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History of Particle Therapy
Proton and Carbon Ion Beam
May 17, 2011
Basis for Interest in 1H and 12CSuperior Distribution of
Biologically Effective Dose: Finite Range
May 17, 2011
Biologically Effective Dose: Finite Range
12C: High LET
Interest in Particle Beam Therapy
May 17, 2011
Particle Beam Centers Dec 2010
Status 1H 12C
Active 30 4
May 17, 2011
Active 30 4
Planned 17 4
Particle Beam Treated Patients
Protons 67097C-ions 7151He 2054 Other Ions 1973
May 17, 2011
Other Ions 1973
Total 78275Jarmann 2011
May 17, 2011
The Proton
Protons: Dominant Particle of the Universe
∼∼∼∼1080+ Protons T1/2 ≥≥≥≥1035 yr
May 17, 2011
Age of Universe is ~10 -25 of T1/2
of Protons
Creation of Protons
Quarks and Gluons at 10 -12 to -6 sec
Combined to Form Protons and
May 17, 2011
Combined to Form Protons and
Neutrons at 10 -6 to ∼∼∼∼1 sec
Protons
Large Number of Quark Anti-quark
Pairs, Interacting with Gluons
May 17, 2011
Pairs, Interacting with Gluons
Life Span of Q Anti Q Pairs ∼∼∼∼ 10-23 sec
1H: Nucleus of Hydrogen Atom
Constituent of Nucleus of All Atoms
Determines: Atomic Number
May 17, 2011
Determines: Atomic Number
Number of Electrons
Chemical Properties
Wm Prout 1775 -1850 http://en.wikipedia.org/wiki/
May 17, 2011
Prout Hypothesis
Atomic Weights are Whole -Number
Multiples of the Atomic Weight of
May 17, 2011
Multiples of the Atomic Weight of
Hydrogen. 1815, 1816
Sir W. H. Bragg
May 17, 2011
Bragg Peak
WM H Bragg 1904 Adelaide, Australia.
Determined Ionization Density of Air
May 17, 2011
Determined Ionization Density of Air
↑↑↑↑ at End of Range Ra αααα Rays
W H Bragg 1912
May 17, 2011
Proton Discovery
May 17, 2011
Eugen Goldstein
Kanalstrahlen Particles 1886
Passing Through Holes in Cathode
May 17, 2011
Passing Through Holes in Cathode
∴∴∴∴Positive Charge
May 17, 2011
Wilhelm Wien
Kanalstrahalen 1898
Positive e/m~104
May 17, 2011
Positive e/m~104
JJ Thomson
1907 and 1913
Confirmed Wien’s Report
May 17, 2011
Confirmed Wien’s Report
Ernest Rutherford
May 17, 2011
Rutherford 1899
Uranium 2 Radiations:
αααα Short Range in Air +
May 17, 2011
β Much Longer Range -
Cavendish Lab ER was 26 y/o
Natural Alchemy 1903
Emission of αααα or β- Particles
Results in New Element with its
May 17, 2011
Results in New Element with its
Distinct Chemical Characteristics
E Rutherford 1919
Nitrogen is Disintegrated by a Swift αααα
The Liberated H Atom was a
May 17, 2011
The Liberated H Atom was a
Constituent of the N Nucleus
May 17, 2011
PMS Blackett
1925 Wilson Cloud Chamber
1st Visualization of Disruption of an
May 17, 2011
1st Visualization of Disruption of an
Atomic Nucleus: αααα→ N →→→→ 17O + H+
Blackett 1925
May 17, 2011
Rutherford 1920
Proposed an Electrically Neutral
Particle and Named it Neutron
May 17, 2011
Particle and Named it Neutron
Chadwick Discovered Neutron 1932
Transmutation of Li 1932
Cockcroft and Walton Accelerator
1st Artificial Alchemy
May 17, 2011
1st Artificial Alchemy
800 KeV H+ →→→→ Lithium →→→→ Two He
1st Splitting of an Atom
Paul Dirac
May 17, 2011
Paul Dirac
1928 Theoretical Basis for Anti Matter.
Symmetry in Nature
May 17, 2011
Symmetry in Nature
Predicted Positron and Anti Proton
Discovered 1932 1955
May 17, 2011
Lawrence, 1928
May 17, 2011
184 MeV in Cyclotron LBL 1962
May 17, 2011
1932
Radioactivity, αααα, ββββ, Electron, Alchemy,
Photon, Proton, Neutron, Positron,
May 17, 2011
Photon, Proton, Neutron, Positron,
Model of Atom, Splitting of Atom
May 17, 2011
Particle Radiation Therapy
May 17, 2011
Robert Wilson
Proposed Protons and Heavier
Particles for Radiation Therapy
May 17, 2011
Particles for Radiation Therapy
SOBP 1946 Radiology
May 17, 2011
Spread Out Bragg Peak Koehler and Preston 1972
May 17, 2011
1H and 12C SOBPWilkens GSI 2011
May 17, 2011
Wilkens and Oelfke 2008
IMPT (GyRBE)IMXT (Gy)
May 17, 2011
Particle RBE
May 17, 2011
Proton RBE
Mean RBE for in vivo Studies
1.10
May 17, 2011
1.10
ICRU: Use 1.10 as a Generic RBE
RB
E
1.5
2.0
2.5
In Vivo Paganetti, etal
May 17, 2011 Dose [Gy]
1 100.5
1.0
12C ion RBE RBE is Quite VariableFunction of: LET
Dose, Dose Rate
May 17, 2011
Dose, Dose Rate Cell Line, TissuepO2
Depth
High LET an Advantage?
An Intrinsic Differential RBE
Normal vs Tumor Cells at Defined pO ?
May 17, 2011
Normal vs Tumor Cells at Defined pO 2?
No Supporting Data
May 17, 2011
Ando etal, Chiba
Spinal Cord Injury
May 17, 2011 •Karger at al., 2006
12C: RBEα/α vs. Remaining Range
5
6
7
8
9
C: R
BEα
/α
M10
SCC25
SQ20B
V79
May 17, 2011
0
1
2
3
4
0.11101001000
Remaining Range (mm)
12C
: RB
E
Belli et al 2008
OERSF0.1 and RBESF0.1 vs. LET of HSG Human Cell
2
3
4
OERSF0.1 and RBESF0.1 vs. LET of HSG Human Cell
May 17, 2011
1
2
10 100 1000
LET (keV/µm)OER RBE
20 40 80 200 500
• Y.Furusawa et al., 2000
RBE at Center of 12C SOBP
SOBP (mm) Clinical RBE30 2.840 2.6
May 17, 2011
40 2.660 2.480 2.3
100 2.2120 2.1
Clinical Studies on Proton
Stereotactic Radiosurgery
May 17, 2011
Stereotactic Radiosurgery
1954-Present
Stereotactic Proton Radiosurgery
UC Berkley 1955
Uppsala 1957
May 17, 2011
Harvard 1961
Dubna 1964
Moscow 1969
C Tobias
May 17, 2011
C Tobias LBL
1952 1st Rad Biol Study of ProtonsLD50 of Rat
May 17, 2011
1954 1st Proton RT of Pituitary of Dog
1957 1st Report of PRT of Humans
Particle Beam Therapy
Carbon, Oxygen and Neon 1975
May 17, 2011
J Castro, T Phillips etal LBL
Fractionated Dose Particle Therapy
1973-Present
May 17, 2011
Potentially Curable Cancer
Patients
MGH Rad Oncology and HCL
1973. Commenced 1.8 -2.1
1973.GyRBE/Fraction
May 17, 2011
1973.GyRBE/Fraction
Single Variable: Dose distribution
May 17, 2011
May 17, 2011
Checking Portal Film on 1 st
Patient Fractionated PRT
May 17, 2011
May 17, 2011
May 17, 2011
May 17, 2011
Fig. 7. a, b and c
Positive Aspects of Particles Gantry, Same Options as for Linac X
rays:
May 17, 2011
Beam NumberDirectionWeighting Modulation4D IGRT
May 17, 2011
Michael Goitein
Computer Based Treatment Planning
Dose Volume Histogram
May 17, 2011
Dose Volume Histogram
Beams Eye View
Michael Goitein
Digital Reconstructed Radiograph
Uncertainty Band on CTV, GTV etc
May 17, 2011
Uncertainty Band on CTV, GTV etc
Correction for Density Heterogeneity
G T Y Chen etal MGH
4 D CT
4D Image Guided Therapy
May 17, 2011
4D Image Guided Therapy
Initial Study: March 2001
May 17, 2011 JHKFlat Couch Top
Standard CT of Moving 6 cm Ball
May 17, 2011
4D CT Lung Ca
May 17, 2011
12C ion Therapy Less Late Morbidity than after Fast Neutron Therapy.
May 17, 2011
Superior Dose Distribution
Lower LET Higher OER 2.2 -2.6 vs 1.7
Skull Base Chordoma 5 Yr LC
Beam # Pts BED Local RefControl
1H 42 72 81% Ares
May 17, 2011
1H 42 72 [38] 81% Ares
12C 84 75 [20] 63% Schulz12 96 100% Ertner19 89 [16] 100% Mizoe
Sacral Chordoma 4-5 Yr LC
Beam # Pts BED Local RefControl
1H 9 77 87% De
May 17, 2011
1H 9 77 87% DeLaney
12C 95 113 88%
Spinal Chordoma: Post Op Metallic Implants Local Failure
Yes 5/13
May 17, 2011
Yes 5/13
No 0/13p=0.03Rutz etal 2007
Skull Base Chondrosarcoma4-5 yr LC
Beam # Pts BED Local RefControl
May 17, 2011
1H 200 70 99% Rosenberg
12C 54 75 90% SchulzErtner
Uveal Melanoma
4505 Patients MGH PSI
Local Control 95% at 10 yrs
May 17, 2011
Retained Eye 94% at 5 yr
Chiba57 Patients LC 97% Eye Retained 95%
Adenoid Cystic Ca
Beam #Pts BED LC Ref
1H + X 23 70 93% Pommier
May 17, 2011
H + X 23 70 93% Pommier3 yr
12C 90 70 79% Mizoe5 yr
29 72 78% Schultz -4 yr Ertner
SCC H/N 5 yr LC
Beam #Pts BED LC Ref
1H + X 16 74 88% Slater
May 17, 2011
1H + X 16 74 88% Slater
12C 15 70 56% Mizoe
Hepatocellular Ca 5 yr LC
Beam # Pts GyRBE Local RefControl
1H 162 72[16] 87% Chiba
May 17, 2011
H 162 72[16] 87% Chiba
12C 47 52.8 [4] 96% Imada
Prostate Ca Beam # Pts GyRBE bDFS Ref1H 196 79[44] 83% Ziet-
T1b2b 10yr man
May 17, 2011
12C 295 84[20] 92% TsujiiT1-2 5 yr
Xray 785 Fav 81[46] 85% Zelef-924 Intmed 76% sky
8 yr
70%
80%
90%
100%Lo
cal C
ontro
l at 5
yea
rs
Chordoma of Skull Base
May 17, 2011
40%
50%
60%
50 60 70 80 90 100
BED (α/βα/βα/βα/β=2)
Loca
l Con
trol a
t 5 y
ears
. . .12C 1H X
70%
80%
90%
100%bN
ED
at 5
yea
rs
Prostate Carcinoma
May 17, 2011
40%
50%
60%
50 60 70 80 90 100
BED (α/βα/βα/βα/β=2)
bNE
D a
t 5 y
ears
. .12C 1H + X
12C 1H Skull Base BED TCP
% BED TCP
% 75 63 72 81 Chordoma
Overlap of BED and TCP
May 17, 2011
75 63 72 81 Chordoma 70 60 68 59
75 90 70 99 Chond ro sarcoma 66 94
Tumor 12C 1H BED] TCP% BED TCP% SCC [H/N] 70 56 74 88 ACC [H/N] 70 79 70 93
Overlap of BED and TCP
May 17, 2011
ACC [H/N] 70 79 70 93 74 81 84 88 HCC 67 86 83 87
Special 12C Results Tsujii
Mucosal Malignant Melanoma 84%
Renal Cell Carcinoma 100%
May 17, 2011
Renal Cell Carcinoma 100%
Retroperitoneal Sarcoma 69%
1H vs 12CHigher 12C TCPs Reflect Higher Doses
in an Important Fraction of Sites
May 17, 2011
in an Important Fraction of Sites
May 17, 2011 Suit and Wolfgang
May 17, 2011
May 17, 2011
May 17, 2011
Depth Dose Curves for 1H and Xray Beams
May 17, 2011
May 17, 2011A Trofimov 2010
Particle Beam Centers
Proton LBL 1954Uppsala 1957
May 17, 2011
MGH/HCL 1961Moscow 1965Lenningrad 1967
Particle Beam Centers
Pion Los Alamos 1974Triumf 1979
May 17, 2011
PSI [SIN] 1980
Particle Beam Centers
12Carbon Ion LBL 1975Chiba 1994
May 17, 2011
Darmstadt 1997
May 17, 2011
6
8
10
12
Pen
umbr
a (9
5%-5
0%)
(mm
) 100 MeV Proton150 MeV Proton200 MeV Proton186 MeV/µ Carbon285 MeV/µ Carbon386 MeV/µ Carbon
6 MV x-ray
May 17, 2011
May 3 2011 May 3 2011 PRCOG Slides
0
2
4
0 5 10 15 20 25 30
Depth in Water Phantom(cm)
Pen
umbr
a (9
5%-5
0%)
(mm
)
Lateral Scattered Dose
Proton (published Q), photon and carbon
10
100
Dos
e E
quiv
ale
nt (m
Sv/
Gy)
.
.
Proton PEM
Proton PBS
6MV IMXTCarbon
May 17, 2011
0.01
0.1
1
0 50 100 150 200
Distance from field edge (cm)
Dos
e E
quiv
ale
nt (m
Sv/
Gy)
.
.
Carbon
May 17, 2011 Webber and Kraft,2009
Patients Treated by 1H and 12C
60000
80000 P
atie
nts
1H
May 17, 2011
0
20000
40000
1994 1998 2002 2006 2010
Years
Pat
ient
s
12C Jarmann
Alchemy
1903 Natural as in Radioactivity Decay
May 17, 2011
1919 αααα Particle Induced N →→→→ 17O
1932 Accelerated H + →→→→ Li →→→→ αααα + αααα
Carl Anderson: Positron 1932
May 17, 2011
Stockholm and Uppsala
Proton Radiation Therapy 1957
Stereotactic Radiosurgery
May 17, 2011
Stereotactic RadiosurgeryPhoton and Proton
Inverse Planning γγγγ50
MGH Neurosurgery and HCL
1961
Stereotactic Radiosurgery of
May 17, 2011
Stereotactic Radiosurgery of
Intracranial Lesions
Robt Stone and J Lawrence
May 17, 2011
FN Therapy of T3 -4 H/N SCC
No Evident Gain in TCP
X ray TCP in 30 -50% Range
May 17, 2011
X ray TCP in 30 -50% Range
Steep Part of Dose Response Curve
FN Therapy Rationale is High LET and RBE, viz
Lower OER
May 17, 2011
Flatter Age Response Function
A Potential Advantage in ↑↑↑↑TCP?
FN Therapy in 2011
Nearly all Centers Closed
Unacceptable NTCP, No Gain
May 17, 2011
Unacceptable NTCP, No Gain
In TCP, Except for Low αααα/ββββ Tumors?
RBE Normal > RBE Tumor
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