The Seventh Blaise Pascal Lecture Wednesday May 19 2010Wednesday May 19, 2010

Ecole PolytechniqueAmphi Faurre

Medical Applications of Laser IonMedical Applications of Laser Ion Acceleration

Toshiki TajimaBlaise Pascal Chair,

Fondation Ecole Normale SupérieureInstitut de Lumière Extrême

andandLMU,MPQ, Garching

Acknowledgments for Advice and Collaboration: G. Mourou, M. Molls, F. Nuesslin, M. Abe, M. Murakami, V. Malka, J. Fuchs, C. Labaune, P. Mora, F. Krausz, D. Habs, T. Esirkepov, S. Bulanov, S. Kawanishi, M. Hegelich, Y. Kishimoto, D. Jung, D. Kiefer, X. Yan, A. Henig, R. Hoerlein, S. Steinke, W. Sandner, Y. Fukuda, A. Faenov, M. Tampo, P. Bolton, N. Rostoker, F. Mako, L. Yin, T. Pikuz, A. Pirozhkov, M. Borghesi, M. Gross, M. Zepf, Y. Gauduel

Chaotic (and thus Violent) Mutations

Cancer causinghuman genomemutations: scary!(Time Magazine)( g )

fundamental to biologyfundamental to biology

5-year survival rates after curative treatment in early cancer stages

M. Molls/ Japan Apr 09

Radiotherapyalone

Surgery alone

Chemotherapy alonea o e

Prostate 79 % (5 y)66 �– 79 % (10 y) 75 �– 85 % Ø

Lung 6 �– 50 %(Stereotact. RT: > 50 %) 30 �– 80 % Ø

Cervix 63 91 % 74 91 % ØCervix 63 �– 91 % 74 �– 91 % Ø

Skin up to 100 % up to 100 % Ø

60 80 % (T1 T2) comparable withAnus 60 �– 80 % (T1, T2)33 �– 58 % (T3, T4)

comparable with results after RT Ø

Rectum ~ 65 % 78 �– 82 % Ø

3Ø: no data in the literature: CHEMOTHERAPY has no curative potential in solid tumors (exception: testicular cancer)

In the last decades: no improvement of survival in metastatic cancer diseases

(macroscopic metastases)M. Molls/ Japan Apr 09p p

4

Data from "Tumor Center München"

M. Molls/ Japan Apr 09

Chemotherapy (medical cancerChemotherapy (medical cancer treatment) has no curativetreatment) has no curative potential in solid tumors!

WHY?WHY?

5

Radiation ChemotherapyM. Molls/ Japan Apr 09

Homogeneous dose distribution The tumor cell kill depends on intrinsic radiation sensitivity DNA repair capacity

Inhomogeneous dose distributionThe tumor cell kill depends on the transport of the substance to the clonogenic cells andradiation sensitivity, DNA repair capacity,

repopulation, oxygenation status etc.. However, the entire tumor can be irradiated homogeneously with that dose, which is

the substance to the clonogenic cells and molecular targets, DNA repair capacity, repopulation, pO2, pH, MDR, etc.. In macroscopic tumors not all the subvolumes of g y

necessary to kill all clonogenic tumor cells, even the most resistant ones.

the tumor, clonogenic cells and relevant molecular targets are reached by those doses of the medical substance which are needed for cell killfor cell kill.

6

Tumor-cells

(Molls, TU München; according to Tannock: Lancet 1998, Nature 2006)

1010

6 Chemoth cycles

106

1086 Chemoth. cycles

104

106

Surger102

104

0 1 2 3 4 5 6

ry

0

10

month0 1 2 3 4 5 6

Macroscopic Tumor: 5mm (more than 107 cells)

7

Microscopic Tumor: < 5mm (1 �– 107 cells)

Cell kill after Chemotherapy: only about 3 logarithmic steps (ordinate)M. Molls/ Japan Apr 09

M. Molls/ Japan Apr 09Prof. Molls (TUM/MAP) says:

䇾Solid tumors which consist in more than about 1000 ll tl t b d b di lcells apparently can not be cured by medical

treatment. This holds true especially for macroscopic tumors which consist in more than 1 to 10 million cells (exception: testicular cancer)( p )

The main problem:The medical substances don�‘t reach all dividing tumor cells and respective molecular targets in a p gconcentration which is high enough to kill the cells. After medical treatment there remain dividing cells

8

After medical treatment there remain dividing cells from which tumor regrowth is starting.䇾

Breast Cancer: Improvement of survival by better diagnostic and earlier detection of the tumorand earlier detection of the tumor

(Patients with breast carcinoma in Brisbane, Australia; Webb et al, The Breast 2004)

Diagnosis Diagnosis1981 - 84 1990 �– 94

Patients 469 520Average age 56 J 53 JAverage age 56 J 53 JTumor < 1cm 11% 22%Tumor > 2cm 44% 34%Tumor > 2cm 44% 34%Lymph node metast. 50% 38%Stage 1 32% 46%gStage 2 61% 47%Stage 3 7% 7%

95 y survival 74% 84%

M. Molls/ Japan Apr 09

Brilliant X-raysDiffraction enhanced imaging: breast, ex vivo

M. Molls/ Japan Apr 09

g g ,

1 CT ex vivo, 2 Brilliant X-ray image ex vivo, 3 Histology

collagen strandsskin-muscle

Ca in collagen

12 3fat1

1: Toshiba AsteionTSX - 021ACT (80 kV )

2

2: DEI 33 keV

3

3: Histology

10CT-scanner (80 kVp)

Bravin et al. Phys Med Biol 52:2197-211, 2007D.Habs

Small-angle X-ray scattering (SAXS)

normal tissuenormal tissue contains collagen fibrils in regular, hexagonal-like arrangement

cancer cells degrade regular structure of collagen fibrils making

canceroushealthy

collagen fibrils, making them thinner and their axial period longer

micro-x-ray beam

vision: direct cancer diagnosis without biopsy

micro x ray beam

11

vision: direct cancer diagnosis without biopsyfrom D.HabsM. Molls/ Japan Apr 09

Medien !Phase contrast imaging: F. Pfeiffer

Medien !

contact: franz.pfeiffer@psi.ch & www:

phase tomograms

contact: franz.pfeiffer@psi.ch & www: http://people.epfl.ch/franz.pfeiffer

absorption tomograms

F. Pfeiffer et al., Phys. Med. Biol. 52, 6923

State-of-the-art 3D phase-contrast tomography at highly brilliant synchrotron radiation sources

(@ESRF Grenoble/ France)

(2mm size)

contact: franz pfeiffer@psi ch &franz.pfeiffer@psi.ch & www: http://people.epfl.ch/franz.pfeiffer

F. Pfeiffer et al., Phys. Med. Biol. 52, 6923 (2007)

Small tumor detection(by such method as Phase Contrast Imaging)

Early tumor detection:

�• Less chance of metastasis

�• Higher Quality-of-Life (QoL)

�• Fit for laser acceleration approach

(compact laser accelerator:

t d f l d )15

not good for large dose)

Sharpness of Dose of Proton Therapy

pro

X-ray IMRT Proton IMRT

ostate caancerrrectum

Surgical sharpness of dose compared withSurgical sharpness of dose compared with X-ray Intensity Modulated Radio Therapy(X-ray IMRT)( y )

Artist�’s view of the Heavy Ion Therapy Center (HIT) in Heidelberg( ) g

17

Suggested Strategy for L I A l tLaser Ion Accelerator

�• Detect early and small (laser-drivenDetect early and small (laser driven brilliant coherent X-rays): micro tumors

�• Small spot irradiation(including scanning): ideal for laser acceleration of ions, as ion therapy is nearly surgically sharp

�• Feedback necessary:�• Feedback necessary: irradiate verify irradiate verify �….

�• Shallow tumors and other shallow treatments (e g ARMD) firsttreatments (e.g. ARMD) first

�• Other industrial applications

Toward Compact Laser-Driven Ion Therapypy

PET or ray image of autoradioactivation

Proton accelerator+gantry

laserlaser

Laser particle therapy (image-guided diagnosis irradiation dose verification)targeting at smaller pre-metastasis tumors with more accuracy

Small tumor treatment

�• 1kg tumor (10cm x10cm x 10cm): 70J proton energy @ 70Gyp gy @ y

�• 1g tumor (1cm x 1cm x 1cm): 70mJ1 t (1 1 1 ) 70 J�• 1mg tumor (1mm x 1mm x 1mm): 70 J

takes about 108 protons at ~100MeV (only 10% of p ( ythe beam assumed to be used to inject, and in turn 10% of which stops at tumor; with 10% laser to pproton efficiency, laser energy of 70mJ); takes 105

protons per laser shot (if 2minutes therapy at 10Hz)p p ( py )

Within grasp!

Macular degenerationARMD (Age Related Macular Degeneration;ຍ㱋ᛶ㯤ᩬ)

21

Spot-Scanning Simulation of Laser Proton Radiotherapy

(Simulation of dose distribution)

ba

distribution)

ba

Spot scanning simulation of laser proton radiotherapy for eyec d

Spot-scanning simulation of laser proton radiotherapy for eye melanoma (a,b) and ARMD (c,d).

Particle-in-cell simulation (PIC) software which calculates the properties of

22laser-accelerated protons, Monte-Carlo simulation software, and visualization tools for the dose evaluation were used. Iso-dose curve:Blue: 25%, Sky blue: 50%, Yellow: 75%, Orange: 90%, Red: 110%. Miyajima(JAEA)2005

Recent breakthroughs in LIAFrom incoherent (or heating) of electrons

to Coherent drive of themto Coherent drive of them

TNSA (T t N l Sh th A l ti )

CAIL (Coherent Acceleration of Ions by Laser)

TNSA (Target Normal Sheath Acceleration)

Tajima et al., 2009

Laser -Thin Foil Interaction

X. Yan et al., 2009

Comparison of the phase space dynamics:toward more Adiabatic Accelerationtoward more Adiabatic Acceleration

TNSA (metallic boundary)

I t i idthIon trapping width:vtr,ion ~ c a0(m/M)

CAIL (with CP)

CAILRev. Accel. Sci. Tech.(Tajima, Habs, Yan, 2009)

Optimal Thickness Scaling

Normalized thickness ~ a0 (normalized intensity)Optimal acceleration of ions

Maximal energy of protons (MeV)LLNL

Normalized thickness a0 (normalized intensity)

LLNL(redef. Ipeak)

a=eE/me c13

55 (MeV)LLNL

(T.Esirkepov et al.2006)

Recent Experimental Breakthroughs

Leadership Nanometer target:by Dieter Habs

LMU,

DLCSharp contrast laser

double plasma,MPQ,Max-Born Institute, LANL

pmirrors

LANL,RAL,PMRC More coherent

electron dynamicselectron dynamicsin ~ a0

Recent experiments in CAIL Regime

Ultrathin film : = a0 , where = d n / nc ( = /a0)CAIL Regime: Overcomes old TNSA regime

0 , c ( 0)High laser contrast: not to destroy ultrathin target

=1

MAP + MBI

(Henig et al, 2009;Steinke et al.)

Conversion efficiency of laser to ion energy

100Two orders of magnitude higher efficiency in CAIL

5x1019 W/cm2 203x10NOVA

100

] 5x10 W/cm6x1019

2x1020

3x10NOVA10

nerg

yci

ency

[%]

RAL

1x10197x1019

2x10

1

er−i

on e

nesi

on e

ffici

e

ASTRA

RAL

187x10

2x10180.1

Lase

rco

nver

sio

thin foil RPA

ASTRA Tajima, et al(2009)

2x1018

0.01

c thin foil RPAthick foil TNSA

0.0110 100 103 104

Laser pulse duration [fs]

Maximum energies of ions

1022 1021 W/cm21000

V/u]

1022

1001020

ergy

[MeV

/

NOVA 203x102x1020

197x102x10201910

1019

ff ion

ene

rg

RAL

2x1020

5x10 2x102019

1

10

protons, nm foilm cu

toff

io

ASTRAprotons, TNSA

RAL5x10

10187x1018

1 protons, nm foil

carbon, clustercarbon, nm foil

Max

imum ASTRA

10 100 103 1040.1

carbon, clusterM

Laser pulse duration [fs]Tajima et al.(2009)

Toward monoenergy spectrum�• Circularly polarized laser irradiation

more adiabatic acceleration more monoenergymore adiabatic acceleration more monoenergy

Carbon spectrum for three consecutive shots using circular polarized light at 5 *10^19 W/cm2 and a DLC foil target thickness of 5.9 nm

Comparison of CP and LP toward monoenergy

Henig et al, PRL (2009)

Energy Gain in Laser Ion acceleration: CAIL (Coherent Acceleration of Ions by Laser) regime

�• When electron dynamics by laser drive is sufficiently y y ycoherent, with coherence parameter of electrons, the ion energy in terms of electron energy is :

Ion energy

(th h t th l t ti th hi h th i )

Electron energy = ponderomotive energy

(the more coherent the electron motion, the higher the ion energy)

ponderomotive energy

maximizes at = 1

CAIL Theory PredictionCAIL (Coherent Acceleration of Ions by Laser) theory has definitiveprediction of max energies

Tajima et alTajima et al. RAST(2009)

For the case of LANLexperiment prediction (relative long pulse with nm targets)

Circularly polarized laser driven

CP laser drives ions out of ultrathin (nm) foil adiabaticallyMonoenergy peak emerges

Bucket trapping ions

Ion

Ion m Vi,trpopulatio

mom

emn

laser

on ntum

laser

P d ti f d i l t

Vi,tr = c (a0m/M)

Ponderomotive force drives electrons,Electrostatic force nearly cancelsSlowly accelerating bucket formed

(X. Yan et al: 2009)

Toward more adiabatic acceleration(4)

The more adiabatic, the longer accelerated, the higher energy, g , g gy

Energy by CP tends to increase as ~ a02

800

1000

CP

V)

1PW

600

800LP

rgy(

MeV

100TW

200

400

ax. E

ner 100TW

0 10 20 30 40 50 60 70 80

0

M

0 10 20 30 40 50 60 70 80Normalized laser amplitude a0

Concave Ultrathin Target Enhances Energy

Concave target focuseslaser energy, doubling the ion energygy

(Wang et al. 2010)

Energy Doubler: Concave Target

At 1020W/cm2 the concave target lets over 100MeV protons, doubling energy over a flat target

Wang et al. 2010

Monoenergetic electron bunch

Ultrathin (2nm) foil (CP) irradiation drives monoenergetic electrons

Ideal for driving coherent brilliant X-rays for phase contrast imagingfor phase contrast imaging

(Kiefer et al, 2009)

MAP MBIMAP + MBI

Adiabatic (Gradual) Acceleration Accelerating structure

Inefficient if suddenlysuddenly

accelerated

protonsAccelerating structure (cf.human trapping width:

vtr,human ~ 1m/s << cs )

Efficient whenwhen

gradually acceleratedaccelerated

Adiabatic acceleration (2) Thick metal target

Most experimental

c

Most experimental configurations of

proton acceleration(2000-2009)

laser protons electronsInnovation (�“Adiabatic

Acceleration�”)(2009-)

= Method to make the electronsc = Method to make the electrons within ion trapping width

H i ELI t tiGraded, thin (nm), or clustered

target and/or circular polarization

However, in ELI automaticvtr, ion ~ c a0(m/M) ~ c

(ultrarelativistic a0 ~ M/m )

Nanostructured target

(Habs, 2009)

Toward Adiabatic Acceleration䠄ca.1999)

Patent (Tajima) : submitted from LLNL (2002); granted (2005)

Why laser-Cluster Interaction ?Why is Laser-Cluster Interaction Strong?

�clusterd phase" vs. "gas", "plasma", "solid phase"

gas࣭plasma࣭solid l t

"Small particle system" and enhanced fluctuation

gas࣭plasma࣭solid cluster like large molecular

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Transverse polarization manifest!

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"Small particle system" and enhanced fluctuation࣭free energy originated from

the surface ࠉ is NOT neglected.

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Freedom of tansverse polarization "through "surfaceࠉࠉࠉࠉࠉࠉࠉࠉࠉࠉ࣭different nature in linear and non-linear dispersion

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44R. H. Doremus, J. Chem. Phys. 40, 2389 (1964)A. Kawabata and R. Kubo, J. Phys. 40, 1765 (1966) (Y.Kishimoto)

Cluster target: order of magnitude energy gainenergy gain

With a modest (140mJ) laser, to go beyond 15MeV/nucleon by clustertargettarget

Clustered target allows another leap in energy of ions

Fukuda et al. (PRL 2009)

Clustered target allows another leap in energy of ions

Off axisparabolaProbe beam

(a) (b) Laser beam

Laser beam

Z

Probe beam

Z = 8.5 mm

Cluster jet x�’

X Y 20

to shadowgraph imaging optics Z = 5.5 mm

FSSRimaging optics Z 5.5 mm

Ly O VIIIHe OVII(c)Z = 3.5 mm4.0 mm

3.8 mm

X =

Z = 1.5 mm2.1 mm

Z = 0.7 mm

2 mm

1.8 mm

1 3 mmerbe

am

Orifice output

x = 6.5 mm

1.3 mm

18.627 Å 18.627 ÅFig.15

Lase

Faenov et al., 2009

CR 39 (Side)(a)

Cluster ions strongly energizedz�’

Laser beamOff axisparabola

1 µm C3H6 foilZ

FSSR( Front)

Laser beam parabola

x�’

X Y 202020

FSSR(Side)

( Front) Clusterjet

1 µm C3H6 foilCR 39 (Front)

1010100 100Ei (keV)

200 200

Ly1010100 100

Ei (keV)200 200

He

(b)

0 01

0.1

f(v)*

107

Ly

Front0.01

0.1

f(v)*

107

He

Side

Front

1E-3

0.01 Side

1E-3

0.01

Faenov et al.,-0.006 -0.003 0.000 0.003 0.006

v/c-0.006 -0.003 0.000 0.003 0.006

v/c

Fig.11

2009

Laser-carbon cluster interaction 㼍㻞 㼘㼍㼙㼐㼍㻤㻞㻜 㻺㼤㼥㻝㻞㻤 㼜㼍㼞㼠㼕㼏㼘㼑㻝㼙㼕㼘㼘㼕㼛㼚㻛㼟㼜

㻞㼤㻝㻜㻠

㻞㻚㻡㼤㻝㻜㻠

㼍㻞㻌㼘㼍㼙㼐㼍㻤㻞㻜㻌㻺㼤㼥㻝㻞㻤㻌㼜㼍㼞㼠㼕㼏㼘㼑㻝㼙㼕㼘㼘㼕㼛㼚㻛㼟㼜

㼀㼛㼠㼍㼘㻲㼕㼑㼘㼐㻵㼛㼚㻱㼛㼚

a0=4 Ion energyl l th

㻝 㻝㻜㻠

㻝㻚㻡㼤㻝㻜㻠

㼚㼑㼞㼓㼥㻌㼇㼍㻚㼡㻚㼉 electron

~ pulse length(laser energy)

㻡㼤㻝㻜㻟

㻝㼤㻝㻜㻠

㻱㼚

ionlaser

㻜㻜 㻞㻜㻜 㻠㻜㻜 㻢㻜㻜 㻤㻜㻜 㻝㻜㻜㻜

㼀㼕㼙㼑㻌㼇㼒㼟㼉

Kishimoto (2009)

Maximum energy vs. laser intensity

㼑㼚㼑㼞㼓㼥㻚㼢㼟㻚㼍

㼍㼠 㼠㻩㻣㻜㻜㼒㼟㼑㼏

Cluster target scaling

㻞 㻝㻜㻞

㻞㻚㻡㼤㻝㻜㻞

㼍㼠㻌㼠㻩㻣㻜㻜㼒㼟㼑㼏

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C i h

㻝㻚㻡㼤㻝㻜㻞

㻞㼤㻝㻜

㼑㼂㼉

Consistent to the Theory by Yan et al (2009)

㻝㼤㻝㻜㻞

㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑 Yan et al. (2009),

though it is based on thin film case

㻡㼤㻝㻜㻝

20max 112 aQ

㻜㻝 㻞 㻟 㻠 㻡 㻢 㻣 㻤

Pulse Strength㻌㼍㻜

Kishimoto, 2009

Ion Energy spectrum r=125 m

㻵㼛㼚㻌㻱㼚㼑㼞㼓㼥㻌㻰㼕㼟㼠㼞㼕㼎㼡㼠㼕㼛㼚

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㼒㻱㼕㼘㼛㼓㼋㼍㻠㼋㼘㻤㻞㻜㼋㻺㼤㼥㻝㻞㻤㼋㼜㻝㼙㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑㼂㼉

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㻝㼤㻝㻜㻙㻝㻜

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㻙㻝㻞

㻝㼤㻝㻜㻙㻝㻝

㻜 㻝 㻞 㻟 㻠 㻡 㻢㻝㼤㻝㻜

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㻝㻝㼤㻝㻜

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㻟㻝㼤㻝㻜

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㻡㻝㼤㻝㻜

㻢

㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑㼂㼉

㻝㼤㻝㻜㻜㻝㼤㻝㻜

㻝㻝㼤㻝㻜

㻞㻝㼤㻝㻜

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㻢

㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑㼂㼉

150.98MeV 178.84MeV114.9MeV 171.71MeV

Kishimoto, 2009

Ion Energy vs. Cluster RadiusCluster target scaling: ion energy ~

1/(cluster radius)

㻡

㼑㼚㼑㼞㼓㼥㻚㼢㼟㻚㼞㼍㼐㼕㼡㼟

㼍㼠㻌㼠㻩㻣㻜㻜㼒㼟㼑㼏

㻝㻚㻣㼤㻝㻜㻡

㻝㻚㻤㼤㻝㻜㻡

㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑㼂㼉

㻝㻚㻡㼤㻝㻜㻡

㻝㻚㻢㼤㻝㻜㻡

㼑㼂㼉

㻡

㻝㻚㻠㼤㻝㻜㻡

㻱㼚㼑㼞㼓㼥㻌㼇㼗㼑

Kishimoto Tajima

㻝㻚㻞㼤㻝㻜㻡

㻝㻚㻟㼤㻝㻜㻡 Kishimoto,Tajima

(2009)

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Radius [nm]

Conclusions�• Cancer: unsolved problem, as fundamental to biology�• Ion beam radiotherapy: superior cure to chemotherapy, though

expensive today�• Detection and cure of small unmetastasized tumor = future

(fundamental cure better quality of life better fit for compact laser(fundamental cure, better quality of life, better fit for compact laser accelerator)

�• Compact laser ion acceleration: niche for small tumors�• Breakthroughs in laser ion acceleration: overcomes the previous

paradigm (TNSA) with the new conditions�• Higher energies higher efficiency and less energy spreadHigher energies, higher efficiency, and less energy spread�• With compact laser (1020W/cm2) 100MeV protons possible�• Feedback therapy essential for small tumors�• Laser-driven compact coherent X-ray source : detect small tumors�• A lot more medical applications on the horizon

Merci Beaucoup et a la Prochaine Fois