Carbon Ion Radiotherapy at NIRS Rationale, Technique, Results and Future… Tadashi KAMADA, MD Research Center for Charged Particle Therapy National Institute of Radiological Sciences Chiba, JAPAN ESTRO Teaching Course on Proton and Ions March 25-29 Uppsala, Sweden
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Carbon Ion Radiotherapy at NIRS
Rationale, Technique, Results and Future…
Tadashi KAMADA, MD
Research Center for Charged Particle Therapy National Institute of Radiological Sciences
Chiba, JAPAN
ESTRO Teaching Course on Proton and Ions March 25-29
Uppsala, Sweden
Rationale Carbon ion beam has a definite range and the Bragg peak. In addition to this physical selectivity, ionization is enormous at the Bragg peak, while remains low at the plateau, showing biological advantages such as cell cycle independent effect.
Therefore, carbon beam could be a potentially curable armament for radio-resistant tumors with minimal normal tissue injury.
“Four Rs” in Radiobiology
From E. Hall : Radiobiology for the Radiologist
1920~1930s in Paris
Repair Redistribution Reoxygenation Repopulation
0
20
40
60
80
100
0 20 40 60 80 100 120 140 160
TUM
OR
CO
NTR
OL(
%)
DOSE (Gy)
γ-ray
Single fraction
5 Fractions 0
20
40
60
80
100
0 20 40 60 80 100 120 140 160
TUM
OR
CO
NTR
OL(
%)
DOSE (GyE)
Carbon 74 keV/ m m
Single fraction
5 Fractions
γ-ray Carbon
5 fractions
Ando et al. unpublished data at NIRS
Repair
Comparison of radiation cell survival levels in synchronized CHO cells irradiated with 4 Gy X-rays
Hypo-fractionation matches with high LET conformal C-ion beam
Experiments with carbon ions and fast neutrons demonstrated that increasing their fraction dose tended to lower the RBE for both the tumor and normal tissues, but the RBE for the tumor did not decrease as rapidly as the RBE for the normal tissues.
These results substantiate that the therapeutic ratio increases rather than decreases even though the fraction dose is increased.
Another Biological Background for Hypofractionated Radiotherapy with Carbon Ion beams
Koike S, et al: Radiat Prot Dos. 2002;99: 405-408. Ando et al. : J.Radiat.Res. 2005;46:51-57. Denekamp J: Int J Radiat Biol. 1997;71: 681-694,.
To prove efficacy and safety of C-ion RT
Carbon Ion Clinical Trials at NIRS
a) Establish safe and precise C- ion RT technique b) Conduct phase I study ⇒ phase II study 1. Achieve local control in radio-resistant tumor 2. Demonstrate hypo-fractionation in common cancer (and conduct comparative study, if necessary)
Based on “high physical selectivity” & “biological effectiveness”
Technical aspect of carbon ion radiotherapy at HIMAC
Fixed beam line Passive beam Hitting a moving target SOBP; Dose description
Key-words
Simulation and Rehearsals Treatment Planning
CT gantry PSD
LED
Obtain CT data (Respiratory-gated)
Immobilization Devices
CT+MRI
CT+PET
Treatment Planning for Head and Neck Tumor Using Fusion Images
ACC
After RT
Before RT
Dose distributions
Fabrication of Bolus and Collimator
Collimator is made of brass
Bolus is fabricated with NC machine
3-D alignment to check accuracy
Treatment in 2007(Pats;642) Bolus≒2,500 Collimator≒1000 *MLC was also used
Trea
tmen
t Pla
nnin
g
Key-Tech for C-ion RT at NIRS
End-expiratory irradiation
Respiration gating for irradiation
Reduction of volume Minohara et al. IJROBP 47:1097-1103, 2000
50%
90%
64GyE/16Fx/4weeks
Patch Field Technique for Ion Beam
CT image 8 years after (Alive NED at 10 years)
Spacer Insertion Liposarcoma of the retroperitoneum(p/o rec) 54F
Spacer
After Gore-Tex
Colon
Before
Retroperitoneal liposarcoma
Before After 6 months
70.4 GyE/16fx with spacer
Key Tech in C-ion RT at HIMAC
• Respiration gating: 3089 patients lung, liver, pancreas, kidney, sarcoma etc • Patch field : 294 patients Head & Neck, para-spinal etc. • Spacer insertion :150 patients pelvis and abdomen
20
More than 3000 patients were treated with these techniques at NIRS.
The Image Intensifier was replaced by high resolution FPD
Treatment Room
Positioning with orthogonal projections
Horizontal Beam
Vertical Beam
I I FPD
Treatment Rooms
Room for Biological Experiments
Beam Lines for Physics Research
Ion Source Linear
Accelerators
Main Accelerator (Synchrotron)
HIMAC(Heavy Ion Medical Accelerator in Chiba)
• Ion : He ~ Ar Max energy: ~800Mev/n • Treatment room(3) Fixed vertical : room A Fixed horizontal : room C Fixed V & H : room B • The accelerated energy V. beam (290 or 350 MeV/u) H beam (290 or 400 MeV/u) • The range of C-ion beam in water 290-MeV/u : 15 cm 350-MeV/u : 20 cm 400-MeV/u : 25 cm • Maximum field size 15 cm by 15 cm
A B C
Specification of HIMAC
Sato et al. Nuclear Physics A. 1995; 588: 229—234 small
To produce uniform irradiation fields, a passive beam delivery system was employed. We use a pair of wobbler magnets and a scatterer. The range shifter is used for adjusting the residual range of carbon ions in the patient. The ridge filter is used to spread out the Bragg peak in the depth-dose distribution of carbon ions.
Kanai et al. IJROBP1999, 44:201-210
Irrespective of the size of SOBP, RBE value was estimated to be 3.0 at the distal part of SOBP. Ridge filter was designed to produce a physical dose gradient of SOBP so that the biological effect along SOBP became uniform. This was based on the biologic response of HSG tumor cells at 10 % survival level. The biologic response flatness along SOBP was checked by measurement of physical dose and dose-averaged LET.
Spread Out Bragg Peak in Carbon Ion Therapy at NURS
Kanai et al. Radiat Res 147:78-85,1997
0
1
2
3
4
5
6
7
0 50 100 150 200
Depth-dose profile of 12C - 290 MeV/n
Rela
tive
Dos
e [G
y or
GyE
]
Depth in Water [mm]
120 mm 100 mm80 mm
60 mm
40 mm
20 mm
Clinical Dose(GyE)
RBE=2.38
Ridge filter
3.0 0.0
0.5
1.0
1.5
2.0
2.5
-50050100150
Carbon 290 MeV/n, 60mm SOBP
HSG
HeLa
T98HT1080
HK
t heor y
Rel
ativ
e B
iolo
gica
l Dos
e
Residual Range [mm]
Biological check
SOBP
Results
The Domain of Carbon Ion Therapy
• with large proportion of hypoxic cells • do not well re-oxygenate • with broad-shouldered dose survival curves by low LET
radiation • slowly proliferating
Tumors ; biological view points for high LET beam(theoretical)
Tumors ; clinical context (practical) •empirically radio-resistant, such as sarcomas, melanoma, RCC, thyroid ca, and re-irradiation •located close to the radiosensitive organs ; para-spinal •decline other therapies such as second surgery, limb amputation, concurrent chemo-radiation etc. •unresectable or medically inoperable •All quest for better outcomes
Protocols and Time Line of Carbon Ion Clinical Trials (1994-2010)
④ 12x/3w
Patient Distribution Enrolled in Carbon Ion Therapy at NIRS (Treatment: June 1994~July 2011)
Prostate 1382(20.9%)
CP:1057
Bone & Soft tissue 901(13.6%)
CP:666
Head & Neck 763(11.5%)
CP:440
Lung 695(10.5%)
CP:118
Liver 443(6.7%)
CP:213
P/O rectum341(5.2%
) CP:274
GYN170(2.6%)
Eye 114(1.7%)
CP:72
Pancreas 175(2.6%)
CP:1
CNS105(1.6%)
Skull Base 81(1.2%)
CP:52
Esophgus65(1.0%)
PA L/N 69(1.0%) CP:62
Lacrimal 23(0.3%)
Scanning 8(0.1%)
Re-irradiation 75(1.1%)
CP:16
Miscellaneous 1208(18.3%)
CP:538
Total 6,619
Clinical Practice: 3,509
1) C-ion RT is successful in the not treatable by other means
• Advanced Head & Neck cancers • Large skull base cancers • Post-op recurrent rectal cancer • Inoperable sarcoma • Re-irradiation after photon radiotherapy
• Lung cancer ( Single irradiation) • Liver cancer ( Two fractions) • Pancreatic cancer (8-12 fractions) • High risk prostate cancer (16 fractions)
2) Promising results are obtained in C-ion hypo- fractionated RT
Dose-fractionations determined by dose escalation studies for carbon ion RT at NIRS
6
Carbon Ion Radiotherapy for Head-and-Neck Tumors
Phase II (9602) n=360 64 or 57.6 GyE/16 fr./4 wks
April 1997~
94 95 96 97 02 03 04 05 98 99 00 01 06 07 08 09
June 1994~
Phase I/II (9301)
18 fr./4 wks
April 1996~
Phase I/II (9504)
16 fr./4 wks
~ ongoing
0 20 40 60 80 100 120 140 160 Tx T1 T2 T3 T4
Rec. after surgery Rec. after chemotherapy
Rec. after surgery & Chemo
Mizoe et al. Int J Radiat Oncol Biol Phys. 2004;60:358-364 Hasegawa et al. Int J Radiat Oncol Biol Phys. 2006;64:396-401 Yanagi et al. Int J Radiat Oncol Biol Phys. 2009;74:15-20
PRO
BABI
LITY
TIME IN MONTHS
5-year Local Control Rate ACC (129) 76% MMM(102) 76% Adeno(42) 77% SCC(20) 70%
Local Control according to Histological Type (Apr 97~Aug 09) Phase II (9602) for Malignant Head-and-Neck Tumors
Carbon Ion Radiotherapy for Head-and-Neck Tumors
Phase II (9602) n=360 64 or 57.6 GyE/16 fr./4 wks
April 1997~
94 95 96 97 02 03 04 05 98 99 00 01 06 07 08 09
June 1994~
Phase I/II (9301)
18 fr./4 wks
April 1996~
Phase I/II (9504)
16 fr./4 wks
~ ongoing
Phase II (with chemo)n=85 Malignant Melanoma
16 fr./4 wks + DAV x 5 courses
April 2001~
Phase II (high dose )n=33 Bone & Soft Tissue
70.4 GyE/16 fr./4 wks
April 2001~
•Late recurrence in ACC with 57.6 GyE •High distant mets in melanoma •Poor local control in sarcomas with standard dose
→ 64 GyE
Local Control of ACC (n=129) according to Carbon ion Dose
57.6 GyE (n=75) 5-year; 73%
64 GyE (n=54) 5-year; 95%
TIME IN MONTHS
PRO
BABI
LITY
OF
LC
Phase II (9602) for Malignant Head-and-Neck Tumors
Combined Chemotherapy and C-ion RT for MMM
Local Control and Overall Survival of Mucosal Malignant Melanomas
TIME IN MONTHS
PRO
BABI
LITY
C-ions alone (n=102) 5-year; 76%
C-ions + DAV n=85) 5-year; 81%
PRO
BABI
LITY
C-ions alone (n=102) 3-year; 53%, 5-year; 37%
C-ions + DAV ( n=85) 3-year; 67%, 5-year; 62%
TIME IN MONTHS
Local Control Overall Survival
Five-year Survival Rates in Mucosal Malignant Melanoma of the Head & Neck
1) Gilligan D et al. Br J Radiol 1991; 64: 1147-1150. 2) Shibuya H et al. IJROBP 1992; 25: 35-39. 3) Chang AE et al. Cancer 1998; 78: 1664-1678. 4) Shah JP et al. Am J Surg 1977; 134: 531-535. 5) Patel SG et al. Head Neck 2002; 24: 247-257. 6) Lund VJ et al. Laryngoscope 1999; 109: 208-211. 7) Chaundhry AP et al. Cancer 1958; 11: 923-928.
Local Control and Overall Survival compared with Carbon Ion Dose
Bone and Soft-Tissue Sarcomas (Head & NECK) Low Dose Carbon vs. High Dose Carbon
TIME IN MONTHS
PRO
BABI
LITY
70.4 GyE (n=33) 3-year; 92%, 5-year; 79%
64 or 57.6 GyE( n=14) 5-year; 24%
PRO
BABI
LITY
70.4 GyE (n=33) 3-y; 76%, 5-y; 54%
64 or 57.6 GyE (n=14) 3-year; 43%, 5-year; 36%
TIME IN MONTHS
Local Control Overall Survival
Jingu et al. IJROBP.2011
Unresectable sacral chordoma 5 years after C-ion RT Sacral osteosarcoma
13 years after C-ion RT
Calf soft tissue sarcoma 5 years after C-ion RT
Pelvis chondrosarcoma 28 months after C-ion RT Married and had her baby
Late Skin Reaction in B & STSs
No of Pts Gr3-4 (%)
2000~2001 25 7 (28)
Total Dose : 73.6 Two direction Skin margin
70.4 or less Three direction or more Reduced skin margin
Risk factor
2002~2005 151 2 (Modified group)
Modifications
Yanagi et al.Radiotherapy and Oncology. 2010;95:60-65
Chordoma of the sacrum Case 1 Case 2 Case 3
•3% of all primary bone sarcoma (50% from sacrum bone) •Radio-chemo-resistant nature •Difficulty in surgery due to its location •Slow growing, sometimes presenting huge tumor size
Chordoma of the sacrum Case 1 Case 2 Case 3
6 years 5 years 6 years
Local Control & Survival Rate in Chordoma(sacrum & mobile spine)
No. Site treatment Local Survival of Pts. 5-year 5year 10year (new pts /y)
MGH 1) 21 S surgery 77% - 50% 1972-1992 (1.1) Sweden 2) 39 S+Sp surgery 44 84% 64% 1963-1998 (1.1)
MGH. 3) 27 S surgery 72 82 62 1982-2002 (2.7 ) + Proton
LBL 4) 14 S surgery 55 85 22 1977-1989 (1.2 ) + He-ion Mayo 5) 52 S surgery 56 74 52 1980-2001 (2.5 ) NIRS 6) 145 S+Sp C-ion 85 85 47 1996-2009.2 (11 ) 1) J Bone Joint Surg. 1998 2) Cancer.2000 3)IJROBP.2006 4) IJROBP.1993 5) J Bone Joint Surg. 2005 6)BJR. 2011
S:sacrum Sp:mobile spine
(disease free)
Factors in Re-irradiation • Regrowth of a radio-resistant clone; cancer stem-like cells? • Tumor bed effect: damage of tumor vasculatures and stromal elements(fibrosis and necrosis) - poor blood supply and impairment of local defense (immune? ) system • Low tolerance of surrounding normal tissue
High risk of serious morbidities with poor tumor control
Re-irradiation
80 70 60 50 40 30 20 10 0
1.0
.8
.6
.4
.2
0.0
Overall Survival (n=60)
Local control(n=68)
Local Control and Survival in Re-irradiation with Carbon Ion Beam
Treatment started as the clinical trial on May 17, 2011.
scatterer collimator compensator ridge filter
Beam delivery techniques
• Broad-beam irradiation
Scanning irradiation
More flexible in irradiation field shaping
wobbler magnets
scanning magnets
range shifter
63
Sep. 2010 - First beam in the scanning treatment room. Jan. 2011 - Commissioning report on the C-ion scanning treatment (170 pages) approved by the extramural review committee for Q/A. Feb. 2011 - IRB review and approval of the clinical protocol of the C-ion scanning. May. 2011 - First patient was treated. (1.5 months behind the schedule due to unstable power supply after the East Japan Earthquake)
From First Beam to First Patient in C-ion Scanning
Scanning : First patient : 5/17/’11 Patient # Site Start
Future Direction in Prostate More Hypo-fractionation : 8 fr./2 wks 4 fr./1wk or more…. Reduce the OAR dose Urethral Dose Reduction
It can be realized with“Dose-painting by precise image guided C-ion RT with scanning”
Beam monitor (scanning treatment)
Fast Re-scanning for Moving Target
↑ Moving target
↑ Position Monitor
Single scanning
8 times rescanning
< ±2.5%
Dose error
Confirmation of the 3D fast scanning(100m/sec) technology for moving target.
Furukawa et al. Med Phys. 2010;37(11):5672-82 Furukawa et al. Med Phys. 2010;37(9):4874-9.
52m
40m
Super MINIMAC - A Future Facility
C-ion : 400 MeV/n Synchrotron : diameter 6 m Gantry : Size 8x10 m (3 rooms) : Weight 100~150 tons
NM:350 tons
SCM:100 tons
C-ion400MeV/n Gantry
Super MINIMAC : Superconducting Magnet Installed Ion Medical Accelerator in Chiba
Specification of Super MINIMAC
◆In the past 17 years, more than 6,600 patients were treated with C-ion RT at NIRS.
◆Almost 50 protocol studies (Phase I/II and Phase II) have been performed to investigate optimal irradiation techniques, dose fractionation, and to find indications for C-ion RT.
◆For various types of tumors, hypofractionated carbon ion radiotherapy (average:13.0 frs per patient) has been established with acceptable morbidities.
◆Better local control and survival are brought by carbon ion therapy in many photon resistant advanced tumors.
◆The next generation carbon therapy system has been under development to provide more advanced treatment.
Clinical Study on C-ion RT at NIRS –Summary
No dose, No effect ! (….with some biological help)