Benefit of Carbon Ion Radiotherapy in the Treatment of
Radio-resistant Tumors
Tadashi Kamada, Hirohiko Tsujii, Hiroshi Tsuji, Tsuyoshi Yanagi, Reiko
Imai, Jun-etsu Mizoe, Tadaaki Miyamoto, Hirotoshi Kato, Shigeru Yamada,
Shingo Kato, Kyousan Yoshikawa, and Susumu Kandatsu
Research Center Hospital for Charged Particle Therapy, National Institute of Radiological Sciences
Chiba 263-8555, JAPAN
Abstract. The Heavy Ion Medical Accelerator in Chiba (HIMAC) is the world’s first heavy ion accelerator complex
dedicated to medical use in a hospital environment. Heavy ions have superior depth-dose distribution and greater
cell-killing ability. In June 1994, clinical research for the treatment of cancer was begun using carbon ions generated by
HIMAC. Until August 2002, a total of 1,297 patients were enrolled in clinical trials. Most of the patients had locally
advanced and/or medically inoperable tumors. Tumors radio-resistant and/or located near critical organs were also
included. The clinical trials revealed that carbon ion radiotherapy provided definite local control and offered a survival
advantage without unacceptable morbidity in a variety of tumors that were hard to cure by other modalities.
We are pleased to report that carbon ion beam shows
remarkable therapeutic efficacy in a variety of tumors
that were difficult to cure with other modalities.
INTRODUCTION
In 1946, Robert Wilson first suggested that beams
of atomic nuclei might have therapeutic usefulness.1
Clinical research using such a beam, a carbon ion beam,
has been rigorously carried out at the National Institute
of Radiological Sciences, Chiba, Japan, since 1994.2
Among the high linear energy transfer (LET)
particle beams used for cancer treatment, the carbon ion
beam possesses unique physical and biological
properties.3, 4 It has a well-defined range and
insignificant scatter in tissues, and the energy release is
enormous at the end of its range. This well-localized
energy deposition (high-dose peak) at the end of the
beam path, called the “Bragg peak”, is a unique
physical characteristic of charged particle beams, as is
the induction of more cell cycle- and
oxygenation-independent, irreversible cell damage than
that observed with low LET radiation.
In order to investigate these useful properties, we
conducted carbon ion radiotherapy clinical trials in
patients with various types of malignant tumors.
PATIENTS AND METHODS
Between June 1994 and August 2002, a total of
1,297 patients were enrolled in clinical trials using
carbon ion beams generated by the Heavy Ion Medical
Accelerator in Chiba (HIMAC). Carbon ion
radiotherapy of these patients was carried out by 37
different phase I/II or phase II protocols. Of these, 17
were already closed for patient registration, and 20are
still on-going. Six phase II protocols were activated for
head and neck, lung, liver, prostate, and bone and soft
tissue tumors. Patients were included in the trials if they
had histologically confirmed malignant tumors, that
were judged unresectable by the referring surgeon, if
they were poor surgical candidates, or if they declined
surgery. Patients who had prior radiation therapy at the
same site were excluded from the study. The tumor had
to be grossly measurable, but the size could not exceed
15 cm. Eligibility criteria included Karnofsky
CP680, Application of Accelerators in Research and Industry: 17th Int'l. Conference, edited by J. L. Duggan and I. L. Morgan
© 2003 American Institute of Physics 0-7354-0149-7/03/$20.00
1142
Tumor sites and annual patient accrual are listed in
Table 1. We treated more than 200 patients/year in
more recent years. Lung, head & neck, prostate, liver,
and bone and soft tissue tumors were the most frequent
5 tumors in the trials.
performance status score > 60, and estimated life
expectancy of at least 6 months. Exclusion criteria were
having another primary tumor or infection at the tumor
site.
TABLE 1. Patient Distribution of Carbon Ion Radiotherapy at NIRS (Treatment: June 1994～August 2002)
Sites
1994 1995 1996 1997 1998 1999 2000 2001 2002 Total
%
Head & Neck
9
10
19
31
22
38
29
39
10
207
16.0
Brain
6
8
10
6
9
7
15
10
3
74
5.7
Base of Skull
6
4
2
2
4
2
20
1.5
Lung
6
11
27
17
28
33
45
51
27
245
18.9
Liver
12
13
19
25
17
22
28
9
145
11.2
Prostate
9
18
10
30
30
31
44
18
190
14.6
Uterus
9
13
11
10
11
13
5
6
78
6.0
Bone/soft tissue
9
13
19
18
25
23
14
121
9.3
Esophagus
1
16
4
2
23
1.8
Pancreas (pre/op)
3
7
8
18
1.4
Rectum (post /ope pelvic rec)
10
5
15
1.2
Eye (advanced)
8
5
13
1.0
Miscellaneous
24
16
30
17
32
14
12
3
148
11.4
Total
21
83
126
159
168
188
201
241
110
1297 100
HIMAC is the world’s first heavy ion accelerator
complex dedicated to medical use.5, 6,7 there are 3
treatment rooms with fixed vertical and/or horizontal
beam lines. The accelerated energy of the vertical beam
is 290 MeV or 350 MeV, and that of the horizontal
beam is 290 MeV or 400 MeV.
The patients were positioned in customized cradles
and immobilized with a low-temperature thermoplastic
sheet. A set of 5-mm thick CT images was taken for
treatment planning with the immobilization devices.
Respiratory gating of both CT acquisition and therapy
was performed when indicated.8 A margin of 5 mm was
usually added to the clinical target volume to create the
planning target volume. The clinical target volume was
covered by at least 90% of the prescribed dose.
Dose was calculated for the target volume and any
nearby critical structures and expressed in
Gray-Equivalent (GyE = carbon physical dose (Gy) x
Relative
Biological
Effectiveness
{RBE}).
Radiobiological studies were carried out in mice and in
5 human cell lines cultured in vitro to estimate RBE
values relative to megavoltage photons. Irrespective of
the size of the SOBP (Spread-out of the Bragg Peak),
the RBE value of carbon ions was estimated to be =3.0
at the distal part of the SOBP. 7
Carbon ion radiotherapy was given once daily, 3 to
4 days a week, for 4 to 24 fractions in 1 to 6 weeks. At
every treatment session, the patient’s position was
verified with a computer-aided on-line positioning
system.
The absence of local failure in the treatment volume
based on CT, MR, and PET imaging was defined as
local control.
The duration of survival and local control were
defined as the interval between the initiation of carbon
ion radiotherapy and the date of death or the date of
diagnosis of local failure, respectively.
For acute reactions, the Radiation Therapy
Oncology Group (RTOG) acute scoring system was
employed, and for late reactions, the Late Effects of
Normal Tissues (LENT) / Subjective, Objective,
Management, and Analytic (SOMA) scoring system
was used in addition to the RTOG/EORTC (European
Organization for Research and Treatment of Cancer)
late scoring system.9, 10
RESULTS
A total of 1,087 patients with a follow-up period of
6 months or more were included in this analysis. Local
tumor control rate and survival in five major tumor
sites; head & neck, lung, liver, prostate, and bone and
soft tissue tumors are summarized in Table 2.
The head & neck protocols were performed on
locally advanced tumors. Two dose-escalating
protocols were carried out, and then a fixed
16-fraction-over-4-weeks
phase-II
study
was
conducted. The two-year local control rates of these
studies were 80, 71 and 69 %, respectively. The
1143
treatment time of 5 weeks was then shortened to 3, 2
and 1 week(s) in the following protocols. The results of
these protocols were also quite favorable. The two-year
local control rates in the first 2 studies were 79 % and
85 % and the three-year survival rates were 50 % and
45 %. A phase II study using 4 fractions in one week is
currently underway.
A fixed 20-fractions-over-5-weeks protocol was
employed for all prostate cancer studies. At first, a
dose-escalation study was carried out, and the optimal
total dose was determined to be 66 GyE. No local
recurrence has been observed during initial 24-month
follow-up, and the survival rates so far are very high.
Unresectable bone and soft tissue tumors were
treated with fixed 16-fractions-over-4-weeks phase-I/II
and-II studies. Despite the fact that bone and soft tissue
tumors are among the most radio-resistant tumors, the
two-year local control rates in 2 studies were 77 % and
90 %, and the three-year survival rate in the phase-I/II
study was 49 %. Carbon ion radiotherapy seems to be a
safe and effective modality in the management of bone
and soft tissue sarcomas not eligible for surgical
resection, providing good local control and offering a
survival advantage without unacceptable morbidity.2
three-year survival rates were 47, 42 and 41%,
respectively. In these studies, non-squamous cell
cancers such as malignant melanoma, adenoid cystic
carcinoma and adeno-carcinoma, all considered to be
radio-resistant, showed better outcomes compared to
squamous cell cancer.
The type of lung cancer chosen for the study was
on-small cell lung cancer. Patients with medically
inoperable stage I tumor were treated by several
protocols.
We
started
with
a
fixed
18-fraction-over-6-weeks dose-escalating study, and
then shortened the overall treatment time to 3 weeks in
the subsequent 3 protocols. The two-year local control
rates were 62 to 100%, and the three-year survival rates
were 65 to 88 %. These results are better than those of
conventional photon radiotherapy, and are almost the
same as those of surgical treatment. We have been
conducting a fixed 4-fractions-over-1-week protocol
for stage I non-small cell lung cancer since 2000. We
are able to give a very high dose in one week without
unacceptable side effects. Although it is too early to
draw definite conclusions, the interim results look quite
promising.
For
liver
cancer,
a
15-fixed-fractions-over-5-weeks
dose-escalating
protocol was
carried out initially. The overall
TABLE 2. Results of carbon ion radiotherapy in 5 major tumors at NIRS (Treatment: June 1994～February 2002)
No. of
2-year
3-year
Protocol
Phase
Material
Treatment
patients
local
survival
(Dosea)/fx/week)
control
47%
80%
17
48.6-70.2/18/6
Locally
I/II
Head & Neck-1
advanced
42
71
19
52.8-64/16/4
Locally
I/II
Head & Neck-2
advanced
41
69
148
57.6or64/16/4
Locally
II
Head & Neck-3
advanced
88
62
47 (+1)
59.4-95.4/18/6
Stage I (peripheral)
I/II
Lung-1
65
86
34
68.4-79.2/9/3
Stage I (peripheral)
I/II
Lung-2
100
14
57.6-64.8/9/3
Stage I (Hilar)
I/II
Lung-3
73
100
50 (+1)
72/9/3
Stage I (peripheral)
II
Lung-4
32
52.8or60/4/1
Stage I (peripheral)
I/II
Lung-6
Liver-1
I/II
T2-4N0M0
49.5-79.5/15/5
24 (+1)
79
50
Liver-2
I/II
T2-4N0M0
48-69.6/4-12/1-3
82 (+4)
85
45
Liver-3
II
T2-4N0M0
52.8/4/1
26
54.0-72.0/20/5
Stage B2-C
I/II
Prostate-1
94
100
35
(+ hormone)
60-66/20/5
Stage B2-C
I/II
Prostate-2
97
100
61
(+ hormone)
63or66/20/5
Stage T1C-C
II
Prostate-3
100
74
(+ hormone)
Bone/soft tissue-1
I/II
Un-resectable
52.8-73.6/16/4
64
77
49
Bone/soft tissue-2
II
Un-resectable
70.4or73.6/16/4
47
90
a)
GyE (gray equivalent)
1144
TABLE 3. Normal tissue morbidity in carbon ion radiotherapy at NIRS (Treatment: June 1994～February 2001)
Early (<3 months)
Late (>3 months)
Sites
No.
0
1
2
3
4
5
No.
0
1
2
3
4
5
Skin
Scalp
84
26
43
14
1
0
0
84
78
6
0
0
0
0
Head & Neck
201
1
83
95
22
0
0
193
80
103 10
0
0
0
Chest
235
2
217
15
1
0
0
226
1
221
4
0
0
0
Upper abdomen
148
14
108
25
1
0
0
148
14
126
6
1
0
0
Lower abdomen
250
187
62
1
0
0
0
248
222
25
1
0
0
0
Others
268
15
152
88
13
0
0
252
34
177 29 10
2
0
Total
1186
245
665
238 38
0
0
1150
429
658 50
11
2
0
(%)
(100) (21) (56) (20) (3) (0) (0)
(100) (37) (57) (4) (1) (0.2) (0)
Mucosa
186
26
70
69
21
0
0
182
142
33
7
0
0
0
Lung
287
267
9
8
3
0
0
273
66
198
9
0
0
0
Intestine
579
494
71
12
2
0
0
551
471
44
18
7
8
0
Bladder/urethra
263
208
51
8
0
0
0
261
176
64
14
7
0
0
3. Blakely, EA, Ngo FQH, Curtis SB, et al: Heavy ion
radiobiology: cellular studies. Adv. Radiat. Biol. 11,
295-378 (1984)
Normal tissue morbidity of carbon ion radiotherapy at
NIRS is listed in Table 3. The incidence of high-grade
reactions was very low through out the study, although
some severe complications were experienced in the
early phase. Analysis using DVHs (Dose Volume
Histograms) of affected organs was rigorously
performed to avoid high-grade complications. Their
incidence as now becomes exceptionally low.
4. Hall, EJ: Radiobiology for the Radiologist. JB Lippincott
Co., Philadelphia, PA, 1988, pp 281-291.
5. Tsujii H, Morita S, Miyamoto T, et al: Preliminary results
of phase I/II carbon-ion therapy. J. Brachyther. Int. 13:1-8
(1997)
CONCLUSIONS
6. Sato K, Yamada H, Ogawa K, et al: Performance of
HIMAC, Nuclear Physics A, 588:229-234 (1995)
Clinical trials revealed that carbon ion radiotherapy
provided definite local control and offered a survival
advantage without unacceptable morbidity in a variety
of tumors that were hard to cure by other modalities.
7. Kanai T, Endo M, Minohara S, et al: Biophysical
characteristics of HIMAC clinical irradiation system for
heavy-ion radiation therapy. Int. J. Radiat. Oncol. Biol.
Phys. 44:201-210 (1999)
ACKNOWLEDGMENTS
8. Minohara S, Kanai T, Endo M, et al: Respiratory gated
irradiation system for heavy-ion radiotherapy. Int. J.
Radiat. Oncol. Biol. Phys. 47:1097-1103 (2000)
We thank the patients who participated in these trials.
These studies were supported by the Research Project
with Heavy Ions at NIRS-HIMAC of the National
Institute of Radiological Sciences.
9. Cox JD, Stetz BS, Pajak TF: Toxicity criteria of the
Radiation Therapy Oncology Group (RTOG) and the
European Organization for Research and Treatment of
Cancer (EORTC). Int. J. Radiat. Oncol. Biol. Phys.
31:1341-1346 (1995)
REFERENCES
10. LENT SOMA Tables: Table of Contents. Radiother.
Oncol. 35:17-60 (1995)
1. Wilson, RR, Radiological use of fast protons. Radiology
47, 487-491 (1947)
2. Kamada, T, Tsujii, H, Tsuji H, et al: Efficacy and Safety
of Carbon Ion Radiotherapy in Bone and Soft Tissue
Sarcomas. J. Clin. Oncol. in press
1145