Carbon Ion Ion Radiotherapy Radiotherapy

NIRS-M- 257 Joint Symposium 2013 on Carbon Ion Radiotherapy

Joint

Joint Symposium Symposium 2013 2013 on on Carbon

Carbon Ion Ion Radiotherapy Radiotherapy

Fostering International Collaboration between Japan and the United States

May 2-3, 2013

DoubleTree Hotel Rochester, Minnesota

A two day symposium sponsored by:

Mayo Clinic Department of Radiation Oncology, Japan National Institute of Radiological Sciences, and Northern Illinois University Institute for Neutron Therapy at Fermilab

JAPAN

USA Mayo Clinic

Department of Radiation Oncology Phone: 507-255-2297

Fax: 507-284-0079 [email protected] [email protected]

Phone: +81-43-206-3025 Fax: +81-43-206-4061

4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan Research Promotion Section

National Institute of Radiological Sciences

NIRS-M- 257

Joint Symposium 2013 on Carbon Ion Radiotherapy

Fostering International Collaboration between Japan and the United States

- 13 ^th NIRS Charged Particle Therapy Research Center Symposium -

May 2-3, 2013

Double Tree Hotel Rochester, Minnesota

A two day symposium sponsored by:

Mayo Clinic Department of Radiation Oncology, Japan National Institute of Radiological Sciences, and Fermi Lab National Accelerator Laboratory/Northern

Illinois University

Dear Colleagues,

We are pleased to welcome you to the Inaugural Joint Symposium on Carbon Ion Radiotherapy on May 2nd and 3rd at the Double Tree Hotel in Rochester, Minnesota.

This two-day symposium on carbon ion radiotherapy is sponsored jointly by Mayo Clinic, the NIU Institute for Neutron Therapy at Fermilab and the National Institute of Radiological Sciences (NIRS) of Japan.

On Day One, physicians from NIRS will present the latest clinical results with carbon ion therapy. There will also be an update on the Heidelberg Ion Therapy Center (HIT) in Germany, the European Network for Light Ion Therapy (ENLIGHT), presentations on the US Vision for hadron therapy from Mayo Clinic and Fermilab/NIU, and relevant radiobiology talks. Day Two will be devoted to presentations and discussions regarding the technology challenges, novel accelerator technologies, beam delivery and gantry designs for ion therapy.

We look forward to a very productive meeting with you all.

Robert C. Miller, M.D.

Mayo Clinic

James S. Welsh, M.D.

NIU Institute for Neutron Therapy at Fermilab

Tadashi Kamada, M.D., Ph.D.

National Institute of

Radiological Sciences, Japan

INDEX

Session 1: Clinical Presentations-NIRS Experience

History of Ion Beam Therapy ・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Hirohiko Tsujii, NIRS

1

Overview of the Carbon Ion Therapy at HIMAC (Including Head and Neck Tumors, and Bone and Soft Tissue Sarcomas) Tadashi Kamada, NIRS

18

Carbon Ion Radiotherapy in a Hypo-fractionation Regimen for StageⅠNon-Small Cell Lung Cancer・・・・・・・・・

Naoyoshi Yamamoto, NIRS

35

Carbon Ion Radiotherapy for Liver Cancer and Prostate Cancer・・・・・・・・・・・・・・・・・・・・・・・・・・

Hiroshi Tsuji, NIRS

46

Carbon Ion Radiotherapy for Patients with Locally Recurrent Rectal Cancer and Pancreas Cancer・・・・・・・・・・

Shigeru Yamada, NIRS

59

Session 2: U.S. and European Perspectives on Carbon Ion Radiotherapy & Radiobiology

Radiobiology of Hypofractionated Radiotherapy・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

David J. Brenner, Columbia

79

Technical and Biological Strategies to Improve the Therapeutic Window in Modern Radiation Oncology・・・・・・・・

Stephanie E. Combs, HIT

* The pages from 87 to 97 are not available in the E-book at request of the author but included in the printed version.

87

ENLIGHT: An Effective Network for Hadron-therapy? ・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Manjit Dosanjh, CERN/ENLIGHT

98

Mayo Clinic Vision for Light Ion Therapy・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Robert C. Miller, Mayo

108

Challenges and Opportunities in Particle Radiation Therapy Research・・・・・・・・・・・・・・・・・・・・・・・・

Bhadrasain Vikram, NIH

116

Current Status & Future Vision: Particle Radiobiology・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Eleanor A. Blakely, Berkeley

117

Session 3: NIRS Experience with Ion Beam Technologies

Overview of NIRS Accelerator Activity ・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Koji Noda, NIRS

131

New Particle Therapy Facility in NIRS, Present and Future Plan・・・・・・・・・・・・・・・・・・・・・・・・・

Toshiyuki Shirai, NIRS

141

Modeling the Clinical and Biological Effect of Therapeutic Carbon Ion Beam・・・・・・・・・・・・・・・・・・・

Naruhiro Matsufuji, NIRS

149

NIRS Scanning System: Present Status and Future Prospects･・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Takuji Furukawa, NIRS

157

TPS for NIRS Scanning: Present Status and Future Prospects・・・・・・・・・・・・・・・・・・・・・・・・・

Taku Inaniwa, NIRS

164

Multi-dimensional Image Guided Particle Therapy・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Shinichiro Mori, NIRS

176

Session 4: US Ion Beam Technologies and Perspectives for the Future

Proton and Carbon Ion CT Imaging for Treatment Planning in Ion Therapy ・・・・・・・・・・・・・・・・・・・・・・・・・・・

George Coutrakon, NIU

187

Advanced Accelerator Technologies for Ion Therapy ・・・・・・・・・・・・・・・・・・・・・・・・・・・・・・

Carol Johnstone, Fermi Lab

194

Joint Symposium 2013 on Carbon Ion Radiotherapy

Fostering International Collaboration between Japan and the United States in Carbon Ion Radiotherapy

A two day symposium sponsored by:

Mayo Clinic Department of Radiation Oncology Japan National Institute of Radiological Sciences

Northern Illinois University Institute for Neutron Therapy at Fermilab Double Tree Hotel, Rochester, MN – May 2-3, 2013

Thursday, May 2, 2013: Clinical Practice, Development Opportunities, and Radiobiology

Time Speakers and Topics

8:00 a.m. Breakfast and Registration Check In 8:30 a.m. Welcome and Introductions

1. Mayo Welcome – Robert C. Miller, M.D.

2. NIRS Welcome – Tadashi Kamada, M.D., Ph.D.

3. NIU/Fermi Lab Welcome – James S. Welsh, M.D.

8:45 a.m. Presentation of Symposium Goals – Michael G. Herman, Ph.D. (Mayo) Session 1: Clinical Presentations – NIRS Experience

Chair, Tadashi Kamada, M.D., Ph.D. (NIRS)

9:00 a.m. History of Ion Beam Therapy Hirohiko Tsujii, M.D., Ph.D. (NIRS)

9:30 a.m. Overview of the Carbon Ion Therapy at HIMAC (Including Head and Neck Tumors, and Bone and Soft Tissue Sarcomas)

Tadashi Kamada, M.D., Ph.D. (NIRS) 10:00 a.m. Break

10:30 a.m. Carbon Ion Radiotherapy in a Hypo-fractionation Regimen for Stage Ⅰ Non-Small Cell Lung Cancer

Naoyoshi Yamamoto, M.D., Ph.D. (NIRS)

11:00 a.m. Carbon Ion Radiotherapy for Liver Cancer and Prostate Cancer Hiroshi Tsuji, M.D., Ph.D. (NIRS)

11:30 a.m. Carbon Ion Radiotherapy for Patients with Locally Recurrent Rectal Cancer and Pancreas Cancer

Shigeru Yamada, M.D., Ph.D. (NIRS)

12:00 p.m. Lunch

Session 2: U.S. and European Perspectives on Carbon Ion Radiotherapy &

Radiobiology

Chair – Robert C. Miller, M.D. (Mayo)

1:00 p.m. Radiobiology of Hypofractionated Radiotherapy David J. Brenner, Ph.D. (Columbia)

1:25 p.m. GSI/HIT Experience with Carbon Ions Stephanie E. Combs, M.D. (HIT)

1:50 p.m. ENLIGHT Vision for Hadron therapy Manjit Dosanjh, Ph.D. (CERN/ENLIGHT)

2:15 p.m. Fermi/NIU Vision for Hadron therapy James S. Welsh, M.D. (NIU/Fermi)

2:40 p.m. Mayo Clinic Vision for Hadron therapy Robert C. Miller, M.D. (Mayo)

3:05 p.m. Break

3:35 p.m. Challenges and Opportunities in Particle Radiation Therapy Research Bhadrasain Vikram, M.D. (NIH)

4:00 p.m. Current Status & Future Vision: Particle Radiobiology Eleanor A. Blakely, Ph.D. (Berkeley)

4:30 p.m. Conclusion of Day #1 Discussion

Friday, May 3, 2013: Technology and Physics Presentations Time Speakers and Topics

8:00 a.m. Breakfast

Session 3: NIRS Experience with Ion Beam Technologies Chair – Koji Noda, Ph.D. (NIRS)

8:30 a.m. Overview of NIRS Accelerator Activity Koji Noda, Ph.D. (NIRS)

9:00 a.m. New Particle Therapy Facility in NIRS, Present and Future Plan Toshiyuki Shirai, Ph.D. (NIRS)

9:30 a.m. Modeling the Clinical and Biological Effect of Therapeutic Carbon Ion Beam

Naruhiro Matsufuji, Ph.D. (NIRS)

10:00 a.m. NIRS Scanning System: Present Status and Future Prospects Takuji Furukawa, Ph.D. (NIRS)

10:30 a.m. Break

11:00 a.m. TPS for NIRS Scanning: Present Status and Future Prospects Taku Inaniwa, Ph.D. (NIRS)

11:30 a.m. Multi-dimensional Image Guided Particle Therapy Shinichiro Mori, Ph.D. (NIRS)

12:00 p.m. Lunch

Session 4: US Ion Beam Technologies and Perspectives for the Future Chair – Michael G. Herman, Ph.D. (Mayo)

1:00 p.m. DOE Perspective on Technology for Ion Therapy Michael Zisman, M.D. (DOE)

1:15 p.m. Ion Workshop Summary Clinical/Radiobiology John O’Connell, M.D. (Walter Reed)

1:45 p.m. Ion Workshop Summary Accelerator and Delivery Chris J. Beltran, Ph.D. (Mayo)

2:15 p.m. Carbon/Proton CT Image-Guidance George Coutrakon, Ph.D. (NIU)

2:45 p.m. Advanced Accelerator Technologies for Ion Therapy Carol Johnstone, Ph.D. (Fermi Lab)

3:15 p.m. Carbon Ion Therapy for Cardiac disease Douglas L. Packer, M.D. (Mayo)

3:45 p.m. Discussion of Symposium Goals

4:45 p.m. Tour of Mayo Clinic and Proton Beam Therapy Program Site

H. Tsujii

National Institute of Radiological Sciences (NIRS) Joint Symposium 2013 on Carbon Ion Radiotherapy Fostering International Collaboration between Japan and the United States

in carbon ion radiotherapy Double Tree Hotel, Rochester, MN – May 2-3, 2013 Joint Symposium 2013 on Carbon Ion Radiotherapy Fostering International Collaboration between Japan and the United States

in carbon ion radiotherapy Double Tree Hotel, Rochester, MN – May 2-3, 2013

History of Ion Beam Therapy

History of Ion Beam Therapy

Neon Carbon Neutron Proton Pion Electron Ｘ-ray

γ-ray ２０Ｎｅ

１２Ｃ

Mass ２０ : １２ : １ ： １ ： 1/7 ：1/1800 : -

１ｎ _１

ｐ

π^- ｅ-

nnn n

nn P P PP

P P Carbon Carbon

Carbon ion Carbon nucleus（6+）

CO2 CH4

nnn nn P P PP

P n P

P P Hydrogen

Hydrogen Proton

（1+）

治療に用いられる粒子線

Nuclei of the atoms that are accelerated to near the light speed is called charged particle beams.

Sir W. H. Bragg, Adelaide, Australia

Ionization density of air increased at end of range in Ra α rays

(Bragg, WH, and Kleeman, R, “On the Ionization Curves of Radium,” Philosophical Magazine, 8: 726-738 (1904).

Bragg curve

•

LET: 20 40 60 80

RBE: 2.0 2.3 2.5 3.0

LET & RBE Values used in Clinical Study

(Carbon ion, 290MeV, SOBP=60mm)

RelativeDose

Density of ionization increases with depth

Bragg-peak Plateau

Equivalent to fast neutron

Peak-to-Plateau Ratio of RBE

for Jejunal Crypt Cell RBE

RBE

Ion Peak/Plateau Ratio Peak/Plateau Ratio

Proton 1.2/1.1 1.1 1.3/1.2 1.1

Helium 1.2/1.1 1.1 1.5/1.3 1.2

Carbon 1.4～1.5/1.3 1.1～1.2 1.6～2.2/1.3 1.2～1.7 Neon 1.5～1.6/1.4 1.1 2.6～3.0/2.1 1.2～1.4 Argon 1.8～2.0/2.1 0.9 3.6～3.8/4.3 0.8～0.9 RBEsd:single dose, RBE2: fractionated

(Goldstein et al.: Radiat. Res. 86, 542-558, 1981)

Carbon-ions have the best balance in terms of dose distribution and

increasing biological effect with depth.

Carbon Proton

Beam Spots vs. Depth - protons and carbon ions -

Carbon

Proton Carbon (285MeV/u)

Proton (150MeV/u)

Comparison of Dose Distribution with Broad Beams

100% 50% 90%

10% 90% 30% 50% 100%

0 20 40 60 80 100 120

0 50 100 150 200 250

深さ（mm）

相 対 線 量

0 20 40 60 80 100 120

0 50 100 150 200250 深さ（mm）

相 対 線 量

Proton Beam Carbon Ion Beam

RelativeDose

RelativeDose

Depth (mm) Depth (mm)

History of Particle Beam RT

Year

1895 Discovery of X-rays 1896 First use of x-rays for RT 1903 Discovery of Bragg peak 1931 First construction of Cyclotron 1946 Proposal for use of ion beam for RT 1954 First proton therapy at LBNL 1961 Proton therapy started at MGH/HCL 1973 Development of CT

1975 First heavy ion therapy at LBNL 1990 Hospital-based proton center atLLUMC 1994 C-ion RT started at NIRS, Japan 1997 C-ion RT started at GSI, Germany(until 2008) 2002 C-ion RT started at Hyogo, Japan 2006 C-ion RT started at Lanzhou, China 2009 C-ion RT started at Heidelberg, Germany 2010 C-ion RT started at Gunma, Japan

W.H.Bragg

E.Lawrence

R. Willson

G.Hounsfield

E.O. Lawrence developed Cyclotron

• Inspired by a paper from Norwegian engineer Rolf Wideroe, Lawrence invented a unique circular particle accelerator, which he referred to as his "proton merry-go- round," but which became better known as thecyclotron(1931).

• Lawrence’s first cyclotron, all of4 inches in diameter, was small enough to hold in one hand. This tiny apparatus of brass and sealing wax, which cost about $25 to build, successfully accelerated hydrogen molecular ions to 80,000 volts.

1932-The 11-Inch Cyclotron,1 pA of 1.2 MeV protons, was housed in a laboratory without shielding.

1937- Historic37-Inch Cyclotron, 8 MeVd (displayed at the Lawrence Hall of Science)

1939 -The 60-Inch Cyclotron, deuteronsto 19 MeV.

•Robert Stone and John Lawrence

→Fast neutron therapy.

•Melvin Calvin used C¹⁴as a tracer to study photosynthesis (Nobel prize).

QuickTime™and a decompressor are needed to see this picture.

1931- The invention of Cyclotron,4-inchdiameter, 80 keV protons → then 9-inch

1933 -The 27-Inch Cyclotron, 4.8MeV p and d, was installed in the Rad Lab on the UC Berkeley campus.

Courtesy of W.Chu

→ 1^stfast neutron therapy in 1939

Fast neutron therapy

by Robert Stone and J Lawrence (1937-1943)

Currently

• Nearly all Centers Closed

• Unacceptably high NTCP

• In TCP, except for low/tumors?

• RBE Normal > RBE Tumor

Author Site No. Cont- Compli- Survival

rolled cation

Caterall (1979) Soft 28 75% 32% -

Ornitz (1980) B&S 20 65% - -

Salinas (1980) B&S 34 62% 12% 59%(5-62mo)

Battermann(1981) B&S 22 36% 27% -

Cohen (1984) B&S 51 47% 38% 39% (>2yr)

Schmitt (1983) Soft 60 50% - -

(1982) Bone 24 50% 33% -

Wambersie (1984) Soft 22 18% 18% -

Duncan (1986) B&S 30 38% 50% -

Schwarz (1998) Soft 1171 50% - -

Local Control, Complications and Survival

in Neutron Therapy for Bone/Soft Tissue Sarcomas

Carbon-ion Therapy in Bone & Soft Tissue Sarcomas Local Control and Morbidity by Dose

50%

(3/6) 67%

(10/15) 81%

(13/16) 87%

(19/23) 89%

(26/29)

0%

(0/6) 0%

(0/15) 0%

(0/16) 6%

(4/61) 33%

(9/27)

70.4 GyE/16fx/4wk

Robert Wilson proposed the use of Bragg Peak for RT in1946.

R.R. Wilson

Dose localization

•Lower entrance dose

•No or low exit dose

•In 1947, the 184-inch cyclotron produced its first high-energy proton beams (380MeV).

•In 1954, the first patient with disseminated breast cancer was treated with protons.

Berkeley

1931: Invention of cyclotron (Ernest Lawrence)

1946: RR Wilson published his seminal paper on particle therapy 1952: Firstbiological investigation with accelerated nuclei

(C Tobias and JH Lawrence)

1954: First therapeutic exposure of humans to protons and alphas (Tobias and JH Lawrence)

1975: Clinical trials with accelerated light ions at LBL (Castro) Gustav Werner Institute and Theodor Svedberg Lab

1949: Synchrocyclotron at the Gustav Werner Institute (Uppsala) 1950s: Pre-therapeutic experiments with protons (B. Larsson) 1957: First patient treated with proton beam

1994: The cyclotron was upgraded Harvard Cyclotron Laboratory

1938: First Harvard Cyclotron completed (Bainbridge, Street and Hickman) 1943: Moved the cyclotron to Los Alamos (RR Wilson)

1949: Second Harvard Cyclotron completed (Norman F. Ramsey): 95-110 MeV protons 1955: Second Harvard Cyclotron: 160 MeV protons

1962: Proton radiotherapy - first steps (Sweet, Kelleberg) 1972: Clinical trials with protons (Suit, Koehler, Goitein, Richard Wilson)

Early History of Proton and Ion-Beam Therapy 1904 WH Bragg and R Kleeman, “On the ionisation curves of radium,” Phil. Mag. 8 (1904)

Sites USA Europe USSR Japan Total Eye (Melanoma) 1,698 2,196 355 44 4,293 35.1%

Skull base &

Intracranial tumor 3,132 15 1,678 58 4,883 39.9%

Head & neck 79 20 0 21 120 1.0%

Thorax & abdomen 2 0 0 127 129 1.1%

Pelvis（incl Prostate） 469 41 242 61 813 6.6%

Others 18 12 77 128 235 1.9%

Unknown 709 27 1,025 0 1,761 14.4%

Total 6,107

(49.9%) 2,311 (18.9%)

3,377 (27.6%)

439 (3.6%)

12,234 (100%)

%

Proton Therapy Facilities and Number of Patients by Tumor （ 1993.05 ）

In the initial phase of proton therapy, indications were mainly focused on ocular melanoma and skull base/intra-cranial neoplasmas.

Proton Medical Research Center of Tsukuba University

Booster Synchrotron of KEK ^Liver34.0%

Lung8.3%

Head & neck6.0%

Skull base6.3%

In proton therapy at Tsukuba University, in advance of the world, major efforts have been placed on treatment ofdeep-seated organsincluding the liver, lung, esophagus as well as the head and neck and bladder.

Esophagus8. 6%

Uterus4.1%

Bladder5.4%

Prostate3.8%

Others12.6%

Metastatic tumor5.1%

Anteriovenous malformation5.4%

R.R. Wilson and C.A. Tobias for Hadron Therapy

Cornelius A. Tobias

1948: Biology experiments using protons 1952: Human exposure to accelerated p, d, He 1954: 1

therapeutic exposure of PBT to humans 1957: 1

Report of PBT of humans

1956-1986: Clinical Trials:

1,500 patients treated with p and He

1st He pat 06/75 1st C pat 05/77 1st Ne pat 11/77 1st Ar pat 03/79 1st Si pat 11/82

Clinical Trials at LBNL/Bevalac, 1975–1992

J.R. Castro conducted clinical trials at LBNL.

1975-1993

He ions = 2,054 pats Neon ions = 433 pats Other ions = 23 pats

Biomed Facility

Carbon ion / EB Doses 10 MeV Electrons :

25, 30, 35 Gy/10 fxs/12 days 308 MeV Carbon:

10,14,17 Gy/10 fxs/11 days

Courtesy of J. Castro

1988

• Early RBE values:

about 2.8-3.0

• Late skin RBE:

~3.0~3.3

( 7-10 years post Rx)

Carbon ion RBE for skin treatment

Clinical Impressions - LBL Heavy Ion trial-

• Potential tumor effectiveness in salivary, bone & soft tissue, bile duct tumors.

• Increased effect in slow growing tumors, hypoxic tumors.

• Increased RBE /normal tissue damage with Neon ions, esp. CNS, GI tract (with 1980’s techniques ).

• Silicon ions : accelerated skin /subcutan damage.

• CARBON IONS MIGHT BE BEST ION FOR CLINICAL TRIAL.

Unfortunately, after > 1,400 patients were

treated the Berkeley facility was closed in 1992

History of Particle Beam RT

Year

1895 Discovery of X-rays 1896 First use of x-rays for RT 1903 Discovery of Bragg peak 1931 First construction of Cyclotron 1946 Proposal for use of ion beam for RT 1954 First proton therapy at LBNL 1961 Proton therapy started at MGH/HCL 1973 Development of CT

1975 First heavy ion therapy at LBNL 1990 Hospital-based proton center atLLUMC 1994 C-ion RT started at NIRS, Japan 1997 C-ion RT started at GSI, Germany(until 2008) 2002 C-ion RT started at Hyogo, Japan 2006 C-ion RT started at Lanzhou, China 2009 C-ion RT started at Heidelberg, Germany 2010 C-ion RT started at Gunma, Japan

J.Castro

Y. Hirao H.Tsujii

G. Kraft J. Debus

T. Kanai T. Nakano Y. Hishikawa

At the PTCOG held in NIRS (1992)

HIMAC

New Treatment Building

Scanning Rotating gantry 1994 Broad beam irrad

2011 Active scanning

Treatment rooms Biological Experiment Ion

Source Linear

Accelerators

Main Accelerator (Synchrotron)

HIMAC

Progress of C-ion RT at NIRS

• Since 1994, carbon ion RT has been focused on development of irradiation technique and dose- fractionation for various types of tumors at NIRS.

• The total number of patients treated by March 2013 is > 7,000 pats.

• The number of the patients enrolled has

increased year after year. This increase is due to the fact that the treatment regimen has become established and smoothly executed as well as the number of fractions and treatment period per patient has been significantly reduced.

RBE vs Fraction Size in Carbon Ion Irradiation

2.2 2.4 2.6 2.8 3 3.2 3.4

2 4 6 8 10 12 14

P.77DoseRBE/010219

77 keV/mm 1.4

1.6 1.8 2 2.2 2.4

0 5 10 15 20

P.42DoseRBE/010219

42 keV/mm

Dose per Fraction（Gy）

Skin

Tumor

Skin

Tumor Dose per Fraction（Gy）

Dose per Fraction（Gy）

Skin

Tumor 1.2

1.4 1.6 1.8 2 2.2

0 5 10 15 20 25 30

P.20DoseRBE/010219

skin tumor

20 keV/mm

Koike S, et al: Radiat Prot Dos. 2002;99: 405-408.

Ando et al. : J.Radiat.Res.,46:51-57, 2005

Single fraction RT with C-ions 34GyE

Pneumonitis appeared corresponding to the high dose area.

. 67 y/o、M

S4, 70mm 72.0GyE/15frs

5 yr

73 y/o, M Ｓ1、48mm 66.0GyE/12frs

2.5 yr

.

1 yr 72 y/o, M S1、46mm 52.8GyE/4frs

. 71 y/o, M S7, 11.2cm 48.0GyE/2frs

2 yr

Chordoma of the Sacrum

3.5 yrs after Case 1.81 y.o.M.

Case 3.83 y.o. M.

Case 2.57 y.o.F.

4.5 yrs after 4 yrs after

Carbon Ion RT

• An advantage for C-ion RT over proton or x-ray RT, suggesting higher biological effects of C-ions, has been demonstrated in:

H&N: Non-SCC (ACC, MM)

Skull base and sacrum: Chordoma, Chondrosarcoma Lung: NSCLC (T2 tumor)

Pelvis and para-spinal regions: B&S sarcoma Prostate: intermediate and high risk group Post-ope local recurrent tumor of rectal cancer Renal cell cancer

• Incidence of GIII late injury was lower for C-ion RT in

chordoma of the skull base, sacral chordoma, H&N tumor,

stage I NSCLC, prostate ca and pancreas ca.

Outline of Carbon Facilities in Operation in the World

Institute /Hospital

Location (Country)

Start year ^Rooms

Irradiation method

Max.

Energy MeV/u

Operation schedule NIRS _(Japan)^{Chiba 1994 ~ 3+2} Layer stacking^Wobbler

HybridScanning

400(C) 24 hours /6 days /10 month

GSI ^Darmstadt_(Germany) ^1997~₂₀₀₈ ¹ RasterScanning 400(C) 3 blocks /year

HIBMC _(Japan)^{Hyogo 2001~ 5} Wobbler 320(C) 230(p)

16 hours / 5 days /12 month

IMP ^Lanzhou_(China) ^{2006~ 2} Layer stacking^Wobbler 100 for V 400 for H

24 hours /7 day /variable

HIT

Heidelber g (Germany)

2009~ 3 RasterScanning 430(C)

250(P) 16 hours / 5 days /12 month

GHMC ^Gunma_(Japan) ^{2010~ 3} Layer stacking^Wobbler 400(C) 8 hours / 5 days /12 month CNAO ^Pavia_(Italy) ^{P: 2011~}_{(C: 2012)} 3 RasterScanning 400(C)

250(P) 220 days/yr

Outline of facilities under Construction or Planning

Institute

/Hospital Location Country Start

year Ion Room Irradiation

method Max. Energy MeV/u Fudan

University

Shanghai

China 2013 C

P 3 Scanning 430 (C)

250 (p)

SAGA-HIMAT Saga

Japan 2013 C 3 Wobbler /

Scanning 400 (C) EBG

MedAustron Wiener Neustadt

Austria 2015 C

P 3 Scanning 400 (C)

iROCK

Kanagawa CC Kanagawa

Japan 2015 C 4 Wobbler /

Scanning 400 (C) PTC

UKGM

Marburg Germany

2013

? C

P 4 Scanning 430 (C)

250 (p)

ETOILE Lyon

France ²⁰¹⁶? C 3 Wobbler 400 (C)

KIRAMS Pusan

Korea 2016

? C 3 Scanning 400 (C)

GSI: principle of beam scanning (1997 - 2009)

In order to get an exact positioning of the target volume the head of the patient is fixed with an individually manufactured mask.

The end of the beam pipe with ionization and multi-wire chambers for the beam control is visible at the left side. During irradiation, the PET cameras above and below the ionization chambers are placed over the patient.

clinical dose (3.3GyE to chordoma)

ID: CIZ251-#44 (FEB05)

clinicaldose[GyE]

Red: GSI

White: HIMAC

~20%

Tumors eligible for C-ion RT so far are:

* Skull base tumours:

o

chordoma

chondrosarcoma

mal. schwannoma

atyp. meningeoma

adenoidcystic ca.

* Tumours close to spinal cord:

o

sacral chordoma

chondrosarcoma

soft tissue sarcoma

* rapidly growing tumours

* metastasizing tumours

* by law: children under 18 Tumors which

are not eligible right now are:

Experiences of GSI (Germany)

• Compact design 60m x 70m

• Raster scanning

• World-wide first ion gantry

• >1000 pats (>15.000fr/yr)

• Low-LET modality:

Protons(later He)

• High-LET modality:

Carbon(Oxygen)

• Ion selection within minutes

Heidelberg Ion Therapy Center (HIT)

(2009~ )

19 Novembre 2009 37

Carbon Ions Clinical Protocols at CNAO

• Chordoma/Chondrosarcoma of Skull Base

• Chordoma/Chondrosarcoma of Column

• H&N Adenocarcinoma

• Salivary glands tumours

• Mucosal & Skin Melanomas

• Bone & Soft Tissue Sarcomas of H&N

• Bone & Soft Tissue Sarcomas of other sides

• Lung

• Digestive Tract

Centro Nazionale di Adroterapia Oncologica (The National Center for Oncological Hadrontherapy)

Proton Carbon

38

MedAustron : Ground floor – functional design

ÖGRO, 20.11.2010

Personaleingang (Medizin, Forschung, Technik) RettungPatienten

137 m

90m

M. Benedikt Synchotron

1 Research room – horizontal fixed beam 3 Treatment rooms

 Horizontal and vertical fixed beam

 Protons and carbon ions

 Horizontal fixed beam

 Protons and carbon ions

 Gantry(-30/+180) in cooperation with PSI

 Protons

Shanghai Particle Therapy Hospital (SPTH) Siemens Synchrotron

Proton 50-250MeVandCarbon 85-430MeV/u Slow extraction of beam over 1-10 s Shift from carbon to proton: less than 1 min.

Proton

Carbon Fudan University

Shanghai Cancer Center (FUSCC)

•Staff: 1800

•In-patient bed: 1250

•2009 workload: Surgery 13,743;

In-pts 18,722 pts Out-pts 516,638

In operation

In planning stage or under construction Gunma University Heavy Ion Medical CenterGunma University Heavy Ion Medical Center

HIMAC, NIRS

Kanagawa Cancer Center Hyogo Ion Beam Medical Center

(Carbon, Proton) Hyogo Ion Beam Medical Center

(Carbon, Proton) SAGA-HIMAT

Carbon Ion Therapy Facilities in Japan

Ion beam therapy in Hyogo (HIBMC)

Proton Carbon-ion

•Energy 70 - 230 MeV 70 - 320 MeV/u

•Range 4 - 30 cm 1.3 - 20 cm

•Gantries 2 none

•Fixed beams 3 (H/V + H) 3 (H/V + Oblique)

Development of Compact Accelerator Development of Compact Accelerator

Ion source

１２０ｍ

６５ｍ

４５ｍ

５７ｍ R&D for small-sizing

（2004～2005）

prototype Gunma University

NIRS

Catalog product for spread ＨＩＭＡＣ

SAGA-HIＭＡＣ

1/3

Small-size and less expensive machine with high performance

Ion generator

Linear accelerator Treatment rooms

synchrotron

PET/CT MRI

simulator

Ent

20m R&D room

Building :60 m x 45 m and 15 m in height

Rooms: 3 rooms (A:horizontal, B:hori.+vert., C: vertical ) for clinic and 1 room for research

Synchrotron:20 m in diameter

Ion species:Carbon only,Max energy:400 MeV/n ( 25 cm in water) Field size:22 cm in diameter, Dose rate:5 GyE/ minute

Gunma University Heavy Ion Medical Center

Research port

A B C

Development of Charged Particle Facility at NIRS

・He～Ar

・E_max800MeV/n

・Wobbler method

・Respiratory gating

・Broad beam method

HIMAC Compact Facility at

Gunma

・C

・Emax400MeV/n

・Spiral wobbler

・Respiratory gating

・Stack layer irrad

New Treatment Research Facility

・C, O,(¹¹C,¹⁵O)

・Emax430MeV/n

・Respiratory gating

・３D Scanning

・Rotating gantry

Photograph of a New Facility

Building facade with green curtain Entrance hall (1F)

Waiting hall (B2F) Treatment Room E (B2F) NIRS, TOSHIBA Co.

NIHON SEKKEI, Inc.

High conformation to irregular shape

High beam efficiency

No need to use bolus and collimator

scanning

magnets range shifter ( tentative)

New Beam Delivery Technique

• Broad-beam

scatterer wobbler

magnets ridge filter compensator collimator

• Scanning

Variable energy( up to147 energies)

100 120 140 160 180 200

-40

-20

0

20

40

Non-gating

Gating Gating

with rescanning (8 times)

100 120 140 160 180 200

-40

-20

0

20

40

100 120 140 160 180 200

-40

-20

0

20

40

0 0.1 0.2 0.3 0.4 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.1

Motion：7mm in gate

Simulation of moving tumor irradiation

In order to avoid hot/cold spot due to target motion, we decided to employ “gating method” with rescanning.

Example:

Φ40mm spherical target

Moving Target Irradiation ～ NIRS approach

Fast Scanning is the key technologyfor completing rescanning within a short time.

How many pats need particle therapy?

Author Type oof Study Conclusion

Bengt (Sweden)

Rad Onc, Physicist, Tumor registry states for Sweden , literature,

# getting RT

2200 – 2,500 / year or

14 ~ 15% of all RT pats Orrecchia (Italy) Estimated based # RT pts 16%

Baron (France) Estimated based # RT pts 14.5%

Mayer (Austria) Estimated based # RT pts 13.5%

Mack Roach III (USA) Estimated based # RT pts SF-Bay area > 1,848/yr

Tsujii (Japan)

Estimated based # RT pts, literature, Statistices, # RT pts

6.5%

Thank You

Tadashi KAMADA, MD

Research Center for Charged Particle Therapy National Institute of Radiological Sciences, Chiba, JAPAN

Over view of Carbon Ion Therapy at HIMAC

(Including Head & Neck Tumors, and Bone & Soft Tissue Sarcomas)

Room for scanning Fusin of auto-activation

& dose distribution in scanning NIRS, Mayo Clinic, and Fermi Lab/NIU Joint Symposium 2013 on Carbon Ion Radiotherapy

Double Tree Hotel, Rochester, MN - May 2-3, 2013

Particle Therapy Research at NIRS

1975-1994 Neutron therapy( about 2000 patients) 1979-1995 Proton therapy (less than 150 patients) 1984~ Heavy ion cancer treatment project 1994~ Carbon ion clinical trial using HIMAC 2003~ Carbon ion “clinical practice” approved 2010~ Compact C-ion facility(1/3size&cost) at Gunma 2011~ Pencil beam scanning clinical application 2013 ~ Almost 8,000 patients received CIRT

Neon

Carbon

２０

Ｎｅ

１２

Ｃ

１

ｎ

Relative mass

： 12 ：1

π

ｅ

１

ｐ

Why Carbon Ion Beam ?

Rationale

• High conformality

• High biological effects Carbon ion beam

A suitable beam for cancer treatment Severe DNA damage

Lessons in

“Neutron therapy”(1975-1994)

High “LET” beam “without” high physical selectivity could never be a major player in

radiation oncology.”

Key point : High LET beam with high physical selectivity(conformality)

Lessons in

“LBNL Ion Therapy”(1975-1992)

Ions for cancer treatment

Heavier than carbon ion like neon ion : High LET at entrance : Risk of normal tissue!

Lighter than carbon ion like helium

: Lower LET at peak : Less biological advantages!

Key point : Not so Heavy and Not so Light !

Not so Heavy and Not so Light-

Carbon is a well balanced particle for cancer treatment !

possesses optimal properties in terms of biologically effective dose localization.

“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

TUMORCONTROL(%)

DOSE (Gy) γ-ray

Single fraction

5 Fractions

0 20 40 60 80 100

0 20 40 60 80 100 120 140 160

TUMORCONTROL(%)

DOSE (GyE) Carbon

74 keV/mm

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

and 2 Gy 70 keV/µm carbon ions.

Kato et al. unpublished data at NIRS

0.0001 0.001 0.01 0.1 1

0 5 10 15 20 25 30 35

Survivngfraction

Dose (Gy)

γ-ray

Hypoxic

Oxic

0.001 0.01 0.1

10 5 10 15 20 25 30 35

Survivingfraction

Dose (GyE)

carbon

74 KeV/ hypoxic

74 KeV/ oxic Oxygen effect

γ-ray Carbon

hypoxic oxic

Ando et al. Int J Radiat Biol 1999

Beyond “4 Rs” with Hypo-F CIRT

 Low repair

 Cell cycle non-specific

 Low OER(re-oxygenation)

 Low repopulation

Advantages of Fractionation ?

Hypo-fractionation matches with high LET “conformal” C-ion beam

Conformal

 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”

Hypo-fractionated

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 (140, 290, and 400 MeV/u) H beam (140, 290, and 430 MeV/u)

• The range of C-ion beam in water 290-MeV/u : 15 cm

400-MeV/u : 25 cm 430-MeV/u : 28 cm

• Maximum field size 15 cm by 15 cm

A C B

Specification of HIMAC

Sato et al. Nuclear Physics A.

1995; 588: 229—234

25０M EURO

Simulation and Rehearsals

Treatment Planning

CT gantry PSD

LED

Obtain CT data

（Respiratory-gated）

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

scatterer ridge filter compensator collimator

HIMAC Beam Delivery Techniques

• Broad-beam(passive) irradiation

wobbler magnets

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.

Compensator and Collimator are used for shaping target volume.

Kanai et al. IJROBP1999, 44:201-210

The Image Intensifier was replaced by high resolution FPD

Treatment Room

Positioning with orthogonal projections

Horizontal Beam Horizontal Beam

Vertical Beam Vertical Beam

I I FPD

End-expiratory irradiation

Respiration gating for irradiation

Reduction of volume

Minohara et al. IJROBP 47:1097-1103, 2000

Site ‘94 ‘95 ‘96 ‘97 ‘98 ‘99 ‘00 ‘01 ‘02 ‘03 ‘04’05 ‘06‘07 ‘08’09 ‘10 H＆N：

All sites Lung :Peripheral Central Locally advanced Med.L/N Liver Prostate:C-ion＋HR C-ion alone B&STS Uterus:Sqcc

Adc Brain Skull base Esoph:Pre-op/Radical PK：pre-op

Radical Rectum（P/0 rec）

Eye melanoma Lacrimal gland

②16/4w

①18X/6w

①18x/6w ③16x/4w

①15x/5w

①20x/5w

①X ray + chemo + C-ion

①16x/4w

①

Preop, Radical (end)

①16x/4w

②9x/3w

③9x/3w

④9x/3w

②12x/3w → 8x/2w → 4x/1w ③4x/1w

⑥4x/1w

②Hormone ③High & Middle risk Low risk

②C-ion alone ③+TMZ

②16x/4w

② ③

①pre-op

Mucosal melanoma16x/4w

Phase I/II Phase II

Sarcomas16x/4wks

②pre-op 8x/2w

①(5x/1w)

⑦16x/4w

1x/1day

④2x/2日

⑤16x/4w

①Pre-op 8x/2w②Radical 12X/3wks

①20x/5w

①12x/3w

③radical12x/3w ④+GEM 16x/4w

Protocols and Time Line of Carbon Ion Clinical Trials (1994-2010)

④12x /3w

Total

7,849 Clinical Practice

(CP): 4,505 Prostate 1718(21.9%)

CP:1386

Sarcoma 1025(13.1%)

CP:773

Head & Neck 848(10.8%)

CP:523 Lung 783(10.0%)

CP:195 Liver 483(6.2%)

CP:249 P/O Rectum

403(5.1%) CP:333 GYN

205(2.6%) CP：9 Eye melanoma

127(1.6%) CP:85

Pancreas 345(4.4%) CP:106 CNS

106(1.4%) PA Lymph node

92(1.2%) CP:85 Esophagus

70(0.9%) Skull base

85(1.1%) CP:56

Lacrimal 23(0.3%)

Scanning

11(0.1%) Miscellaneous 1525(19.4%)

CP:705

Patient Distribution Enrolled in Carbon Ion Therapy at NIRS (Treatment: June 1994～February 2013)

1) C-ion RT is successful in the not treatable by other means

• Advanced Head & Neck cancers

• Large skull base cancers

• Inoperable sarcoma

• Post-op recurrent rectal cancer

• 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

All 16 fractions In 4 weeks

Head-and-Neck Cancers

0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 0

10 20 30 40 50 60 70 80 90 100

TIME IN MONTHS

April 1997～August 2011

Local Control according to Histological Types

5-year Local Control Rate Adenoid cystic carcinoma (156) 76%

Malignant melanoma (102) 79%

Adenocarcinoma (50) 82%

Squamous cell carcinoma (25) 77%

MELANOMA

36 M

Combined Chemotherapy and C-ion RT for MMM

Local Control and Overall Survival of Mucosal Malignant Melanomas

TIME IN MONTHS

PROBABILITY

C-ions alone (n=102) 5-year; 76%

C-ions + DAV n=85) 5-year; 81%

PROBABILITY

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.

Authors N 5-ye ar O S (% )

Radiothera p y G illigan ¹⁾ 28 18

(+/ - Su rgery) Shibuya²⁾ 28 25

Su rge ry Chang ³⁾ 163 32

(+/ - RT , +/- Chemo ) Shah^{4 )} 74 22

Patel⁵⁾ 59 35

Lund⁶⁾ 58 28

C haudhry⁷⁾ 41 17

Carb on ion alone N IRS 102 37

Carb on ion + Chemo N IRS 85 62

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

PROBABILITY

70.4 GyE (n=33) 3-year; 92%, 5-year; 79%

64 or 57.6 GyE( n=14) 5-year; 24%

PROBABILITY 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

IJROBP 2012

Case: 76 y.o. Female

Chordoma originating from the clivus Carbon ion dose: 60.8 GyE/16 frs.

Pre-treatment Dose distribution 67 months later

Clinical characteristics of the reported cases of skull base chordoma

Median dose Median

f/u (y)

Local control rate (%)

Authors N 3-y 5-y 10-y

Photon Catton et al . 1996 24 50 5.2 23 15

Romero et al. 1993 18 50 3.1 17

Forsyth et al. 1993 39 50 8.3 39 31

Magrini et al. 1992 12 58 6 25 25

Proton (+/- photon)

Munzenrider et al.

(MGH) 1999 169 66-83 3.4 73 54

Noel et al. (CPO) 2003 100 67 2.6 86 (2y) 54 (4y) Igaki et al. (Tsukuba)

2004 13 72 5.8 67 46

Ares et al. (PSI) 2009 42 73.5 3.2

(mean) 81

Helium Castro et al. (LB) 1994 53 65 4.3 63

Carbon Shults-Ertner et al.

(GSI) 2007 96 60 2.6

(mean) 81 70

Present study 44 60.8 4.8 91 88 79

These sarcomas were treated at NIRS and all have been controlled. Sarcoma

Bone and Soft Tissue Sarcomas Result of CIRT: Phase II Study n=495 pts

2-year(%) 5-year (%)

Local Control 85 69

Overall Survival 79 59

Local Control

n=514 lesions

Overall Survival n=495

pts

Bone and Soft Tissue Sarcomas Late Morbidities after CIRT: Phase II Study

Impairment ADL (peripheral nerve dysfunction) : 27 Femoral neck fracture : 4 ( all ilioacetabular sarcoma )

Grade

Number 0 1 2 3 4 5

Skin/soft tissue

506 4 475 20 8 1 0

GI tract 439 437 2 0 0 0 0

Spinal cord

46 45 0 1 0 0 0

Edema 14 8 5 1 0 0 0

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

Local Control and Survival Rate in Sacral Chordoma 1996.6-2012.2 n=185

Follow-up period : 68 mths (7- 165)Median Age : 67 yo ( 26-87) Median volume : 636 cm³ 5y-LC: 78%, 5y-OS: 85%

97% pts remained ambulatory

LC OS

mths

S u rv iv a l p e rc e n ta g e