Heavy-ion physics applied to cancer therapy: between basic science and

medicine

aInstitute for Nuclear Research, MoscowbFrankfurt Institute for Advanced Studies, Frankfurt am Main

c Kurchatov Institute, Moscow

 Igor Pshenichnov a,b 

in collaboration with Lucas Burigo b, Alexander Botvina a,b, Igor Mishustin b,c, Marcus Bleicher b 

Dual Year Russia­Spain, Barcelona, 8­11 Nov, 2011

I. Introduction: photons vs protons vs carbon beams for cancer therapy

Ions can be well focused on tumor volume ...

12C beam

... focused on tumor and sparing healthy tissues and organs at risk

12C beam

Some 7000 patients treated worldwide so far.

Note: some70 000 treatedwith protons 

The success of heavy-ion therapy is based on precise dose delivery

● 12C beams are used to treat tumors: at GSI, Germany, 440 patients treated in 1997-2008at NIRS, Chiba, Japan, 5196 patients at HIMAC in 1994-2010

● Since 2009 more than 400 patients were treated with 12C beams at HIT, a new center in Heidelberg

GSI, Darmstadt

HIMAC, Chiba

Heidelberg

Presently only proton therapy in Russia: JINR in Dubna, ITEP, INR in Moscow

Several new heavy-ion therapy centers are under construction or commissioning:

● Proton/Ion facility in Marburg, Germany (Rhoen Klinikum AG), construction started in 2007

● North European Radiooncological Center Kiel - NRoCKat University Medical Center Schleswig-Holstein, Germany,construction started in 2008

● Still some financial problems have to be solved for both new German centers, but the technology itself seems to be quite mature

● National Centre of Oncological Hadrontherapy (СNAO), in Pavia, Italy, construction completed

● Shanghai Proton and Heavy Ion Hospital, scheduled completion in 2014

Schanghai

Marburg

Treatment planning and dose delivery: 1970s

Example of an early computer­generated 2D treatment plan of prostate cancer. The structures have all been entered by hand from orthogonal radiographs. 

T.L.Phillips, Rad. Res. 158(2002)389 

Head treatment at Bevalac

Tremendous progress in treatment planning and dose delivery: 2010s

Beam scanning, HIT in Heidelberg

● Full 3D and 4D (with accounting for organ movement during irradiation) treatment planning

● Active beam scanning technique: fast variation of beam energy and direction

● Biological dose optimizationM.Krämer, M.Durante, Eur. Phys. J. D 60(2010)195

scanned beam at HITon radiochromic film 

Each treatment planning system needs detailed information on physics and radiobiology of therapeutic beams:

M.Krämer, M.Durante,  Eur. Phys. J. D 60(2010)195

● Physical beam model: physical dose Dion

, lateral beam spread,

production of secondary particles etc.

● Radiobiological model, e.g. Local Effect Model (LEM):calculates RBE = D

X-ray/D

ion, defined for a given rate of cell

survival, predicts survival rate in mixed radiation fields

● Reliable ab initio predictions of cell survival and therapeutical RBE values based on ion track physics are not yet possible. Empirical information collected in radiobiological experiments or in patient treatment is used.

Monte Carlo modeling in particle therapy: ● Monte Carlo codes can be used:– for calculating libraries of dose-distributions at various beam

energies (dose kernels) as input to an analytical treatmentplanning system

– for verification of results of analytical treatment planningsystems with accounting for biological effects

– for calculations of out-of-field doses

● Currently the FLUKA MC code is used at HIT, Hidelberg for these purposes

● MC still remains too slow (hours) compared to analytical treatment planning systems (minutes)

● Other tools, e.g., MCNPX, SHIELD-HIT, Geant4, can be also used

In this talk: focus on physics of therapeutic ion beams and how it can be simulated with Geant4

● Brief review of related physics phenomena

● Ab initio Monte Carlo modeling of fragmentation reactions and comparison of results with experimental data

● Importance of nuclear fragmentation (macro scale)– Beam attenuation due to fragmentation of beam nuclei– Production of secondary nuclear fragments– Production of secondary neutrons

● Microdosimetry measurements as estimations of biological quality of radiation. Monte Carlo simulations and comparison to data

Calculations have to take into account ionization energy loss,

multiple Coulomb scattering and nuclear fragmentation reactions

Ionization energy loss: ­dE/dx ~ 1/β 2~1/E

MCS ­ multiple events, small scattering angles(formulas, approximations)

Nuclear fragmentation ­ single events, many secondary particles of various kinds produced at large angles (hardly described by a formula or by a list of channels) 

(continuous slowing down: formulas, approximations or tables)

12C

12C

12C12C

12C16O

10C

15O

12C

15O

10C

Fragmentation of 400 A MeV 12C beam

Data: E. Haettner et al., Rad. Prot. Dosim. 122 (2006)48

● Up to 70% of beam nuclei are fragmented

● Secondary fragments are created, from protons till Boron with various radiobiological properties

● A lot of work for nuclear fragmentation models!

lines ­ MCHIT

Our research tool: Monte Carlo for Heavy Ion Therapy (MCHIT) – a Geant4-based application

● Based on  our expertise in heavy­ion physics (NMD, UrQMD and SMM).

● Intended for benchmarking of Geant4 models to experimental data relevant  to particle therapy and to other models on the market.

● Works with simple phantoms and beam­line elements, but the very same  physics models can be used for Monte Carlo treatment planning by others.

MCHIT@FIAS

  

Geant4-based therapy simulators

gMocren project:  a DICOM image rendererand dose overlap displayhttp://geant4.kek.jp/gMocren/

ThIS : a Geant4­based Therapeutic Irradiation Simulator http://www.creatis.insa­lyon.fr/rio/ThIS

Can be used to validate  existing treatment planning systems

Indispensable for research work: doses tohealthy tissues, treatment room shielding etc. 

Geant4 is a rapidly developing toolkit for nuclear, particle, space and medical physics

Geant4 collaboration

Collaborators also from non­member institutions, 

includingBudker Inst. of Physics

IHEP ProtvinoMEPHI Moscow 

Pittsburg University

*) papers based on Geant4 (ISI, 22.09.09)

*)

*)

http://geant4.cern.ch/geant4/

II. Artist's view of a nucleus-nucleus collision

Fast stage 10­23 – 10­22   s

Spectator A*

Spectator B*

A

B

knock­out nucleons

It is recommended to use Light­Ion BinaryCascade and QMD  to simulate fast stage in MCHIT. 

Statisticaldecay

Nucleus-nucleus collision models of Geant4 for ion therapy

Ion Binary Cascade model considers nucleus-nucleus collisions as a set of individual nucleon-nucleon collisions in the participant zone.

− Estimates the excitation energy of residual nuclei as the sum of energies for holes (knocked-out nucleons) and particles (trapped nucleons).

− Pauli-blocking is applied to NN collisions leading to occupied levels

− Local density approximation and scalar potentials for nucleons− It is not intended for use when one of the nuclei is much larger

then carbon nucleus−

In G4QMD model each nucleon is seen as a Gaussian wave packet.− Propagation with scattering term which take into account Pauli

principle− Self-generating potential is used in G4QMD

Both models are connected to de-excitation models of Geant4 to simulate further decays of hot (pre)fragments

Decay of residual nuclei: sequential evaporation vs simultaneous break-up?

Evaporation 10­18  ­10­16 s

Fermi break-up model for decays of light nuclei (A<17) ● Excitation energies of light nuclei can

be comparable to their total binding energies: explosive decays.

● Production of fragments is considered in their ground states and low-energy excited states stable to nucleon emission.

● The probability of a given decay channel is defined by its statistical weight.

● Long list of possible decay channels (e.g. 200 channels for 12C, 1000 for 16O)

● G4 version follows the F77 code written by A.Botvina.

Wassily Kandinsky“Several circles”, 1926Guggenheim Museum, NY

Explosive decays of 12C relevant to carbon ion therapy

Several fixes made to Geant4 implementation of the model. Now good agreement between F77and C++ versions of Fermi break­up model is obtained.

H

He

LiBe

III. Calculations of yields of secondary particles with MCHIT

12C beam 330 MeV/nucleon: 100 events

charged particles: blue – nucleonsand nuclear fragments;  red – fast electrons

green ­ neutrons of all energies

Models at work, BIC vs QMD: energy spectra

waterphantom

detectors: particle ID, energy, angle

12CGSI experiment:

QMD is  closer to data, but still not perfect

Data: E. Haetneret al.

Models at work, BIC vs QMD: angular distributions

waterphantom

detectors: particle ID, energy, angle

12CGSI experiment:

QMD is better compared to BIC

Data: E. Haetneret al.

IV. Impact of radiation at microscopic scale: ion tracks inside nuclei of mammalian cells

12C 9.5 MeV/nucleon and 238U 3 MeV/nucleon by in-beam microscopy. Proteins 53BP1 and RPA related to DNA repair were made fluorescent. B. Jacob et al., Rad. Res. 171 (2009) 405

Energy imparted to tissue per unit of track length is an important characteristic of radiation. Can one make a radiation detector of an equivalent size? 

DNA is densely packed inside cell nuclei

http://www.dnaftb.org

http://www.dynamicscience.com.au

Effects of radiation: single and double strand breaks in DNA and LET

http://www.ptb.de/

● Single strand breaks are usually repaired by the cell

● It is more difficult to repair double and multiple strand breaks

● Therefore, the energy deposited per unit length of particle track (LET) really matters to the biological action of radiation

● LET values of ~20 eV/nm (20 keV/µm) are critical

Tissue-equivalent proportional counter (TEPC) aka Rossi counter

A plastic sphere filled with low­pressure gas,equivalent to 2.7 µm sphere of tissue,an object of a cell nucleus size. 

gas

D=12.7 mm1.27 mm

Ionization in TEPC: equivalent to  energy left by a particle in a single cell.

Lineal energy: y=ε /<l>~ LET

<l>=2/3 D – mean chord

ε – energy in TEPC

wall

Simulations of TEPC response to ionization by charged particles

P.J. Taddei et al., Radiat. Meas. 43 (2008) 1498

View of two events simulated with MCHIT. Here thresholds for electron production are higher. Note a very rare fragmentation reaction in the wall happened in the second event.

TEPCs in water phantom

G.Martino, M.Durante, D. Schardt,PMB 55 (2010) 3441

Simulation of experimental setup at GSI

beam

Each counter is replaced by aring to reduce the number of MChistories.

Rings are properly locatedto avoid interference

Total doses far from the beam: MCHIT describes the data

Data by G.Martino, M.Durante, D. Schardt,Phys. Med. Biol. 55 (2010) 3441

G. Martino, D. Schardt, M. Durante et al.,Presented at 12th Workshop on Ion Beams In Biology and Medicine (IBIBAM), Koeln, 2009

Calculated and measured lineal energy spectrabeam

neutron contribution

secondary protonsand alphas

Data by G.Martino,M.Durante, D. Schardt,PMB 55 (2010) 3441

Conclusions●Methods used to model detectors in nuclear and particle physics experiments are also successful to simulate particle therapy.

●The MCHIT model based on Geant4 toolkit (with QMD+Fermi break-up) is able to describe the yields of secondary nuclei from fragmentation of 12C in water.

●The model describes microdosimetry spectra in the treatment field of 12C beams and out of the field. These lineal energy distributions characterize the energy imparted to the objects of a size of a single cell nucleus (~3 µm).

Links between Russia and Spain are even deeper as one can imagine...

● Artem, Far East of Russia

● A house of a couple of retired construction workers

● Apparent influence of A.Gaudi masterpieces!

http://ria.ru/photolents/20110928/445372771.htmlhttp://drugoi.livejournal.com/3623104.html

Thank you for your attention!

Many thanks to the organizers for the great hospitality in Barcelona!