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640 Charged Particle and Photon Interactions with Matter

without basic knowledge can easily employ the system. The schematic diagram of the system is

shown in Figure 23.17. It is designed so that all dose calculations are performed at the dose calcula-

tion center using a high-performance computer. First, a user sends a data set of CT images and a

treatment plan to the center through the network; then, a simplied voxel phantom of the patient

is automatically constructed in a short time; and a Monte Carlo calculation is performed utilizing

super-parallel computing; then the calculated dose distribution is sent back to the clinic and used for

therapy

planning or QA/QC.

Concerning

voxel phantoms on patients, we investigated how many tissues having different

elemental compositions are necessary to obtain sufcient dose accuracy. Consequently, it was con-

rmed that a phantom consisting of six tissues of skin, muscle, adipose, lung, cortical bone, and

bone marrow can give doses with very high accuracy. Obviously inaccurate doses are obtained

when other tissues are substituted for skeletal tissue that has a high proportion of the relatively high

atomic number element Ca. Further, it was found that substitution of adipose tissue by other tissues

could

cause signicant error in some cases.

23.5.2 doSiMetry in accidentS

Electron spin magnetic resonance (ESR) dosimetry using tooth enamel has been utilized in retro-

spective dose assessments in accidents where no other dosimetry method is available. Accumulated

dose in tooth enamel can be estimated from the ESR signals. However, the information needed

in accidents is not the enamel dose but doses for other important organs; then, conversion coef-

cients from the tooth enamel dose to organ doses must be prepared. Further, the variations of the

enamel dose due to tooth position, irradiation conditions such as photon energy and incident direc-

tion should be investigated for reliable measurements. For this purpose, a series of studies using

phantoms

have been carried out.

Takahashi

et al. (2002, 2003) investigated the characteristics of tooth doses using both a physi-

cal phantom and computational phantoms. A voxel phantom was constructed from CT images of a

realistic physical phantom having real human teeth. An example of CT images on this phantom is

IMAGINE system

Hospital

Transfer of

CT data

Dose calculation center

Monte Carlo calculation

on the ITBL computer

Consideration

of irradiation

head

Construction of

voxel phantom

Transfer of

dose distribution

Network

erapy planning

Quality assurance

Figure 23.17 Schematic diagram of the dose calculation system IMAGINE for supporting medical

facilities

through the network.

ComputationalHuman Phantoms and Their Applications toRadiation Dosimetry 641

shown in Figure 23.18. Thermoluminescence dosimeters (TLDs) were placed at the different tooth

positions in the physical phantom to evaluate enamel doses. Then irradiation experiments were car-

ried out and compared with simulation using the constructed voxel phantom. They showed good

agreement, further, various characteristics of tooth doses were claried by simulations under vari-

ous conditions. Also, conversion coefcients from the tooth enamel dose to important organ doses

have been prepared. This study was extended by Ulanovsky et al. (2005).

23.5.3 aniMal phantoMS

In recent years, animal phantoms have been developed and used for diverse purposes. A mouse

phantom was developed by Dogdas et al. (2007) at the University of South California and modied

by Kinase et al. (2008) at JAEA for dosimetry use. The phantom called Digimouse was segmented

from CT and cryosection data. The voxel size is 100 × 100 × 100μm

and the body weight is 28g.

Further, Kinase (2008) constructed a frog phantom based on segmented images from cryosection

data provided on a website of Lawrence Berkley National Laboratory (Johnson and Robertson,

2008). The frog phantom shown in Figure 23.19 has a voxel size of 250 × 250 × 250mm

, body

weight

of 35

with 15 organs and tissues.

The

mouse phantom is intended for use mainly for radiopharmaceutical development (Kinase

etal., 2009). In developing a pharmaceutical, the effect examined using animal experiments needs

to be extrapolated to humans, considering the doses delivered to the tumor and organs. Then,

accurate doses should be estimated both for the animal and humans.

The objective of the frog phantom is to provide fundamental data on environmental protection

for animals and plants, the necessity of which was clearly stated in the new ICRP Publication

(ICRP, 2007). The frog is among the reference animals and plants for the purpose of environ-

mental protection (Pentreath, 2005). Presently, dose evaluations for the reference animals and

plants are performed using extremely simplied phantoms, which, except for some exceptions,

do not have explicit organs. Thus, internal dosimetry is largely impossible with these simplied

phantoms.

Figure 23.20 compares AFs for photons and electrons among the mouse, the frog, and two human

phantoms (Kinase, 2008; Kinase et al., 2008, 2009). Here, kidneys were taken as the source and

Figure 23.18 CT image of the physical phantom used for analyses of tooth enamel doses for external

photon

exposure.

642 Charged Particle and Photon Interactions with Matter

target organs. The self-AFs for photons show a large difference between the animal phantoms and

the human phantoms reecting their organ sizes. While the self-AFs for electrons are identical at

low energy below a few hundred keV because the electron penetration range is very short, they devi-

ate greatly as the electron energy increases. When comparing animal doses to human doses, these

features

must be taken into account.

23.6 summary

In radiation protection, computational phantoms have played an important role in helping to obtain

fundamental data necessary for dosimetry. The use of phantoms started with stylized phantoms

that express human bodies with mathematical equations, and developed into more realistic voxel

phantoms based on medical images. These phantoms have been employed to calculate organ doses

and effective doses with Monte Carlo simulations both in external and internal exposure. In radia-

tion protection, dose quantities have been prepared mostly for the reference Caucasian adults, while

Japanese voxel phantoms have been developed to investigate difference between the Caucasian and

the

Japanese phantoms. It has been conrmed that the dose difference due to race is not signicant

–1

–2

–3

–2

–1

(a) (b)Photon energy(MeV) Electron energy(MeV)

–2

–1

Human male

Human female

Mouse

Frog

Human male

Human female

Mouse

Frog

Figure 23.20 Comparison of self-AFs in kidneys for photons and electrons among humans, a mouse and

frog. (a) Photon and (b) electron.

Figure 23.19 Frog phantom developed by Kinase at JAEA. (From Kinase, S., J. Nucl. Sci. Technol., 45,

1049,

2008. With permission.)

ComputationalHuman Phantoms and Their Applications toRadiation Dosimetry 643

from a viewpoint of radiation protection. On the other hand, individual organ doses can vary greatly

according to conditions, and this suggests that sophisticated phantoms must be used if accurate

doses

for specic individuals are needed.

Voxel

phantom techniques have proved to be quite useful and applied to various elds. These

cover quite a wide range of elds such as medical applications both in diagnostics and therapy,

retrospective dosimetry in accidents, exposure assessment of electromagnetic elds, environmen-

tal studies, and the development of radiopharmaceuticals. Thus, many voxel phantoms have been

developed including animal phantoms. Obviously one important application is in the medical

eld. An example of the dose calculation system for x-ray therapy was shown in this chapter;

meanwhile, a therapy-planning system for boron neutron capture therapy (BNCT) has been devel-

oped at JAEA and played an important role in BNCT in Japan, though details are not described

here. Further, dose evaluation for radiation diagnoses would also be important, since advanced

diagnoses leading to relatively high doses such as CT, PET, and SPECT have begun to be used.

Furthermore, various advanced phantoms are being developed, though all of these could not

be discussed in this chapter. These include 4D phantoms that move with time, hybrid phantoms

that have merits of both stylized and voxel phantoms, multi-scale phantoms that consider ner

structures of organ and tissues, etc. Among these, the development of multi-scale phantoms that

perform microdosimetric simulation at cellular levels besides current macroscopic simulation is an

important subject to relate dosimetry more directly to radiation effects; and in this simulation the

knowledge

compiled in this book would be widely utilized.

the basis of these versatile technical improvements and expanding demands, applications of

computational

human phantoms would be expected to increase more and more in the future.

aCknowledgments

The author would like to thank Dr. K. Sato, Dr. S. Kinase, Dr. F. Takahashi, and Dr. R. Watanabe

for their kind support in preparing materials. The author is grateful to Dr. A. Endo for his valuable

advice

on this chapter.

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647

Cancer Therapy with

Heavy-Ion

Beams

Koji Noda

National Institute of Radiological Sciences

Chiba,

Japan

Tadashi Kamada

National Institute of Radiological Sciences

Chiba,

Japan

Contents

24.1 Introduction ..........................................................................................................................648

24.2 Clinical

Trial of Cancer Therapy with Carbon Beam ..........................................................648

24.2.1

Clinical

Trials with Carbon Beam............................................................................649

24.2.2

Results

of Clinical Trials with Carbon Beam...........................................................649

24.2.2.1

Head

and Neck Cancers.............................................................................650

24.2.2.2

Skull Base Tumors.....................................................................................650

24.2.2.3 Lung

Cancer (Non-Small-Cell Lung Cancer)............................................. 651

24.2.2.4

Liver

Cancer (Hepatocellular Carcinoma)................................................. 651

24.2.2.5

Prostate

Cancer.......................................................................................... 651

24.2.2.6

Bone

and Soft Tissue Tumors .................................................................... 652

24.2.3

Analysis of Tumor Control Probability ....................................................................653

24.3 Radiation

Quality of Carbon-Ion.......................................................................................... 653

24.4

Development

of Accelerator and Beam-Delivery Systems................................................... 657

24.4.1

Heavy-Ion

Therapy Facility...................................................................................... 657

24.4.1.1

Respiratory-Gated

Irradiation Method ...................................................... 658

24.4.1.2

Layer-Stacking Irradiation Method ........................................................... 659

24.4.2 Development

of Compact Carbon-Ion Radiotherapy Facility ..................................659

24.4.2.1

Standard-Type

Carbon-Ion Radiotherapy Facility in Japan ...................... 659

24.4.2.2

Compact

Heavy-Ion Radiotherapy Facility in Europe................................660

24.4.3

Development

of Next-Generation Irradiation Systems............................................. 661

24.4.3.1

Development of Phase-Controlled Rescanning Method............................ 661

24.4.3.2 Development

of Fast 3D Scanning Method ...............................................662

24.4.3.3

Fast

3D Raster-Scanning Experiment........................................................662

24.5

The

Future of Carbon-Ion Radiotherapy ..............................................................................664

24.5.1

Concomitant

Chemo-Carbon-Ion Radiotherapy ......................................................644

24.5.2

Development of Novel Irradiation Techniques.........................................................664

24.5.3 Promotion

of Short-Course Hypofractionation in Carbon-Ion Radiotherapy..........665

24.5.4

Diagnostic

Imaging for Treatment and Biological Studies........................................665

24.5.5

Comparative

Studies.................................................................................................665

24.6

Conclusion ............................................................................................................................ 667

Acknowledgments..........................................................................................................................667

References...................................................................................................................................... 667

648 Charged Particle and Photon Interactions with Matter

24.1 introduCtion

Heavy-ion beams have drawn growing interest for their use in cancer treatment not only due to

their high dose localization at the Bragg peak, but also due to the high biological effect in this

region.

In 1946, R.R. Wilson proposed the clinical applications of protons and heavier ions in the

treatment of human cancer (Wilson, 1946). Pioneering work on clinical applications of proton

and helium beams was carried out (Tobias etal., 1952) using the 184 in. synchrocyclotron at the

Lawrence Berkeley National Laboratory (LBNL). More than 1000 patients had been treated since

1957. Between 1977 and 1992, 433 patients were treated with heavy-ion beams accelerated by

the Bevalac (Alonso, 1993). Encouraged by the prospective results of heavy-ion radiotherapy at

LBNL and the recent progresses in the accelerator and beam-delivery technologies (Chu etal.,

1993), the National Institute of Radiological Sciences (NIRS) decided to carry out heavy-ion

radiotherapy. The construction project of the Heavy-Ion Medical Accelerator in Chiba (HIMAC)

(Hirao etal., 1992) was promoted by NIRS as one of the projects of “Comprehensive 10-year strat-

egy for cancer control” that was initiated by the Japanese government in 1984. The construction

of the HIMAC facility was completed in 1993, and it was the rst heavy-ion medical accelerator

facility dedicated to cancer radiotherapy in the world. On June 21, 1994, NIRS began heavy-ion

radiotherapy using carbon-ion beams generated by the HIMAC accelerator complex. Since then,

clinical studies to develop safe and secure irradiation technologies and optimized dose fraction-

ation for various diseases have been conducted. More than 4500 patients have been treated with

HIMAC at NIRS, and the clinical efcacy of carbon-ion radiotherapy has been demonstrated for

various diseases.

Owing to high dose localization and high biological effect of the carbon-ion beam used in cancer

radiotherapy, the carbon-ion beam is expected to be effective against intractable, photon-resistant

cancers, and to greatly reduce the treatment period compared with photon or proton radiotherapy.

The results of our previous and ongoing clinical studies, and a number of irradiation technologies

developed, suggest that we are indeed reaching these goals. Nonetheless, the data collected to date

may not be sufcient to fully prove the efcacy of carbon-ion radiotherapy, and more clinical data

are

still needed.

present, carbon-ion radiotherapy is carried out at three facilities in the world (two in Japan

and one in China), ve new facilities (three in Germany, one in Italy, and one in Japan) are under

construction, and at least four more facilities in European Union and in Japan are very close to start-

ing construction. These facilities, either performing or planning carbon-ion radiotherapy, have been

collaborating

in their research and exchanging results with each other.

this chapter, we introduce the past, present, and future of carbon-ion radiotherapy in conjunc-

tion

with the development of the accelerator and beam-delivery systems, especially at NIRS.

24.2 CliniCal trial oF CanCer therapy with Carbon beam

A carbon-ion beam produces maximum ionization at the Bragg peak. It allows a high local-

ized dose to be given safely even with critical organs in close proximity to the target lesion. In

addition to this physical selectivity, a carbon beam possesses high radiobiological effectiveness

at the Bragg peak, such as a small difference in radiation sensitivity through the cell cycle.

Carbon beams are therefore expected to be less toxic to the surrounding normal tissues and

have higher effects on intractable malignant tumors. These features of carbon beams are most

advantageous in cancer therapy. The purpose of the clinical research at NIRS on carbon beams

is to prove the efcacy and safety of carbon therapy in cancer treatment. All the carbon thera-

pies were performed as prospective phase I/II dose escalation studies and phase II xed-dose

clinical trials in an attempt to identify tumor sites suitable for this treatment, including radio-

resistant tumors, and to determine optimal dose fractionation, especially for hypofractionation

in common cancers.

Cancer Therapy with Heavy-Ion Beams 649

24.2.1 clinical trialS with carbon beaM

Carbon-ion radiotherapy has focused mainly on malignant diseases that are difcult to cure by con-

ventional radiotherapy, among which are head and neck cancer, skull base tumor, lung cancer, liver

cancer, prostate cancer, bone and soft tissue tumor, postoperative local recurrence of rectal cancer,

and so on. The total number of patients enrolled by February 2009 was 4504, with various types of

tumors

being treated (Figure 24.1).

the phase I/II studies, to conrm the safety of carbon-ion radiotherapy and obtain informa-

tion concerning the antitumor effect, the number of fractions and treatment period were xed for

each disease and the total dose was gradually increased by 5%–10%. When the recommended

dose was determined during the phase I/II studies, it was incorporated into the phase II stud-

ies. As shown in Figure 24.2, the number of patients enrolled has increased year by year. This

increase occurred in conjunction with the treatment regimen becoming established and smoothly

executed, and, as a result, the number of fractions and treatment period per patient could be

greatly reduced.

Since a carbon-ion beam has the therapeutically advantageous feature of a higher biological

effect at deeper sites from the surface of the body, treatment can be completed in a shorter period.

For stage-I non-small-cell lung cancer (NSCLC) and liver cancer, for example, treatment can be

completed in one or two irradiation fractions. For prostate cancer and bone/soft tissue tumors, it

is completed in 16 fractions, which is about half the number of fractions employed in x-ray and

proton beam radiotherapy. The average number of treatment fractions per patient is now 12 and

the treatment period is about 3 weeks at NIRS.

24.2.2 reSultS of clinical trialS with carbon beaM

More than 50 protocols for various tumors were designed and used in clinical studies. Details

of treatment results of head and neck cancer, skull base tumor, lung cancer, liver cancer, prostate

cancer, and bone and soft tissue tumor are summarized below.

Miscellaneous

1280 (28.4%)

Clin. practice: 807

Total

4504

Clin. practice:

2048

Prostate

746 (16.6%)

Clin. practice: 473

Lung

536 (11.9%)

Clin. practice: 31

H&N

510 (11.3%)

Clin. practice: 223

Liver

273 (6.1%)

Clin. practice: 66

GYN

137 (3.0%)

P/O Rectum

125 (2.8%)

Clin. practice: 87

Pancreas

113 (2.5%)

CNS

103 (2.3%)

Eye melanoma

92 (2.0%)

Clin. practice: 50

Skull base

60 (1.3%)

Clin. practice: 31

Esophagus

59 (1.3%)

Lacrimal

16 (0.4%)

Bone and soft tissue

sarcoma

454 (10.1%)

Clin. practice: 280

Figure 24.1 Distribution of tumors treated for patients enrolled for carbon-ion radiotherapy (June 1994 to

February

2009).