011).
76J. Seco and N. Depauw, Proof of principle study of the use of a CMOSactive pixel sensor for proton radiography, Med. Phys. 38, 622623(2011).
77B. Han, X. G. Xu, and G. T. Chen, Proton radiography and fluoroscopyof lung tumors: A Monte Carlo study using patient-specific 4DCTphantoms, Med. Phys. 38, 19031911 (2011).
78P. A. Rigg, C. L. Schwartz, R. S. Hixson, G. E. Hogan, K. K. Kwiatkow-ski, F. G. Mariam, M. Marr-Lyon, F. E. Merrill, C. L. Morris, P. Rightly,A. Saunders, and D. Tupa, Proton radiography and accurate densitymeasurements: A window into shock wave processes, Phys. Rev. B 77,220101 (2008).
79F. E. Merrill, A. A. Golubev, F. G. Mariam, V. I. Turtikov, and D. Var-entsov, Proton microscopy at FAIR, AIP Conf. Proc. 1195, 667670(2009).
80H. Paganetti, Interpretation of proton relative biological effectivenessusing lesion induction, lesion repair, and cellular dose distribution, Med.Phys. 32, 25482556 (2005).
81B. Andisheh, A. Brahme, M. A. Bitaraf, P. Mavroidis, and B. K. Lind,Clinical and radiobiological advantages of single-dose stereotactic light-ion radiation therapy for large intracranial arteriovenous malformations.Technical note, J. Neurosurg. 111, 919926 (2009).
82A. Brahme, Recent advances in light ion therapy, Int. J. Radiat. Oncol.Biol. Phys. 58, 203216 (2004).
83Gunma University Heavy Ion Medical Center webpage. http://heavy-ion.showa.gunma-u.ac.jp/en/index.html
84V. 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
1726 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1726
Medical Physics, Vol. 39, No. 4, April 2012
http://dx.doi.org/10.3109/08820538.2011.570846http://dx.doi.org/10.2147/OPTHhttp://dx.doi.org/10.1118/1.3291648http://dx.doi.org/10.1016/j.ophtha.2006.05.036http://dx.doi.org/10.1016/j.ophtha.2006.05.036http://dx.doi.org/10.1097/IAE.0b013e3181ad2692http://dx.doi.org/10.1097/IAE.0b013e3181dee621http://dx.doi.org/10.1097/JTO.0b013e3181560a68http://dx.doi.org/10.3109/0284186X.2011.590148http://dx.doi.org/10.1158/1078-0432.CCR-04-1350http://dx.doi.org/10.1016/j.ijrobp.2004.01.032http://dx.doi.org/10.1016/j.ijrobp.2004.01.032http://dx.doi.org/10.1269/jrr.10016http://dx.doi.org/10.1016/j.ijrobp.2007.05.018http://dx.doi.org/10.1016/j.ijrobp.2005.04.022http://dx.doi.org/10.1378/chest.126.4.1198http://dx.doi.org/10.1016/S0167-8140(02)00367-5http://dx.doi.org/10.1016/j.radonc.2010.04.016http://dx.doi.org/10.1088/0031-9155/29/5/008http://dx.doi.org/10.1016/j.radonc.2004.02.007http://dx.doi.org/10.1016/S0360-3016(00)00524-1http://dx.doi.org/10.1016/S0360-3016(00)00524-1http://dx.doi.org/10.1088/0031-9155/37/1/016http://dx.doi.org/10.1088/0031-9155/53/9/003http://dx.doi.org/10.1186/1748-717X-5-61http://dx.doi.org/10.1088/0031-9155/54/16/001http://dx.doi.org/10.1126/science.327.5962.142http://dx.doi.org/10.1088/1367-2630/11/2/025001http://dx.doi.org/10.1088/0031-9155/44/11/308http://dx.doi.org/10.3109/0284186X.2011.582513http://dx.doi.org/10.1088/1742-6596/41/1/047http://dx.doi.org/10.1007/s00411-006-0088-6http://dx.doi.org/10.3109/09553002.2010.537431http://dx.doi.org/10.1038/nrc2391http://dx.doi.org/10.1103/RevModPhys.83.1245http://dx.doi.org/10.1159/000156557http://dx.doi.org/10.1126/science.160.3825.303http://dx.doi.org/10.2307/3576668http://dx.doi.org/10.1088/0031-9155/56/8/006http://dx.doi.org/10.1118/1.3496327http://dx.doi.org/10.1118/1.3555039http://dx.doi.org/10.1103/PhysRevB.77.220101http://dx.doi.org/10.1063/1.3295228http://dx.doi.org/10.1118/1.1949807http://dx.doi.org/10.1118/1.1949807http://dx.doi.org/10.3171/2007.10.17205http://heavy-ion.showa.gunma-u.ac.jp/en/index.htmlhttp://heavy-ion.showa.gunma-u.ac.jp/en/index.htmlhttp://heavy-ion.showa.gunma-u.ac.jp/en/index.htmlhttp://heavy-ion.showa.gunma-u.ac.jp/en/index.htmlhttp://dx.doi.org/10.3171/2007.10.17205http://dx.doi.org/10.1118/1.1949807http://dx.doi.org/10.1118/1.1949807http://dx.doi.org/10.1063/1.3295228http://dx.doi.org/10.1103/PhysRevB.77.220101http://dx.doi.org/10.1118/1.3555039http://dx.doi.org/10.1118/1.3496327http://dx.doi.org/10.1088/0031-9155/56/8/006http://dx.doi.org/10.2307/3576668http://dx.doi.org/10.1126/science.160.3825.303http://dx.doi.org/10.1159/000156557http://dx.doi.org/10.1103/RevModPhys.83.1245http://dx.doi.org/10.1038/nrc2391http://dx.doi.org/10.3109/09553002.2010.537431http://dx.doi.org/10.1007/s00411-006-0088-6http://dx.doi.org/10.1088/1742-6596/41/1/047http://dx.doi.org/10.3109/0284186X.2011.582513http://dx.doi.org/10.1088/0031-9155/44/11/308http://dx.doi.org/10.1088/1367-2630/11/2/025001http://dx.doi.org/10.1126/science.327.5962.142http://dx.doi.org/10.1088/0031-9155/54/16/001http://dx.doi.org/10.1186/1748-717X-5-61http://dx.doi.org/10.1088/0031-9155/53/9/003http://dx.doi.org/10.1088/0031-9155/37/1/016http://dx.doi.org/10.1016/S0360-3016(00)00524-1http://dx.doi.org/10.1016/S0360-3016(00)00524-1http://dx.doi.org/10.1016/j.radonc.2004.02.007http://dx.doi.org/10.1088/0031-9155/29/5/008http://dx.doi.org/10.1016/j.radonc.2010.04.016http://dx.doi.org/10.1016/S0167-8140(02)00367-5http://dx.doi.org/10.1378/chest.126.4.1198http://dx.doi.org/10.1016/j.ijrobp.2005.04.022http://dx.doi.org/10.1016/j.ijrobp.2007.05.018http://dx.doi.org/10.1269/jrr.10016http://dx.doi.org/10.1016/j.ijrobp.2004.01.032http://dx.doi.org/10.1016/j.ijrobp.2004.01.032http://dx.doi.org/10.1158/1078-0432.CCR-04-1350http://dx.doi.org/10.3109/0284186X.2011.590148http://dx.doi.org/10.1097/JTO.0b013e3181560a68http://dx.doi.org/10.1097/IAE.0b013e3181dee621http://dx.doi.org/10.1097/IAE.0b013e3181ad2692http://dx.doi.org/10.1016/j.ophtha.2006.05.036http://dx.doi.org/10.1016/j.ophtha.2006.05.036http://dx.doi.org/10.1118/1.3291648http://dx.doi.org/10.2147/OPTHhttp://dx.doi.org/10.3109/08820538.2011.5708467/29/2019 Ions for Non Malignancies
12/12
Committee for Practice Guidelines, European Heart Rhythm Association,Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines for the man-agement of patients with atrial fibrillation: full text: A report of the Amer-ican College of Cardiology/American Heart Association Task Force onpractice guidelines and the European Society of Cardiology Committeefor Practice Guidelines (Writing Committee to Revise the 2001 guide-lines for the management of patients with atrial fibrillation) developed incollaboration with the European Heart Rhythm Association and the HeartRhythm Society, Europace 8, 651745 (2006).
85T. Terasawa, E. M. Balk, M. Chung, A. C. Garlitski, A. A. Alsheikh-Ali,J. Lau, and S. Ip, Systematic review: Comparative effectiveness of ra-diofrequency catheter ablation for atrial fibrillation, Ann. Intern. Med.151,191202 (2009).
86A. 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 efficacy of catheterablation of atrial fibrillation, J. Interv. Card. Electrophysiol. 15,145155 (2006).
87R. M. Sullivan and A. Mazur, Stereotactic robotic radiosurgery(CyberHeart): A cyber revolution in cardiac ablation?, Heart Rhythm. 7,811812 (2010).
88A. Sharma, D. Wong, G. Weidlich, T. Fogarty, A. Jack, T. Sumanaweera,and P. Maguire, Noninvasive stereotactic radiosurgery (CyberHeart) forcreation of ablation lesions in the atrium, Heart Rhythm. 7, 802810(2010).
89M. 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 amelioratesarrhythmogenic substrates in hearts after myocardial infarction, Cardio-vasc. Res. 72, 412421 (2006).
90M. 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 heavyion irradiation, Am. J. Physiol. Heart. Circ. Physiol. 298, H1014H1021(2010).
91T. Elsasser, W. Kraft-Weyrather, T. Friedrich, M. Durante, G. Iancu, M.Kramer, G. Kragl, S. Brons, M. Winter, K. J. Weber, and M. Scholz,Quantification of the relative biological effectiveness for ion beamradiotherapy: Direct experimental comparison of proton and carbon ionbeams and a novel approach for treatment planning, Int. J. Radiat.Oncol., Biol., Phys. 78, 11771183 (2010).
92L. Paulis and T. Unger, Novel therapeutic targets for hypertension,Nat. Rev. Cardiol. 7, 431441 (2010).
93Symplicity HTN-2 Investigators, Renal sympathetic denervation inpatients with treatment-resistant hypertension (The Symplicity HTN-2Trial): A randomised controlled trial, Lancet 376, 19031909 (2010).
94Symplicity HTN-1 Investigators, Catheter-based renal sympathetic de-nervation for resistant hypertension: durability of blood pressure reduc-tion out to 24 months, Hypertension 57, 911917 (2011).
95E. J. Dropcho, Neurotoxicity of radiation therapy, Neurol. Clin. 28,217234 (2010).
96S. Fridberg and B. I. Ruden, Hypofractionation in radiotherapy. Aninvestigation of injured Swedish women, treated for cancer of the breast,Acta Oncol. 48, 822831 (2009).
97I. Suramo, M. Paivansalo, and V. Myllyla, Cranio-caudal movements ofthe liver, pancreas and kidneys in respiration, Acta Radiol. Diagn. 25,129131 (1984).
98E. Rietzel and C. Bert, Respiratory motion management in particletherapy, Med. Phys. 37, 449460 (2010).
99C. Bert, A. Gemmel, N. Saito, N. Chaudhri, D. Schardt, M. Durante, G.Kraft, and E. Rietzel, Dosimetric precision of an ion beam tracking sys-tem, Radiat Oncol. 5, 61 (2010).
100T. Nomiya, H. Tsuji, N. Hirasawa, H. Kato, T. Kamada, J. Mizoe, H.Kishi, K. Kamura, H. Wada, K. Nemoto, and H. Tsujii, Carbon ion radi-ation therapy for primary renal cell carcinoma: initial clinical experi-ence, Int. J. Radiat. Oncol., Biol., Phys. 72, 828833 (2008).
101Y. Aoka, T. Kamada, M. Kawana, Y. Yamada, T. Nishikawa, H. Kasa-nuki, and H. Tsujii, Primary cardiac angiosarcoma treated with carbon-ion radiotherapy, Lancet Oncol. 5, 636638 (2004).
102S. M. Zenklusen, E. Pedroni, and D. A. Meer, Study on repainting strat-egies for treating moderately moving targets with proton pencil beamscanning at the new Gantry 2 at PSI, Phys. Med. Biol. 55, 51035121(2010).
103C. Bert and E. Rietzel, 4D treatment planning for scanned ion beams,Radiat. Oncol. 2, 24 (2007).
104R. Luchtenborg, N. Saito, M. Durante, and C. Bert, Experimental verifi-cation of a real-time compensation functionality for dose changes due totarget motion in scanned particle therapy, Med Phys. 38, 54485458(2011).
105Y. Y. Vinogradskiy, P. Balter, D. S. Followill, P. E. Alvarez, R. A.White, and G. Starkschall, Verification of four-dimensional photon dosecalculations, Med. Phys. 36, 34383447 (2009).
106D. S. Followill, D. R. Evans, C. Cherry, A. Molineu, G. Fisher, W. F.Hanson, and G. S. Ibbott, Design, development, and implementation ofthe radiological physics centers pelvis and thorax anthropomorphic qual-ity assurance phantoms, Med. Phys. 34, 20702076 (2007).
107J. Biederer and M. Heller, Artificial thorax for MR imaging studies inporcine heart-lung preparations, Radiology 226, 250255 (2003).
108K. Parodi, N. Saito, N. Chaudhri, C. Richter, M. Durante, W. Enghardt,E. Rietzel, and C. Bert, 4D in-beam positron emission tomography forverification of motion-compensated ion beam therapy, Med. Phys. 36,42304243 (2009).
1727 Bert, Engenhart-Cabillic, and Durante: Particle therapy for noncancer d iseases 1727
Medical Physics, Vol. 39, No. 4, April 2012
http://dx.doi.org/10.1093/europace/eul097http://dx.doi.org/10.1007/s10840-006-9005-9http://dx.doi.org/10.1016/j.hrthm.2010.02.033http://dx.doi.org/10.1016/j.hrthm.2010.02.010http://dx.doi.org/10.1016/j.cardiores.2006.09.010http://dx.doi.org/10.1016/j.cardiores.2006.09.010http://dx.doi.org/10.1152/ajpheart.00160.2009http://dx.doi.org/10.1016/j.ijrobp.2010.05.014http://dx.doi.org/10.1016/j.ijrobp.2010.05.014http://dx.doi.org/10.1038/nrcardio.2010.85http://dx.doi.org/10.1016/S0140-6736(10)62039-9http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.163014http://dx.doi.org/10.1016/j.ncl.2009.09.008http://dx.doi.org/10.1080/02841860902824917http://dx.doi.org/10.1118/1.3250856http://dx.doi.org/10.1186/1748-717X-5-61http://dx.doi.org/10.1016/j.ijrobp.2008.01.043http://dx.doi.org/10.1016/S1470-2045(04)01600-6http://dx.doi.org/10.1088/0031-9155/55/17/014http://dx.doi.org/10.1186/1748-717X-2-24http://dx.doi.org/10.1118/1.3633891http://dx.doi.org/10.1118/1.3157233http://dx.doi.org/10.1118/1.2737158http://dx.doi.org/10.1148/radiol.2261011275http://dx.doi.org/10.1118/1.3196236http://dx.doi.org/10.1118/1.3196236http://dx.doi.org/10.1148/radiol.2261011275http://dx.doi.org/10.1118/1.2737158http://dx.doi.org/10.1118/1.3157233http://dx.doi.org/10.1118/1.3633891http://dx.doi.org/10.1186/1748-717X-2-24http://dx.doi.org/10.1088/0031-9155/55/17/014http://dx.doi.org/10.1016/S1470-2045(04)01600-6http://dx.doi.org/10.1016/j.ijrobp.2008.01.043http://dx.doi.org/10.1186/1748-717X-5-61http://dx.doi.org/10.1118/1.3250856http://dx.doi.org/10.1080/02841860902824917http://dx.doi.org/10.1016/j.ncl.2009.09.008http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.163014http://dx.doi.org/10.1016/S0140-6736(10)62039-9http://dx.doi.org/10.1038/nrcardio.2010.85http://dx.doi.org/10.1016/j.ijrobp.2010.05.014http://dx.doi.org/10.1016/j.ijrobp.2010.05.014http://dx.doi.org/10.1152/ajpheart.00160.2009http://dx.doi.org/10.1016/j.cardiores.2006.09.010http://dx.doi.org/10.1016/j.cardiores.2006.09.010http://dx.doi.org/10.1016/j.hrthm.2010.02.010http://dx.doi.org/10.1016/j.hrthm.2010.02.033http://dx.doi.org/10.1007/s10840-006-9005-9http://dx.doi.org/10.1093/europace/eul097Top Related