Current plans for research in heavyion therapy at GSI

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Current plans for research in heavy-ion therapy
at GSI
Marco Durante
BASROC, Oxford, September 23, 2008
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Rationale for heavy-ion therapy at GSI
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Advantages of heavy-ion therapy
Tumor
Normal tissue
Relative dose
Depth (mm)
Potential advantages
E LET Dose RBE OER Cell-cycle dependence Fra
ctionation dependence
high low low high
low high ? 1 gt
1 ? 3 (X,g) lt 3 high
low high low
High RBE in the tumor, low in the tissue High
tumor dose, normal tissue sparing Effective for
radioresistant tumors Effective against
hypoxic tumor cells Increased lethality in the
target because cells in radioresistant (S) phase
are sensitized Fractionation spares normal
tissue more than tumor
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Comparison of Treatment Plans C-ions vs. IMRT
Heavy Ions (2 Fields)
IMRT (9 Fields)
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Comparison of Treatment Plans C-ions vs. protons
H-ions (CapeTown, SA)
C-ions (GSI)
H
C
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Passive beam modulation (NIRS)
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Principle of raster scanning (GSI)
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Adenocystic Carcinomacombined photons and
C12-Boost
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Recurrent Chordoma60 GyEJ.Debus,D.Schulz-Ertner
et al
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• Clivus Chondrosarcomas

• Patient23 years old
• Diagnosis Chondrosarcoma
• Subtotal surgery
• Postoperative radiationtherapy60Gye
• 3 fields with 20 fraction

vor Bestrahlung
6 Weeks after carbon tfeatment with a dose of 60
Gye
D.Schulz-Ertner et al.
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Adenoidcystic carcinomas
Photon-IMRT with and without carbon boost
carbon
without carbon
Tumorkontrolle
Schulz-Ertner, Cancer 2005
tumorcontrol
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Carbon treatment of Chordomas and
-Chondrosarcomeas at the brainstem
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GSI
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Heavy Ion Therapy at the SIS Darmstadt

• More than 400 patients
• 5-year tumor control rates
• 75-95
• Innovations
• Tumor conform irradiation
• ? Rasterscan System
• Biological treatment planning
• ? Local Effect Model LEM
• In vivo beam control
• ? On-line PET control

GSI Darmstadt FZ Dresden DKFZ Heidelberg Univ.Hei
delberg
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Carbon and Proton Therapy in Europe
Facilities in Europe
HIT Heidelberg Ion beam Therapy
From 2009 no more therapy at GSI
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The NIRS experience

• Clinical experiences have demonstrated that C-ion
  RT is effective in such regions as the head and
  neck, skull base, lung, liver, prostate, bone and
  soft tissues, and pelvic recurrence of rectal
  cancer, as well as for histological types
  including adenocarcinoma, adenoid cystic
  carcinoma, malignant melanoma and various types
  of sarcomas, against which photon therapy could
  be less effective. Furthermore, when compared
  with photon and proton RT, a significant
  reduction of overall treatment time and fractions
  has been accomplished without enhancing
  toxicities.

NIRS annual report 2008, Tsujii et al.
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NIRS annual report 2008, Tsujii et al.
Lung
Prostate
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Future research activities
Biomat
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Basic radiobiology of heavy ions applications in
hadrontherapy and space radiation protection
g-rays
silicon
iron
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Key research areas in hadrontherapy

• Moving targets
• TPS RBE modelling, improvement of the LEM model
  to reduce uncertainty
• Biological optimization of TPS
• Secondary cancer risk
• New ions lighter (He, Li), heavier (O, Ne) or
  unstable (p-, 9C,.)
• Animal/tissue experiments on individual
  sensitivity

GSI as the main research center for hadrontherapy
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3D online motion compensation (3D-OMC)
suitable motion tracking system
magnetic scanner system
PMMA wedge system
dynamic treatment plan
static
moving, non-compensated
moving, compensated
7th FP Infrastructure ULICE project
Gerhard Kraft Christoph Bert
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Influence of target motion
static
compensated
not compensated
T6.0s, ?270º
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Verification of treatment plans Wilma
Kraft-Weyrather
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Verification of treatment plans WKWeyrather et al.
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Principle of the Local-Effect-Model (LEM)

• Input parameters
• radial dose distribution
• size of cell nucleus
• x-ray sensitivity (?/? ratio)

The model is currently used in the commercial
Siemens TPS yet the highest uncertainty is
associated to the RBE model
Michael Scholz
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High Dose Cluster Effects (LEM-II)

• Experiments with plasmids
• Non-linear yield of DSB
• Clustered SSBs reason for non-linearity
• Stagger size between 5 bp and 60 bp

Elsässer and Scholz Rad.Res. 2007
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Energy dependent track center (LEM III)
track center extension depends on particle
energy (adiabaticity principle) gt rmin40nmb
bv/c 40nm - empirically adjusted for
best agreement with ion data
Elsässer et al., Int.J.Radiat Oncol Biol Phys 2008
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Accuracy of LEM
Different human cell lines of tumor and normal
tissue
distal SOBP (77 keV/mm)
Plateau (13 keV/mm)
RBE(a/b low)gtRBE(a/b high)
Exp. Data Suzuki et al., IJROBP 2000
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Comparison different Ions
HSG
Data Furusawa et al. , Radiat. Res. 154 ,
485-496 (2000)
Elsässer Scholz
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Radiotherapy and secondary cancers

• Cancer survivors represent about 3.5 of US
  population
• Second primary malignancies in this high-risk
  group accounts for about 16 of all cancers
• Three possible causes
• Continuing lifestyle
• Genetic predisposition
• Treatment of the primary cancer
• Assessment is difficult because of lack of
  controls
• Prostate and cervix cancer surgery is an
  alternative
• Hodgkins lymphoma risk of breast cancer very
  high
• Radiation-induced secondary cancers are mostly
  carcinomas, but a sarcomas in heavily irradiated
  sites are also observed

Brenner et al., Cancer (2000)
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New treatment modalities
Hadron therapy
IMRT
Substantial increase in beam-on time
Neutron production
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Projected cancer risk for IMRT vs. 3D-CRT
More monitor units (x2-3)? increased leakage
radiation (about 0.1 from the head, but up to 3
from MLC) More fields ? bigger volume of normal
tissue is exposed ? higher risk (?? Depends on
radiobiology..)
Hall and Wu, IJROBP 2003 Kry et al., IJROBP 2006
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Pediatric patients
Hall, IJROBP 2006
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Neutron fluence measurements with therapeutic
charged particle beams
Schardt et al., Radiat. Prot. Dosim. 2007
200 MeV/u 12C
12.8 cm thick Water (Beam stops)
300 cm
-2 30 grad
BaF2 crystal scintillator For 10 MeV to several
GeV neutron energy
NE102A plastic scintillator as ?E counter
BaF2 crystal scintillator as E counter
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SCATTER-RADIATION DURING RADIOTHERAPY

• Dose estimates for collimator scatter, leakage
  dose, phantom scatter and neutron dose
  equivalent for photons, protons and ionsStovall
  M, Blackwell CR, Cundiff J, Novack DH, Palta JR,
  Wagner LK, Webster EW, Shalek RJ. Med Phys.
  22(1)63-82, 1995.d'Errico F, Luszik-Bhadra M,
  Nath R, Siebert BR, Wolf U. Health Phys.
  80(1)4-11, 2001.Gunzert-Marx K, Schardt D,
  Simon R. Radiother. Oncol 73S92-S95, 2004.

Dose equivalent in Sv per treated MU for photons
and per treatment proton for spot scanned proton
and 12C radiotherapy (in brackets for 10000MU
and about 1012 protons or 1010 C-ions for a
typical treatment with 70 Gy or GyE).
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Experiment configurations
with phantom
during therapy
12C
12C
Patient
Phantom
TEPC for in-phantom dose measurements
NEMUS
EURATOM 7th FP ALLEGRO project
0 170 deg.
WENDI-II
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Out-of-field particle dose
Dieter Schardt Giovanna Martino
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In patient dosimetry(uterus dose for a pregnant
woman)
Total dose about 0.3 mSv (preliminary, July 2008)
Courtesy of Georg Fehrenbacher
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High uncertainty on this plot!
C, scanning
Hall, IJROBP 2006 and discussion in red/green
journals 2007-2008
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The RBE problem
Neutrons
ICRP Pub. 92, 2003
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Uncertainty on late effects of heavy ions

• Dose Equivalent
• H Flux x LET x Q(LET)
• Risk R0 x H
• NCRP recommended approach of propagation of
  uncertainties in individual risk factors
• epidemiology, dose-rate, quality factor, and
  physical uncertainties

M. Durante F.A. Cucinotta, Nature Rev. Cancer,
June 2008
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Light ion LET 150 keV/µm
HZE ion LET 150 keV/µm

• Few damaged cells
• Mostly non-viable

S ? 0.4 (primary ion) S ? 1 (delta rays)

• Many damaged cells
• Mostly viable

S ? 0.1
Smaller risk
Larger risk?
Courtesy of D.T. Goodhead
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AML incidence in CBA mice exposed to Fe-ions or
g-rays
Courtesy of M. Weil
Radiation Leukemogenesis NSCOR
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Tumor induction after local irradiation of mice
legs by C-ions
Ando et al. J. Radiat. Res. 2005
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Frequency distribution of aberrant
chromosomes/cell (Dose 0.3 Gy)
Chromosomal aberrations induced by 1 GeV/n
Fe-ions (147 keV/mm) in human blood lymphocytes
visualized at the 1 post-irradiation cycle
Durante et al., Radiat. Res. 2002, 2006
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48 h
144 h
RBE decreases in surviving cells Durante
Cucinotta, Lancet Oncol. 2006 Nature Rev. Cancer
2008
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Neoplastic transformation in therapy fields
Courtesy of D. Bettega W. Kraft-Weyrather
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Chromosome aberrations - in vivo exposure (cancer
patients)

• Analysis of aberrations in the blood of
• prostate cancer patients before, during
• and after therapy. Start January 2006
• Patients are treated with a C ion boost
• (6x 3 GyE) and IMRT (30x2Gy) or
• Patients are solely treated with IMRT
• (39x2Gy)

• Questions to be addressed
• Relationship between dose and aberration yield
• Is there a fingerprint of high LET radiation ?
• Are there interindividual differences in
  radiosensitivity

Sylvia Ritter
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Image of Albert Einstein produced with the GSI
rasterscan system using a 430 MeV/u carbon beam
of 1,7 mm width (FWHM). The picture consists of
105x120 pixel filled by 1.5.10 10 particles given
in 80 spills (5 sec. each) of the SOS
accelerator. Original size of the picture 15 x
18 cm
Thank you very much!