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660 Charged Particle and Photon Interactions with Matter
since 2006. This facility consists of an ECR ion source, an RFQ and an APF-IH linac, a synchrotron
ring, three treatment rooms, and one experimental room for basic research. In this facility, a C
4+
beam, which is generated by a compact 10GHz ECR ion source, is accelerated to 4 MeV/n through
the injector linac cascade. After fully stripped, the C
6+
beam is injected into the synchrotron by a
multiturn injection scheme and is accelerated to 400MeV/n at maximum. All of the magnets in the
beam transport lines are made of laminated steel in order to change the beam line quickly within
1min. The beam-delivery system employs a spiral beam-wobbling method (Komori etal., 2004;
Yonai etal., 2008) for forming a uniform lateral dose distribution with a relatively thin scatterer.
The facility size was downsized to be one-third of the HIMAC facility. An image of the Gunma
University
facility with installed devices is shown in Figure 24.11.
24.4.2.2 Compact
h
eavy-ion
r
adiotherapy
Facility in e
urope
In Europe, the Heidelberg ion therapy (HIT) facility was constructed in Heidelberg, Germany,
based on the developments and experiences at GSI. Further, the Proton and Ion Medical Machine
Study (PIMMS) project was also started in 1996. Based on the PIMMS design modied by the
PMMS/TERA project, the Centro Nazionale di Adroterapia Oncologica (CNAO) facility has been
under
construction in Pavia, Italy, since 2003.
24.4.2.2.1
HIT Facility
The HIT facility, which is a hospital-based light-ion accelerator facility for the clinic in Heidelberg,
was proposed (Eickhoff etal., 2004). At present, almost all beam commissionings have been suc-
cessfully completed. The HIT facility consists of two ECR ion sources, an RFQ and IH linac cas-
cade, a synchrotron ring, and two treatment rooms with a horizontal beam-delivery system and one
rotating gantry. Light ions (p, He, C, and O) generated by the ECR ion sources are accelerated to
7MeV/n by the RFQ and IH linac cascade and are injected into the synchrotron. The ions extracted
slowly by the RF-KO method are delivered to each treatment room. The residual range of C
6+
ions
Treatment room
Synchrotron
10 GHz-ECR
Injector linac
RFQ and APF-IH
65 m
45 m
Figure 24.11 Image view of the standard-type carbon-ion radiotherapy facility at the Gunma University.
(Adapted
from Noda, K. et al., J. Radiat Res., 48, A43, 2007.)
Cancer Therapy with Heavy-Ion Beams 661
is designed to be 30 cm at maximum, which corresponds to 430MeV/n. The main characteristic of
this facility is the application of the raster-scanning method with an active variation in intensity,
energy, and beam size both in the two horizontal irradiation ports and in the rotating gantry. Using
the developed technologies in the HIT project, two other facilities (Marburg and Kiel) are under
construction
in Germany.
24.4.2.2.2
CNAO Facility
The Italian hadron therapy center, CNAO, is presently under construction in Pavia, Italy. The CNAO
project will be devoted to the treatment of deeply seated tumors with proton and carbon-ion beams
and to clinical and radiobiological research (Rossi, 2006). The CNAO accelerator is designed based
on the modied PIMMS. The facility consists of two ECR ion sources, a 7MeV/n injector linac cas-
cade designed by GSI, and a 400MeV/n synchrotron ring. The CNAO synchrotron consists of two
symmetric achromatic arcs connected by two dispersion-free straights and has a circumference of
approximately 78m. The extraction scheme employs both the acceleration-driven and RF-KO meth-
ods under the third-order slow extraction condition. In the nal phase, the CNAO project will have
ve treatment rooms (three rooms with xed beams and two rooms with gantries) and one experi-
mental room. In the rst phase, three treatment rooms will be equipped with four xed beams, three
horizontal and one vertical. As a beam-delivery method, CNAO will employ the active scanning
method
that was developed at GSI.
24.4.3 developMent of next-generation irradiation SySteMS
In the HIMAC treatments, we have sometimes observed shrinkage in the size of the target as well
as a change in its shape during the course of the treatment. In order to keep the sophisticated con-
formations of the dose distributions even in such cases, a strict requirement has been that treatment
planning be carried out just before each fractional irradiation, which is called adaptive therapy. For
this purpose, 3D scanning with a pencil beam should be employed, as it does not use a bolus and
patient collimators requiring long manufacturing time. It is also well known that 3D scanning has
brought about high treatment accuracy in the case of a xed target (Kanai etal., 1980; Haberer etal.,
1993; Pedroni etal., 1995). However, this method has not yet been put into practical use for the treat-
ment of a target moving with respiration. Since the HIMAC facility should carry out treatments not
only for xed targets but also for moving targets, we have developed a 3D scanning method that can
treat both moving and xed targets. Then, in cooperation with a rotating gantry, the 3D scanning
method can achieve a higher accuracy of treatment even for a target close to critical organs by the
multi-eld optimization method (Lomax, 1999), as compared with conventional carbon-ion radio-
therapy. On the basis of these new developments, we have also designed and developed a rotating
gantry
incorporating the 3D scanning method (Furukawa etal., 2008a).
24.4.3.1
development
of p
hase-Controlled
r
escanning
m
ethod
In 3D scanning, an interplay effect between the scanning motion and the target motion brings about
hot and/or cold spots in the target volume, even when using the respiration-gated irradiation method,
because the sizes of the distal and lateral dose proles of the pencil beam are comparable to the
residual motion range. Therefore, the phase-controlled rescanning (PCR) method (Furukawa etal.,
2007), which is combined with the rescanning technique and gated irradiation, is employed in order
to avoid producing hot/cold spots. In the PCR method, rescanning on a slice is completed during
one gate generated in the expiration period of the patient’s breathing. Since the moving-target posi-
tion is averaged in both the lateral and distal directions, the hot and/or cold spots are not produced.
A simulation study revealed that the PCR method provided a feasible solution with a dynamic
beam-intensity control technique (Sato etal., 2007) based on the RF-KO slow extraction method.
In the PCR method, it is noted that the irradiation time for each depth slice should be adjusted to be
662 Charged Particle and Photon Interactions with Matter
within 1–2s of the respiration-gate duration. Consequently, we obtained a practicable solution for
moving-target
irradiation by the fast raster-scanning method with rescanning and gating functions.
24.4.3.2
development
of Fast 3
d scanning
m
ethod
In the PCR method, fast scanning is an essential technology in order to complete one fractional irra-
diation within a tolerable period even under several-times rescanning. For this purpose, we devel-
oped (1) new treatment planning, (2) modied synchrotron operation, and (3) fast-scanning magnet.
24.4.3.2.1
New Treatment Planning
A new treatment-planning system (Inaniwa etal., 2007a, 2008) has been developed for 3D scanning
with a pencil beam. A biological-dose distribution of a pencil beam is obtained by combining the
measured physical-dose distribution and the RBE obtained through measured α and β values in the
LQ model, as mentioned in Section 24.3. Using the biological-dose distribution, the new treatment
planning optimizes the assignment of spot positions and their weights so as to give the prescribed
dose
on a target and to signicantly reduce the dose on surrounding normal tissues.
For
fast 3D scanning, raster scanning is employed instead of spot scanning, in order to save the
beam-off time during beam movement between spot positions. However, raster scanning causes an
extra dose due to beam movement between spot positions, and the extra dose is proportional to the
beam intensity delivered. On the other hand, the fast scanning requires high beam intensity. As a
result, it has been difcult for fast raster scanning to yield uniform dose distribution due to the high
extra dose. However, since the HIMAC synchrotron has delivered a highly reproducible beam with
a uniform time structure (Sato etal., 2007), the extra dose can be predicted and taken into account
in the treatment planning. Consequently, the new treatment planning can increase the scanning
speed by around ve times. Applying a modied “travelling-salesman problem,” further, the path
length of raster scanning can be shortened by 20%–30%. The new treatment planning was devel-
oped
according to the above considerations.
24.4.3.2.2
Modied Operation of Synchrotron
On the basis of the high beam-utilization efciency of around 100% in the scanning method and an
intensity upgrade to 2 × 10
10
carbon-ions by suppressing both the transverse and longitudinal space–
charge effects, we can complete the single-fractional irradiation of almost all treatment procedures
in a single-operation cycle of the synchrotron. This single-cycle operation can signicantly reduce
dead time, such as beam injection, acceleration, and deceleration. As a result, we have proposed
extended attop operation in the single-cycle operation of the synchrotron. In this operation mode,
stability of the beam was tested, and it was veried that the position and prole stabilities were
less than ±0.5 mm at the isocenter during 100s of extended attop operation. This extended attop
operation can shorten the irradiation time by a factor of 2 and has been routinely utilized for 3D
scanning
experiments.
24.4.3.2.3
High-Speed Scanning Magnet
The scanning speed is designed to be 100 and 50mm/ms in horizontal and vertical directions,
respectively, faster by around one order than that of conventional spot scanning. In order to increase
the scanning speed, we designed the scanning magnet with slits at both ends of the magnetic pole,
based on a thermal analysis including an eddy current loss and a hysteresis loss. The result of a
preliminary test showed a temperature rise of around 30 degree at maximum, which was consistent
with
the thermal analysis, under the designed scanning speed.
24.4.3.3 Fast
3
d raster-scanning
e
xperiment
At the rst stage, we carried out a fast raster-scanning experiment using the HIMAC spot-
scanning test line (Urakabe etal., 2001). The irradiation control system was modied so as to
Cancer Therapy with Heavy-Ion Beams 663
be capable of raster-scanning irradiation instead of spot-scanning irradiation. In the experi-
ment, we adapted the measured dose response of the pencil beam with an energy of 350 MeV/n,
corresponding to a 22 cm range in water. The beam size at the entrance and the width of the
Gaussian-shaped mini-SOBP were 3.5 and 4 mm at one standard deviation, respectively. As a
result of the experiment, it was veried that the new treatment planning could accurately provide
a 3D dose distribution, as shown in Figure 24.12. In the PCR experiment, the dose distributions
with/without the PCR method were measured two dimensionally. As shown in Figure 24.13, it
was conrmed that the PCR method provided a uniform dose distribution even for a moving
target (Furukawa etal., 2008b). Owing to both the new treatment planning and extended attop
operations, the irradiation time was shortened by around ten times compared with that of the
conventional spot scanning.
We constructed a test irradiation port, which was installed with the fast-scanning magnets,
in order to verify the design goal of fast 3D scanning. Figure 24.14 shows the test port for the
fast 3D scanning experiment. In a preliminary test, we irradiated a spherically shaped target
with a 6 cm diameter and obtained uniform 3D dose distribution within 10s even under 10 times
rescanning.
0 200
–50
0
50
(a) (b)Water frame
1.0
0.8
0.6
0.4
0.2
0.0
–50
0.0
0.2
0.4
0.6
0.8
1.0
0
50
CT frame
Figure 24.12 Dose distribution obtained by new treatment planning. (a) Dose distribution in water frame.
Solid lines with circles (measured physical doses) represent the physical-dose distribution designed to obtain
the biological distribution (black line). (b) Dose distribution reprocessed on a CT image. (From Inaniwa, T.
etal.,
Nucl. Instrum. Meth. B., 266, 2194, 2008. With permission.)
100 200 300 400 500 600
100
200
300
400
500
(a) (b)
0
2,560
5,120
7,680
10,240
12,800
15,360
16,384
15,360
16,384
100 200 300 400 500 600
100
200
300
400
500
0
2,560
5,120
7,680
10,240
12,800
Figure 24.13 Dose distributions by the PCR method. (a) Without PCR. (b) With PCR (eight times res-
canning). (From Furukawa, T. etal., Development of scanning system at HIMAC, in Proceedings of the 11th
EPAC,
Genoa, Italy, pp. 1794–1796, 2008b.)
664 Charged Particle and Photon Interactions with Matter
24.5 the Future oF Carbon-ion radiotherapy
While the clinical studies conducted at NIRS over the past 15 years established the basic usefulness
of carbon-ion radiotherapy, clinical studies and basic research aimed at developing the next genera-
tion of therapies have already started. Our specic approaches to future research on carbon-ion
radiotherapy
are as follows.
24.5.1 concoMitant cheMo-carbon-ion radiotherapy
Local control is mandatory for curing cancer, and a good local control has been achieved with carbon
beams. Depending on the type of cancer, however, improving local control does not always prolong
the survival period. In locally advanced malignant melanoma, in particular, long-term survival was
not always obtained despite the fact that local control was signicantly improved through carbon-ion
radiotherapy. There are patients who, although good local control was obtained, do not attain long-
term survival because distant metastasis develops or second and third foci (colonies) sometimes
appear. To improve long-term survival, we have used carbon-ion radiotherapy in combination with
chemotherapy and have obtained favorable results. We have established safe methods for carbon-
ion radiotherapy for many patients with inoperable cancers. As the next step, it will be necessary to
develop therapies for improving survival rates, bearing in mind that cancer is a systemic disease.
24.5.2 developMent of novel irradiation techniQueS
A great advantage of carbon-ion radiotherapy is that it permits a conformed irradiation of various
target sites compared to other radiotherapies. Layer-stacking irradiation, a new scanning irradiation
(a)
(b) (c)
(d)
Figure 24.14 Test irradiation port of fast 3D raster-scanning experiment: (a) scanning magnets,
(b)position monitor, (c) dose monitor, (d) range shifter.
Cancer Therapy with Heavy-Ion Beams 665
method adaptive to respiratory movement, and an on-demand irradiation system sensitive to
day-to-day or time-to-time changes in the tumor or body have been under development to obtain
further
improvements in carbon-ion dose distribution.
24.5.3 proMotion of Short-courSe hypofractionation in carbon-ion radiotherapy
Carbon-ion radiotherapy is performed in only two institutions in Japan, and as the number of patients
treated continues to rise at a remarkable rate, there is an increasing demand for greater treatment
efciency. In this respect, short-course hypofractionation is effective and greatly contributes to the
efcient utilization of restricted resources. Very-short-course irradiation consisting of only one or
two sessions developed for lung and liver cancer has been acknowledged internationally, and the
extension of this technique to other cancers is the next step. Studies have already been initiated to
develop short-term irradiation modes for other regions by analyzing data obtained from previous
application instances of a clinical practice. The specic practice is to set up groups with different
irradiation periods and different numbers of irradiation fractions for the same disease, and then con-
duct
randomized comparative intergroup studies to determine the most efcient irradiation period.
24.5.4 diagnoStic iMaging for treatMent and biological StudieS
Advanced diagnostic techniques have played a major role in the improvement of therapeutic results,
and their further advancement is highly desirable. The introduction of new diagnostic equipment,
such as PET, multi-detector computed tomography (MDCT), and high-T MRI, enables early small
cancers to be accurately diagnosed. To utilize the information for actual carbon-ion radiotherapy,
it is necessary to consider not only the relationship between the focus (tumor) and surrounding
organs, but also the integration of different images and the deformation and movement of organs
associated with respiration. Specic studies may include early assessment of therapeutic effects
and analysis of prognostic factors by combining various diagnostic imaging techniques and creat-
ing fusion images. The studies may also include advancement of treatment planning by utilizing
imaging equipment that temporally traces the dynamics of fusion images and 4D CT. Recently,
imaging of the state of oxygen as well as sugar and amino acid metabolism in the tumor has become
possible, and an important research issue in the near future will be how these techniques can be
applied to treatment.
In various biological studies, to further enhance the effectiveness of carbon-ion radiotherapy and
verify the safety, samples and data obtained from clinical studies on carbon-ion radiotherapy are
indispensable, and close cooperation is important. Clinical application of the knowledge obtained
both from these studies and from drugs (e.g., anticancer agents, sensitizers, and protective agents) to
improve
treatment outcomes is also a target of clinical research.
24.5.5 coMparative StudieS
Comparative studies, already feasible at present, to further clarify the usefulness (indications) of
carbon-ion radiotherapy include those in which the same protocol is applied to other therapies, the
backgrounds of subjects are matched, and the treatment desired by study participants is offered.
In such cases, consent from study participants is easily obtained, study costs are low, and agree-
ment among participating facilities is relatively easily obtained, since the treatment desired by each
patient is provided on the basis of cooperation with other institutions. Another method is to deter-
mine the inclusion criteria for patients already treated, and then to comparatively analyze the thera-
peutic results in a matched-pair study. This is feasible if consent is obtained from the institutions
performing
the therapies being compared.
When
comparing various therapies, the results of randomized controlled studies provide the
strongest evidence at present. Theodore S. Lawrence, editor of the Journal of Clinical Oncology,
666 Charged Particle and Photon Interactions with Matter
has made the following statement about the need for randomized controlled studies when comparing
different therapies, or different types of therapeutic equipment, in the eld of radiation oncology
(Lawrence
etal., 2007):
In medical oncology, there is a need to compare drug treatment A to drug treatment B. It is not pos-
sible to determine which is better without carrying out a randomized trial. In radiation oncology, one
can know, based on physics, that protons deliver a better dose distribution than photons or that IMRT
is superior to three-dimensional conformal therapy. If treatment planning and delivery are carried
out properly, which can be dened by a set of rules, there is no debate; this is a matter of physics. The
big question is: is the clinical improvement worth the added expense? What kind of trial needs to be
designed to answer this question? It will be difcult to run a randomized trial in the United States ask-
ing whether a treatment that is superior based on physics is worth it. Would patients permit themselves
to
be randomly assigned to the standard but less expensive therapy?
Previous progress in radiation oncology is inextricably linked to the development of irradiation
equipment, but no randomized controlled study has been conducted for the purpose of the introduc-
tion of new therapeutic equipment. No randomized controlled study was conducted in the shift from
cobalt irradiation equipment to linac x-ray systems, but if that had been done, there would have been
little difference between cobalt and linac in the treatment results in patients with early laryngeal
glottic cancer. Cobalt irradiation has advantages in terms of both cost and equipment maintenance,
and the results of linac x-ray irradiation may be poor unless the correct energy is selected. Cobalt
irradiation is sufcient to treat laryngeal cancer, and it is unnecessary to introduce linac irradia-
tion to achieve successful treatment for this cancer. However, almost no treatment with cobalt is
performed in developed countries. The distribution of the very-high-energy x-rays of linac allows
safer treatment of foci (tumors) existing at a deep site, and the design of a study to determine the
difference between cobalt and linac irradiation in patients with laryngeal cancer is itself a problem.
Randomized controlled study protocols should be considered for studies aimed at making the
usefulness of carbon-ion radiotherapy clearer and which may lead to more efcient operation,
such as extended indications of short-term hypofractionation, or to more effective treatment and
improved local effect. However, at present, most of the patients receiving carbon-ion radiotherapy
visit the clinic looking for this treatment, and it is difcult to obtain consent for a randomized con-
trolled study from patients. It is difcult to conduct a randomized study between different types of
equipment even in the United States, where the use of randomized controlled studies is advanced; it
is
equally, if not more, difcult in Japan.
table 24.1
Carbon-ion
r
adiotherapy
Facilities in the w
orld
under operation start no. of patients until
NIRS
(Japan) 1994 4504 February 2009
GSI (Germany) 1997 384 October 2007
HIBMC (Japan) 2002 454 December 2008
IMP (China) 2006 109 March 2009
5451
Sources:
Amaldi, U. and Kraft, G., J. Radiat. Res. 48, A27, 2007;
Noda, K , J. Radiat. Res., 48, A43, 2007.
Notes: Under construction: Gunma (Japan), HIT (Germany), CNAO
(Italy), Marburg (Germany), and Kiel (Germany). Plan in
progress: ETOILE (France), Med-Austron (Austria), Saga
(Japan), and Kanagawa (Japan).
Cancer Therapy with Heavy-Ion Beams 667
Accordingly, future comparative studies on heavy-ion radiotherapy will follow these guidelines:
1. Clinical
studies will use the same protocol that is applied to other therapies
2. Matched-pair controlled studies in subjects will be matched to those receiving other therapies
3. Studies
will compare different charged particle therapies
24.6 ConClusion
More than 5000 patients were treated with carbon-ion radiotherapy at four facilities worldwide by
the end of 2008. The therapeutic results are internationally acknowledged. A considerable number
of carbon-ion radiotherapy systems are under construction in European countries and in Japan, as
summarized in Table 24.1, offering the prospect of achieving more reliable and safer cancer therapy
in
the near future (Amaldi and Kraft, 2007).
In
industrialized countries, the number of patients with cancer is increasing steadily with the
aging
of the population. The development of therapies for curing cancer with safety and assurance,
and with less suffering, even among the elderly, is strongly desired by such countries. Owing to
the results of previous studies, carbon-ion radiotherapy has been recognized as a treatment that
can achieve this goal. Studies conducted over the past 10 years have made it possible to reduce the
cost of a carbon-ion radiotherapy system to about one-third of that of HIMAC. Next-generation
carbon-ion radiotherapy equipment will provide more advanced treatment at a drastically reduced
cost. To achieve this, cooperation between equipment manufacturers and researchers in this eld is
indispensable,
and government support is critical.
Future
carbon-ion radiotherapy will provide cancer treatment with less suffering for many intrac-
table cancers using more advanced systems and, hopefully, recent molecular biological techniques.
aCknowledgments
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tion quality and TCP in carbon-ion radiotherapy, and to the other members of the Research Center
of
Charged Particle Therapy at NIRS for their useful discussion and warm support.
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