Ohno The EPMA Journal 2013, 4:9
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REVIEW

Open AccessParticle radiotherapy with carbon ion beams
Tatsuya Ohno
Abstract
Carbon ion radiotherapy offers superior dose conformity in the treatment of deep-seated malignant tumours
compared with conventional X-ray therapy. In addition, carbon ion beams have a higher relative biologicaleffectiveness compared with protons or X-ray beams. The algorithm of treatment planning and beam delivery
system is tailored to the individual parameters of the patient. The present article reviews the available literatures forvarious disease sites including the head and neck, skull base, lung, liver, prostate, bone and soft tissues and pelvic
recurrence of rectal cancer as well as physical and biological properties.
Keywords: Carbon ion radiotherapy, Cancer treatment, High LET, Particle radiotherapy, Personalised medicine

Review
History

Since the discovery of X-rays by Röntgen in 1895, X-rays,
γ-rays and electron beams have been widely used in the
management of malignant tumours as a conventional
radiotherapy (RT). In 1946, Wilson R. firstly proposed the
medical use of proton for cancer therapy, and the first
patient was treated at the Lawrence Berkeley National Laboratory (LBNL) in the USA in 1954 [1]. The
efficacy of heavy ions for clinical use had been investigated at LBNL between 1977 and 1992, in which mostpatients were treated with helium and neon ions [1]. In
1994, clinical trial on carbon ion RT (C-ion RT) was
launched at the National Institute of Radiological Sciences (NIRS) in Japan. At present, particle beams with
protons or carbon ions have been applied gradually inclinics. More than 96,000 patients have been treatedwith particle beams around the world, of which about
10% were treated with C-ion RT.
Characteristics of carbon ionsPhysical aspects

The application of RT is based on the fundamental
principle of achieving precise dose localisation in the target lesion while causing minimal damage to surrounding
normal tissues. Energy deposition of carbon ion beams increases with penetration depth up to the sharp maximum
Correspondence: tohno@gunma-u.ac.jp
Gunma University Heavy Ion Medical Center, Gunma University, Showa
3-39-22, Maebashi, Gunma 371-8511, Japan

at the end of their range, known as the Bragg peak. Because the original peak is too narrow and sharp to completely cover the target lesion, broadening of the narrow
peak (spread-out Bragg peak (SOBP)) according to the sizeof the lesion is used in cancer treatment [1,2]. This resultsin carbon ion beams allowing a highly localised depositionof energy that can be utilised for increasing radiation doses
to tumours while minimising irradiation to adjacent normal tissues (personalised cancer treatment). Proton therapy
also possesses this property. However, the lateral fall-off
around the target is steeper with carbon ion beams thanproton beams. In the region beyond the distal end of thepeak, almost no dose is deposited with protons, while asmall dose is deposited with carbon ions. This is because
primary carbon ions undergo nuclear interactions and fragment into particles with a lower atomic number, producing
a fragmentation tail beyond the peak [1]. Figure 1 shows
the difference of dose distribution by one port between carbon ion beams and X-rays. The algorithm of treatment
planning and beam delivery system is tailored to the individual parameters of the patient.

Biological aspects

RT works by damaging the DNA of cancer cells. X-rays
commonly cause single-strand DNA break, and doublestrand DNA break by two hits is essential for cancer cell
death. However, cells have mechanisms for repairing
single-strand DNA damage, and some of them may survive even after treatment. Carbon ion beams deliver alarger mean energy per unit length (linear energy transfer (LET)) of their trajectory in the body compared with© 2013 Ohno; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.

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targetdepth

Carbon ion beams

Relative dose

Relative dose

X-raysLess toxic

targetdepth

Figure 1 The difference of dose distribution by one port between carbon ion beams and X-rays.

low-LET radiations such as protons or photons. As a result, carbon ion beams, which are high-LET radiation,commonly cause double-strand DNA break by one hit,
resulting in the most significant event for cancer cell
death [3].
LET has been used to evaluate the biological effects ofradiations based on the fact that, as LET increases to
100 keV/μm, the larger relative biological effectiveness(RBE) also increases [4]. LET of neutron beams remains
uniform at any depth in the body. In contrast, LET ofcarbon ion beams increases steadily from the point of incidence in the body with increasing depth to reach amaximum in the peak region. This property becomes atherapeutic advantage when carbon ion beams are used
as cancer therapy for deep-seated tumours. In Japan,
where a beam-scattering method with a passive beam
delivery system is used, RBE of three is assumed at the
distal part of the SOBP [5]. In the present review, thedose of carbon ion RT (C-ion RT) is expressed as ‘Gy(RBE)’ (physical carbon ion dose (Gy) × RBE).
High-LET heavy ions also have various biological advantages compared with protons or X-ray beams: decreased oxygen enhancement ratio, diminished capacity
for sublethal and potentially lethal damage repairs, reduced cell cycle-dependent radiosensitivity, potential
suppression of metastases and efficacy for cancer stemlike cells [6-8]. These characteristics offer theoretical advantage for tumours such as adenocarcinoma, adenoid
cystic carcinoma, malignant melanoma and sarcoma thatare highly resistant to low-LET irradiation and thatsometimes cannot be controlled even with simple dose
escalation.

Clinical results of carbon ion radiotherapy
Facilities

At present, there are only five C-ion RT centres in operation in the world [1]: the National Institute of Radiological Sciences in Chiba, Japan, since 1994, Hyogo Ion
Beam Medical Center (HIBMC) in Hyogo, Japan, since2001, the Institute of Modern Physics in Lanzhou,
China, since 2006, Heidelberg Ion-Beam Therapy Center(HIT) in Heidelberg, Germany, since 2009 and Gunma
University Heavy Ion Medical Center, Gunma, Japan,
since 2010 [9]. NIRS is the first C-ion RT facility inJapan using the Heavy Ion Medical Accelerator in
Chiba, and it has been used to treat cancers of various
sites in more than 6,500 patients. Among the above
five facilities, HIBMC and HIT have also performed
proton therapy. In addition, at least seven new C-ion
RT centres are under development, one in Italy, two in
Germany, one in Austria, one in China and two inJapan [1].
Head and neck tumour

Head and neck cancer consists of paranasal andsinonasal cancer and cancer of the salivary gland, lip,oral cavity, pharynx and larynx. Histologically, squamouscell carcinoma is the most common histology. However,photon-resistant type of tumours such as adenocarcinoma, adenoid cystic carcinoma, malignant melanoma
and sarcoma are sometimes observed. C-ion RT has
been employed mainly for locally advanced nonsquamous cell carcinomas arising from the paranasal
sinus, nasal cavity, salivary gland, pharynx and oralcavity.

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Mizoe et al. reported the clinical results of a phase II
study of C-ion RT alone in 236 patients with head andneck cancers [10]. Approximately 90% of the patients
had locally advanced disease (T3, T4, local recurrence orresidual disease after surgery), and they were treatedwith 57.6 Gy(RBE) in 16 fractions. The 5-year local control rate by histological type was 75% for the 85 patientswith malignant melanoma, 73% for the 69 with adenoid
cystic carcinoma, 73% for the 27 with adenocarcinoma,
61% for the 13 with papillary adenocarcinoma, 61% for
the 12 with squamous cell carcinoma and 24% for the 14
with sarcomas. The 5-year overall survival rate was 68%
for adenoid cystic carcinoma, 56% for adenocarcinoma
and 35% for malignant melanoma. The 5-year overall
survival rate by histological type was 35% for malignant
melanoma, 68% for adenoid cystic carcinoma, 56% foradenocarcinoma, 31% for papillary adenocarcinoma, 17%
for squamous cell carcinoma and 36% for sarcomas. The
5-year overall survival rate was 68% for adenoid cystic
carcinoma, 56% for adenocarcinoma and 35% for malignant melanoma. Although normal tissue reactions included early grade 3 skin and mucosal reactions inapproximately 10% of the subjects, late reactions were
grade 2 or less. No serious toxicity related to C-ion RT
was observed during the follow-up period. This study
demonstrated that a relatively higher local control rate
was achieved in non-squamous cell carcinomas with acceptable toxicities and that a more intensive approach is
required for sarcoma.
Jingu et al. reported the improvement of local control
with high-dose (70.4 Gy(RBE) in 16 fractions) C-ion RT
for 27 patients with unresectable bone and soft tissue
sarcoma of the head and neck [11]. The 3-year local
control rate and overall survival rate were 91.8% and74.1%, respectively. A comparison with historical results
showed that the 3-year local control rate with 70.4 Gy(RBE) was significantly higher than that with 57.6 or
64.0 Gy(RBE) (92% vs. 24%, p < 0.0001). In addition,
the overall survival with 70.4 Gy(RBE) tended to behigher than that with 57.6 or 64.0 Gy(RBE) (74% vs.
43%, p = 0.09). Regarding the late toxicities, visual loss
was observed in one eye of one patient whose optic
nerve was entirely involved by the tumour. Severe painin the maxillary bone (grade 3) from sequestrum formation was observed in four patients.
Malignant mucosal melanoma in the head and neckhas a poor prognosis, the 5-year overall survival rateusually being about 30% or less [12,13], with a low local
control rate and frequent distant metastases. At NIRS,
based on the poor survival of malignant mucosal melanoma by C-ion RT alone [14], a new protocol of C-ion RT
combined with systemic chemotherapy was developed[15]. Forty-six patients with malignant mucosal melanoma in the head and neck were prospectively treatedPage 3 of 7with concurrent C-ion RT (57.6 or 64.0 Gy(RBE) in 16
fractions) and chemotherapy consisting of dacarbazine,
nimustine hydrochloride and vincristine (DAV therapy).
The 3-year local control rate, distant metastasis-free survival rate and overall survival rate of all patients were
81.1%, 37.6% and 65.3% with a median follow-up time of
19.0 months, showing promising improvement of survival. Further observation will be necessary to confirm
the long-term efficacy and toxicities.
Skull base tumour

In the treatment of skull base tumours, critical organs
such as cranial nerves, eyes, cochlea, brain stem andbrain tissue limit the application of high-dose irradiation
to the target lesion. Chordomas and chondrosarcomas,
known as photon-resistant tumours, have been treatedwith proton therapy or C-ion RT.
The generally accepted treatment for chordomas of theskull base is resection followed by adjuvant radiation therapy for residual disease. Takahashi et al. recommended a
combination of surgical removal of the tumour aroundthe brainstem and the optic nerve with post-operative
C-ion RT in order to improve survival and quality oflife [16]. Munzenrider et al. reported that the local
control rate was 73% at 5 years after proton therapy,
and this decreased to 54% at 10 years, indicating thepossibility of local recurrence even after 5 years [17].
At NIRS, as a result of a dose escalation study of CIRT
for skull base tumours, a dose fractionation of 60.8 Gy(RBE)/16 fractions for 4 weeks was decided as therecommended dose because of acceptable normal tissue
reactions and good local tumour control (100%) [18]. The
latest data from NIRS demonstrated that the 5-year and10-year local control rates were 88% and 80% in patients
receiving this regimen, and they were without severe grade
3 or more late toxicities [1]. Tsujii pointed out that C-ion
RT holds a promising potential of improving long-term
results, most likely due to increased biological effects ofcarbon ions as well as the sharp lateral fall-off permitting
better sparing of critical organs [1].
At the Gesellschaft für Schwerionenforschung (GSI) in
Darmstadt, Germany, 96 patients with chordoma of theskull base have been treated with C-ion RT [19]. The
5-year local control rate was 70% for the entire population and 100% for 12 patients receiving more than 60
Gy(RBE). The 5-year overall survival rate was 89%. In
addition, 54 patients with low-grade and intermediategrade chondrosarcomas of the skull base have beentreated with carbon ion radiation therapy at GSI [20].
Median total dose was 60 Gy(RBE). Only two patientsdeveloped local recurrences. The 5-year local control
and overall survival rates were 90% and 98%. Therefore, similar excellent local control rates were obtained
from both NIRS and GSI experiences.

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Non-small cell lung cancer

Hepatocellular carcinoma

Surgery is the standard treatment of choice for earlystage non-small cell lung tumours, but radiotherapy is agood option for those who cannot undergo surgery. For
peripheral-type stage I non-small cell lung cancers, thelocal control rates in T1 (≤3 cm) and T2 (>3 cm) were64% and 50% for conventional photon therapy [21], 79%
to 92% and 30% to 79% for stereotactic body RT [22-24],
and 82% and 89% and 49% and 62% for proton therapy[25,26], respectively. Timmerman et al. recently reported
that the estimated 3-year primary tumour control andoverall survival rates with stereotactic body RT with 54
Gy/three fractions (T1, 80%; T2, 20%) were 98% and 56%[27]. However, grades 3 and 4 toxicities were reported in
13% and 4% of the patients, respectively. Although tumour
control is clearly related to radiation dose, higher doses
come at the cost of toxicity to normal tissues. Figure 2
shows the comparison of dose distribution between
stereotactic body RT and C-ion RT for stage I non-small
cell lung cancer. The low-dose irradiated volume of lungtissues is lower in C-ion RT than in stereotactic body RT.
In C-ion RT, for peripheral-type stage I non-small celllung cancers, the fraction number and treatment time
have been reduced in gradual steps from 18 fractions/
6 weeks through 9 fractions/3 weeks and 4 fractions/
1 week and eventually to single-fraction treatment. In
129 patients treated at NIRS with the nine- and fourfraction regimens, there were no serious toxic reactions, their 5-year overall survival rates were 50.0%
and 45.0%, and their 5-year local control rates were95% and 90%, respectively [28,29]. Especially, local control of T2 (tumour size > 3 cm) treated with nine or four
fractions was 85%, demonstrating the advantage of C-ion
RT for larger tumour control without severe toxicities.
Considering the theoretical advantage of C-ion RT,
challenging locally advanced non-small cell lung cancer in combination with concurrent chemotherapy is
warranted in the future.

In Japan, chronic hepatitis C is associated with 90% of hepatocellular carcinoma (HCC) cases, and HCC is associated with liver cirrhosis in 85% of all cases. The patientswith HCC often require repeated therapies due to themulticentric nature of carcinogenesis in liver cirrhosis.
Thus, both radical efficacy and minimal invasiveness are
required for the treatment of HCC. As local therapy, avariety of treatment modalities such as complete surgicalresection, hepatic transplantation, radiofrequency ablation,
microwave coagulation therapy, percutaneous ethanol injection and transarterial chemoembolisation have beenused so far, but each of them still has its specific limitations especially for larger tumours (>3 cm) [30].
Since the tolerance of the liver to irradiation is generally
poor, limited-dose X-ray therapy for HCC has resulted inpoor local control and survival. For unresectable HCC patients with or without portal vein tumour thrombosis, the5-year survival rate ranges from 9% to 25% after 50 Gy[30]. Attempts to improve clinical outcomes for patientswith hepatocellular carcinoma have led to the use of
charged-particle therapy. Tsukuba University reported thatthe 3-year local control and survival rates in the porta
hepatis group (72.6 Gy(RBE) in 22 fractions) were 86%
and 45% [31]. The corresponding rates in the non-porta
hepatis group (66 Gy(RBE) in ten fractions) were 95% and
49% [32]. At NIRS, characteristics of the patients undergoing C-ion RT included a disease status for which othertherapies appeared to offer no potential of sufficient efficacy or other treatments had proved to be ineffective in
local tumour control [33]. In 69 patients treated with 52.8
Gy(RBE) in four fractions for 1 week, post-treatment impairment in hepatic function was minimal. The local control and survival rates at 3 years were 88% and 44% in the
porta hepatis group and 96% and 61% in the non-porta
hepatis group. Therefore, in comparison with proton therapy, C-ion RT could offer smaller fractionation regimen
with comparable high local control.

Stereotactic body RTwith 10 ports

C-ion RT
with 4 ports
90%
70%
50%

30%
10%

Figure 2 The difference of composite dose distribution between stereotactic body RT and C-ion RT for stage I non-small cell lungcancer. The low-dose irradiated volume of lung tissues is lower in C-ion RT than in stereotactic body RT.

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Prostate cancer

Okada et al. reported a retrospective analysis of 740
prostate cancer patients in order to compare late radiation toxicity and biochemical control in different dose
fractionation schedules of C-ion RT [34]. C-ion RT was
administered at a total dose of 63 Gy(RBE) or 66 Gy(RBE) in 20 fractions for 5 weeks or a dose of 57.6 Gy(RBE) in 16 fractions for 4 weeks. Patients in both theintermediate- and high-risk groups received androgendeprivation therapy (ADT) combined with C-ion RT.
Neoadjuvant ADT was administered for 2 to 6 months.
Adjuvant ADT was continued for a total duration of 6months for intermediate-risk patients and for more than
24 to 36 months for high-risk patients. ADT use did not
differ by fractionation regimen. Regarding dose fraction,
the 5-year biochemical relapse-free (BRF) rate of all patients treated with 16 fractions of C-ion RT (88.5%) was
nearly the same as that of those treated with 20 fractions(90.2%). Only one case of late grade 3 genitourinary
morbidity was observed in the 20-fraction group, andnone of the patients developed late grade 4 or higher
complications. The incidence of late grade 2 rectal complications was 3.2% for 66.0 Gy(RBE)/20 fractions, 2.3%
for 63.0 Gy(RBE)/20 fractions and 1.5% for 57.6 Gy(RBE)/16 fractions. The incidence of late grade 2 genitourinary complications was 13.6% for 66.0 Gy(RBE)/20
fractions, 6.5% for 63.0 Gy(RBE)/20 fractions and 2.0%
for 57.6 Gy(RBE)/16 fractions. Thus, C-ion RT of 57.6
Gy(RBE) in 16 fractions over 4 weeks, which is only half
the fractions and time used by most of the intensitymodulated radiation therapies and proton beam therapies, could provide a lower incidence of late rectal toxicity
than 20 fractions, with a comparable BRF rate.
Bone and soft tissue tumour

A phase I/II dose escalation study was conducted at
NIRS in 57 patients with 64 sites of bone and soft tissue
sarcomas [35]. At a dose of 73.6 Gy(RBE), 7 of 17 patients developed grade 3 acute skin reaction, and a doseof 70.4 Gy(RBE) or less was recommended for the following phase II study. Although the majority of the tumours were huge (median clinical target volume was559 cm3) and unresectable, local control rates were 88%
and 73% at 1 year and 3 years, and overall survival rates
were 82% and 46% at 1 year and 3 years. The latest dataof 95 patients with medically unresectable sacral
chordomas at NIRS showed 5-year local control andoverall survival rates of 86% and 88%, respectively [36].
Regarding toxicities, 2 patients experienced severe skinor soft tissue complications requiring skin grafts, and 15
patients experienced severe sciatic nerve complications
requiring continuing medication. Based on the analysisof dose-volume histograms, irradiated sciatic nerves ofmore than 10 cm in length and a total dose of more than

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70 Gy(RBE) were possible thresholds for sciatic nerve injury. Considering the fact that the local control rate isabout 60% to 80% in total excision cases and 25% to
50% in subtotal resection cases, C-ion RT seems to be a
promising alternative to surgery.
The 5-year overall survival rates for patients withosteosarcoma of the trunk who underwent resection
were 26% to 41%, while those not receiving surgery were0% to 10% [37,38]. Matsunobu et al. reported a retrospective analysis of 78 patients with medically inoperable
osteosarcoma of the trunk [39]. None of the patients developed grade 3 or 4 late toxicities. The 5-year local control and overall survival rates were 62% and 33%,
respectively. Multivariate analysis demonstrated thatpoor performance status (PS = 2) and large clinical target volume (≥500 cm3) were unfavourable prognostic
factors for survival. Again, C-ion RT for inoperable
osteosarcoma of the trunk could be a promisingalternative.
OthersC-ion RT has been applied to other cancer sites such as
pelvic recurrence after surgery for rectal cancer [40], eyemelanoma [41], renal cell carcinoma [42], gynaecologicalcancers [43,44] and pancreatic cancer [45]. Althoughmost of the cases were photon-resistant tumours, the efficacy of hypofractionated C-ion RT has been demonstrated with acceptable toxicities.
Cost-effectivenessIn Japan, where everyone is covered by health insurance
schemes, all can receive medical treatment equally.
However, medical care costs for malignant neoplasms
are escalating. Although C-ion RT is, at least in theory,
effective, and promising clinical outcomes based on prospective trials have been reported, due to the high construction and operation costs of the accelerator system,
there is still controversy on whether carbon ion RT is
too expensive for the potential outcome improvements
claimed.
In cooperation with Gunma University Hospital (GUH)and NIRS, the cost-effectiveness of carbon ion radiotherapy was compared with conventional multimodality therapy in the treatment of patients with locally recurrent
rectal cancer [46]. Direct costs for diagnosis, recurrent
treatment, follow-up, visits, supportive therapy, complications and admission were computed for each individual
using a sample of 25 patients presenting with this condition at NIRS and GUH. Patients received only radical surgery for primary rectal adenocarcinoma and had isolated
unresectable pelvic recurrence. Fourteen and 11 patients
receiving treatment for local recurrence were followed at
NIRS and GUH, respectively. Treatment was carried out
with C-ion RT alone at NIRS, while multimodality therapy

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including three-dimensional conformal radiotherapy, chemotherapy and hyperthermia was performed at Gunma University Hospital. The 2-year overall survival rate was 85% and
55% for C-ion RT and multimodality treatment, respectively.
The mean cost was 4,803,946 JPY for the C-ion RT groupand 4,611,100 JPY for the multimodality treatment group.
The incremental cost-effectiveness ratio for C-ion RT was
6,428 JPY per 1% increase in survival, demonstrating thecost-effectiveness of C-ion RT. The median duration of total
hospitalisation was 37 days for C-ion RT and 66 days for themultimodality treatment group.
At GSI, the cost-effectiveness of C-ion RT for patientswith skull base chordoma was analysed based on thevarious scenarios for the local control rate and reimbursements of C-ion RT [47]. When local control rate
for skull base chordoma achieved with C-ion RT exceeds
70%, the overall treatment costs for C-ion RT are lower
than for conventional RT. The cost-effectiveness ratio
for C-ion RT is 2,539 euros per 1% increase in survival
or 7,692 euros per additional life year.

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beam delivery system is tailored to the individual parameters of the patient. The biological benefits of C-ion RT
have been demonstrated in inoperable cases with various
types of sarcoma, adenocarcinoma, adenoid cystic carcinoma and malignant melanoma arising from various
sites that are well known as photon-resistant tumours.
For non-small cell lung cancer (stage I) and hepatocellular carcinoma, short-course C-ion RT using small fraction resulted in high local control. The potential benefit
exists in larger tumour (>3 cm) because low-dose irradiated volume of normal tissues is lower compared withstereotactic body RT and because higher dose with highLET beams can be given. In intermediate- and high-risk
groups of prostate cancer, the regimen with 16 fractionsfor 4 weeks attained excellent biochemical relapse-freerate without severe late toxicities. On the other hand,definite proportions of the patient population who receive C-ion RT develop distant metastasis even after excellent local control. Further clinical trials consisting of
C-ion RT with existing or developing cancer therapy will
be required in order to investigate survival benefit.

Recommendations

Based on the clinical trials conducted at NIRS and GSI,
C-ion RT has the following characteristics: (1) By location, C-ion RT is effective in tumours of the head andneck, skull base, lung, liver, prostate, bone and soft tissue sarcoma, etc. (2) By pathological type, it is effective
against non-squamous cell types of tumours for whichphoton therapy has little effectiveness, including adenocarcinoma, adenoid cystic carcinoma, malignant melanoma, sarcoma, etc. (3) Compared with photon therapy,
small-fraction regimens (from a single fraction to 16 fractions) can be performed within a short treatment period.
Outlook

Since the tailor-made treatment planning and beam delivery systems are still developing in the field of C-ion
RT, personalised cancer treatment will be further improved in the next decade. Especially, the managementof organ motion, tumour shrinkage and deformation andimage-guided adaptive treatment strategy will enhance
the high precision of beam delivery. Unfortunately, due
to the limited number of facilities, most clinical data
have been reported from a single institution. In order toincrease the impact of evidence level, multi-institutional
clinical trials on seeking optimal dose and fractionationof C-ion RT, combined treatments of C-ion RT withexisting or developing cancer therapy, and socio-economical
impact of small-fraction regimens of C-ion RT will bewarranted.

Conclusions
Based on the unique biophysical characteristics of carbon ion beams, the algorithm of treatment planning andCompeting interests
The author declares that he has no competing interests.
Acknowledgements
The author thanks Dr. Kanai, Dr. Yamada, and Dr. Nakano of Gunma
University for providing scientific suggestions. This work was supported by
the Heavy Ion project of Gunma University.
Received: 28 December 2012 Accepted: 20 February 2013
Published: 4 March 2013
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doi:10.1186/1878-5085-4-9
Cite this article as: Ohno: Particle radiotherapy with carbon ion beams.
The EPMA Journal 2013 4:9.