Biophysics - GSI

GSI Summer School 7/8/2008
Biophysics
Prof. Dr. Marco Durante

Table of contents
1. Radioactivity
2. Interaction of radiation with matter
3. Radiobiology
Acute (deterministic) effects
Late (stochastic) effects
Cancer
Noncancer
4. Heavy ions
Space radiation
5. Radiotherapy
Conventional X-ray therapy
Hadrontherapy

November 1895: Roentgen discovers x rays

February 1896: Becquerel discovers radioactivity
1 Bq= 1 disintegration/second

α, β, γ-rays

Interaction of x or γ rays
(photons) with matter: Ionization

Interaction of electrons or ions with
matter:
Ionization (Coulomb interaction)
electron

Radiation Dose
• Radiation effects depends on DOSE= Energy Deposited
by Radiation per Unit Target Mass
• Dose is measured in Gray (Gy) (=1 joule / kg)
• ..but different radiations have different effectiveness (Q)
• Equivalent dose= QxD is measured in Sievert (Sv)
• For X-, γ-rays and electrons: 1 Gy = 1 Sv
• But, for example: 1 mGy α-particles= 20 mSv (Q=20)
• Mammography= 0.01 mSv
• Average background radiation dose on Earth= 3 mSv/year
• Average background radiation dose in space= 1 mSv/day
• Whole-body CT scan=10 mSv
• Occupational limit= 50 mSv/year
• Lethal dose= 4.5 Sv
• Radiotherapy= 60 Gy (to the tumor)

Dose Ranges
(mSievert)
0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000
0 1000 2000 3000 4000 5000 6000 7000 8000 9000 10000
0 100 200 300 400 500 600 700 800 900 1000
0 10 20 30 40
Typical annual dose for commercial airline flight crews
50 60 70 80 90 100
0 1 2 Natural 3 background 4 5 6 7 8 9 10
NRC Dose Limit for Public
0 0.1 0. 2 0.3 0. 4 0. 5 0.6 0.7 0.8 0. 9 1
EPA Clean-up Standards NRC Clean-up Standards
ICRP Negligible Dose
Typical mission dose on ISS
Thyroid (I-123)
Total Body Therapy Total Tumor Dose
A-bomb survivors
Human LD50
Significant cancer risk at > 200 mSv
(UNSCEAR)
Bone (Tc-99m)
Site Decommissioning/License Termination
Occupational Limit NRC, EPA
0 0.01 0.02 0.03 0.04 0.05 0.0 6 0.0 7 0.08 0.0 9 0.1
3-Mile Island Ave Ind
Cancer Radiotherapy
Experimental Radiobiology
Cancer Epidemiology
Low Dose studies
Dental X-ray
Medical Diagnostics
Chest X-ray
Regulatory Standards

How does radiation injure people?
• High energy radiation breaks chemical
bonds.
• This creates free radicals, like those produced
by other insults as well as by normal cellular
processes in the body.
• The free radicals can change chemicals in the body.
-
+

How does ionizing radiation damage DNA?

How does this damage from ionizing
radiation effect our bodies?
Sufficient Cell Killing
Radiation Sickness
Sufficient Genetic
Alterations
Cancer

RADIATION SICKNESS
System effected/ Syndrome Symptoms Dose
Nervous system
CNS or Cerebrovascular
Syndrome
G.I. system
Gastrointestinal Syndrome
Blood cells / bone marrow
Hematopoietic Syndrome
Skin
Erethema
Ovaries/
Testes
Shock, severe
nausea,
disorientation,
seizures, coma
Nausea, vomiting,
diarrhea,
dehydration
Chills, fatigue,
hemorrhage,
ulceration,
infections, anemia
100 Gy
10 Gy
3-8 Gy
Burning/ infection, 10 Gy
sloughing of skin,
hair loss
Sterility 0.6-0.8 Gy
2-6 Gy

Radiation sickness is possible during radiotherapy, in nuclear
accidents, or from nuclear terrorism
Radioactive
Dispersal Device
(RDD)
Alexander Litvinenko was
poisoned in 2006 with the αradioactive
210 Po
(166 TBq/g and 0.5 µSv/Bq by
ingestion 50 ng are enough
to give a lethal dose of 4.5 Sv!)
Time fuse
Radioactive
material
Detonator
Conventional
explosive
(e.g. fertilizer,
semtex)
Argun, Chechnya, 1999 – A
container filled with
radioactive materials
found attached to an
explosive mine hidden
near a railway line. It
is safely defused.
The location is Argun,
near the Chechen capital
of Grozny, where a
Chechen group, led by
Shamil Basayev, operated
an explosives workshop.

Stochastic late effects

Radiation and Cancer:
A-bomb survivors
87,000 survivors followed
7,800 cancer deaths observed
7,400 expected
Therefore: 400 excess cancers

Extrapolating radiation risks
from high to low doses

Lifetime cancer mortality risk
as a function of age at exposure

Non-Cancer Risks- Acute Gamma Rays
ISS
Mars
Preston et al. Rad. Res. (2003)

Radiation-induced Radiation induced cataracts: Severe
atomic bomb-induced bomb induced cataract
Image from woman who was 21 yrs old at time of the blast, exposed on
the street 805 meters from the hypocenter with acute symptoms.
Photo courtesy of Dr. Tsugihiko Tokunaga

Hereditary Effects
Children of the survivors of the A-bomb attacks have
been studied for:
Untoward pregnancy outcomes
Death of live-born children
Sex chromosome abnormalities
Electrophoretic variants of blood proteins
But no statistically significant effects have been
observed

High-energy
High energy heavy ions
50 um
electrons

(1)
(2)
All radiation tracks are highly structured on the scale of DNA
Heavy ions
electron
DNA
Delta-ray electron
©DTG
21.8.03

An Analogy for Structured Energy Deposition and its Consequences
Low LET radiation produces isotropic damage to organized targets.
High LET radiation produces correlated damage to organized targets.
LET: Linear Energy Transfer
1 Dose Unit
Low LET radiation deposits
energy in a uniform pattern
1 Dose Unit
High LET radiation deposits
energy in a non-uniform pattern

Why are we interested in energetic
heavy ions? ions
Heavy ion radiation is not present naturally on
Earth

The Space Radiation Environment
Solar particle events (SPE) (generally associated with Coronal Mass Ejections
from the Sun):
medium to high energy protons
largest doses occur during maximum solar activity
not currently predictable
MAIN PROBLEM: develop realistic forecasting and warning strategies
Trapped Radiation:
medium energy protons and electrons
effectively mitigated by shielding
mainly relevant to ISS
MAIN PROBLEM: develop accurate dynamic model
Galactic Cosmic Rays (GCR)
high energy protons
highly charged, energetic atomic nuclei (HZE particles)
not effectively shielded (break up into lighter, more penetrating pieces)
abundances and energies quite well known
MAIN PROBLEM: biological effects poorly understood but known to be most
significant space radiation hazard

Trapped radiation belts – measurements
on MIR 18

Relative contribution
1,E+00
1,E-01
1,E-02
1,E-03
1,E-04
1,E-05
1,E-06
1,E-07
Relative contribution of different ions to
flux, flux,
dose, and dose equivalent from
galactic cosmic radiation
Flux Dose Dose equivalent
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Atomic number (Z)

4-6 crew to lunar surface for extended-duration stay
CEV:Earth-moon cruise – 4 days
Low lunar orbit (LLO) operations- 1 day
Untended lunar orbit operations – 4-14 days
Low lunar orbit operations – 1 day
Moon-Earth cruise – 4 days
Lunar Lander: Lunar
surface operations
60-90 days
2015-2020
2014
4-6 crew to Low Earth Orbit
Crew Exploration Vehicle: Launch Environment
LEO Environment
Earth entry, water (or land) recovery
2025+
2020
Crew TBD to Mars Vicinity
Transit vehicle: Earth-Mars cruise – 6-9 months
Mars vicinity operations – 30-90 days
Mars-Earth cruise – 9-12 months
4-6 crew to lunar surface for
long-duration stay
Lunar Habitat: Lunar surface
operations 60-90 days
Crew TBD to Mars surface
Surface Habitat
2030+
NASA ESMD

Dose (mSv)
10 4
1000
100
10
Radiation doses in different missions
Apollo Skylab
Past Future
STS/Mir
Shuttle
1
Population
per year
Gemini
0.1
1950 1970 1990 2010 2030 2050
Year
ISS
Mars
Moon
Callisto
Astronauts
career
RadWork
per year

ROUGH GUIDES
THE ROUGH GUIDE to
The Moon
& Mars
Health in Deep
Space
1. Protection from space
radiation (particularly very
high energy heavy ions)
2. Psychosocial and
behavioural problems
3. Physiological changes
caused by microgravity
Modified by Mike Lockwood

Biological effects of heavy ions
No human epidemiological
data
γ-rays heavy ions

γ-rays
silicon
iron
Tracks in cells
Cucinotta and Durante, Lancet Oncol. 2006

Dose distribution in micrometer scale
sparsely ionizing photons densely ionizing particles

Chromosomal aberrations induced by heavy ions
3 Gy γ-rays 0.3 Gy Feions
Durante et al., Radiation Research 2002

Cell killing by different radiation types

Definition of RBE

Relative Biological Effectiveness for Cell Inactivation by Ionizing Radiations
© DTG 5.11.03

Tumor Prevalence (%)
100
80
60
40
20
Harderian gland tumors in mice
Iron
Neon
10-3 10-2 10-1 100 101 102 103 0
Fluence, µm 2
Helium
Proton
γ-rays

The good side of radiation: radiation:
radiotherapy

Radiotherapy
Also called “Radiation Therapy”
Part of multi-disciplinary approach to cancer care
Useful for 50-60% of all cancer patients
Can be given for cure or palliation
Mainly used for loco-regional treatment
Benefits and side-effects are usually limited to
the area(s) being treated

Radiotherapy Treatment Goals
maximize the therapeutic radio TR=
probability of tumour control_(TCP)____
probability of normal tissue toxicity (NTCP)
For palliation (e.g. bone metastasis), it is
possible to obtain symptom improvement
without eradicating the tumour

Therapeutic window

Types of radiotherapy
Radiosensitive
Lymphomas
Germ cell tumours
Small cell carcinomas
Radioresistant
Melanoma
Sarcomas
Glioblastomas
External beam (teletherapy)
- Conformal therapy, IMRT (X-rays), hadrontherapy (protons or Cions)
Brachytherapy
– Intracavitary
– Interstitial
– Surface molds
Systemic
– Radioactive Iodine, Strontium, Radio-labeled antibodies

Treatment
planning
Generally, the
total dose to the
tumor is about 60
Gy, given in daily
fractions of 2 Gy
to spare the
normal tissue
X-rays produced
by LINACS (6-15
MV) are normally
used

April 11, 2001
(just prior to 1000cGy/1fr/1day orthovoltage
treatment using 300kvp photons)

Treated area close-up (1 year post radiation)

Side-effects Side effects of Radiotherapy
Acute (1 month)
Pneumonitis/fibrosis of lungs
Hypothyroidism
Xerostomia
Enteritis
Infertility/menopause
Long-term (10-20 years)
Increased risk of secondary cancers
Increased heart disease if chest region treated

Charged particles for therapy

Depth dose distribution of various radiation modalities

Principle of raster scanning

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

Slices of a tumor treated at GSI

Protontherapy
Choroidal
and iris
melanoma
(60 MeV)
Deep
tumors
(250 MeV)

C-ions ions vs. X-ray ray therapy

Biological
effective dose
W. K. Weyrather, GSI

Tissue dependence of RBE

Bestrahlungsraum: Cave M
Röntgenröhre
Bildverstärker
Patientenmaske
Strahlaustrittsfenster
Patientenmonitor
Patient
PET-Kamera
Patiententisch

Adenocystic Carcinoma
O.Jaeckl DKFZ
C12
boost

Adenocystic Carcinoma
combined photons and C12-Boost
C12 Boost
Prior RT 6 weeks after RT

• Clivus Chondrosarcomas
• Patient:23 years old
• Diagnosis: Chondrosarcoma
• Subtotal surgery
• Postoperative radiationtherapy:60Gye
• 3 fields with 20 fraction
vor Bestrahlung
6 Weeks after carbon
tfeatment with a dose of 60 Gye
D.Schulz-Ertner et al.

Adenoidcystic carcinomas:
Photon-IMRT with and without carbon boost
Überleben Tumorkontrolle
survival tumorcontrol
carbon
without carbon
[Schulz-Ertner, Cancer 2005]

Dose –Tumorcontrol curve for Chordomas
Lokale Tumorkontrolle [%] 5J.
Heavy ions, Castro, 1996
Protons, Munzenrider, 1994
Protons, Hug, 1999
GSI
FSRT, Debus, 2000
Konventionelle RT
mittlere Dosis [Gy]

Future developments
European projects
Darmstadt since 1997
Heidelberg: first RT 2007 ,
Pavia : first RT 2008 ,
Marburg , Wiener Neustadt , Lyon.
Japanese projects
Chiba 1994,
Hyogo 2003 , Gunma

Particle Beam Therapy Facilities in Japan
Cover Area
Gunma Heavy Ion Science Center
C-ion, ion, Micro beam radiotherapy
Gunma Prf.
Niigata Prf.
Nagano Prf.
Tochigi Prf
Saitama Prf.
Wakasa Bay Research
Center(Suruga)
Proton
Hyougo Particle therapy
Center
Proton(2001~)
C-ion(2001~)
Sizuoka Cancer
Center
Proton
Tsukuba University
Proton (1983 〜)
National Cancer
Center Kashiwa
Branch
Proton (1999 〜)
National Institute of
Radiological Sciences
Proton(1979 〜)
C-ion (1996〜)
Working
Construction

Advantages of heavy ion therapy
• Inverse dose profile: higher target dose
lower dose to normal tissue
• Millimeter-precision treatment
• PET beam verification
• High biological effectiveness in the target
• Low biological effectiveness in the entrance channel
• Biological based treatment planning
• Little side effects
• Good tumor control rates 80-90%
Future
• Heavy ion center at Heidelberg
• Many projects over the world
• Treatment of moving organs
• Biologically optimized treatment

Thank you for attention! attention
If you want to learn
more…….
Tuesday, August 12, 3 pm
A primer on heavy ion
physics
Thursday, August 14, 3 pm
A primer on heavy ion
biology