Radiation Biology (MPHY

5172)

9/5/2024
Housekeeping Issues

n Instructors
¨ Jianling Yuan, yuanm033@[Link]
¨ Lindsey Sloan, sloan153@[Link]

Classic radiobiology Cancer Biology

Clinical application Chemotherapy and Immune Therapeutics
Syllabus
ABR Exam – Medical Physics
ABR Exam – Medical Physics
ABR Medical Physics Part I Content Guide
On exam 2 and 3, there may be different
versions of the cancer biology questions
for physics students

Alternatively, there may be additional

questions for rad onc residents
ABR Medical Physics Part I Sample
Questions
A fetus receives a dose of 2 Gy during weeks 20 to 39 pregnancy. After birth, the child has an
increased risk for what condition?

A. Trisomy 21
B. Leukemia
C. Microcephaly
D. Neonatal death

For ionizing radiation, how does the OER vary as LET increases from 1 to 100 KeV/μm?

A. Increases
B. Decreases
C. Remains the same
D. Increases then decreases
E. Decreases then increases

[Link]
ABR Exam – Medical Physics
ABR Exam – Rad Onc Residents
ABR Rad Onc Residents Exam

Protected study time

 iv. Clinical consequence and relevance of hypoxia in tumors and tumor progressions
[Link] and neovasculogenesis
v.
iv.
Reoxygenation after irradiation
Clinical consequence and relevance of hypoxia in tumors and tumor progressions
vi.
v. Cellular and molecular
Reoxygenation responses to hypoxia and hypoxia-induced signal transduction
after irradiation
vii.
vi. Cellularand
Cellular composition of tumorsto hypoxia and hypoxia-induced signal transduction
molecular responses
viii.
vii. Immune
Cellular microenvironment
composition of tumors and role of inflammation
viii. Immune microenvironment and role of inflammation
VI. Cancer biology
VI. Cancer
a. Cellbiology
and tissue kinetics

ABR Study Guide

a. [Link] and tissue
Methods tokinetics
assess cell cycle kinetics
i. Methods
ii. Proteins to assess cell cycle
involved kinetics
in cell cycle control and checkpoint initiation (e.g., CDKs, cyclins,
ii. Proteins involved in cell cycle control and checkpoint initiation (e.g., CDKs, cyclins,
CDK inhibitors)
iii. Phases CDKofinhibitors)
cell cycle and radiation sensitivity
iii. Phases of cell cycle and radiation sensitivity
iv. Cell cycle arrest and redistribution after irradiation
iv. Cell cycle arrest and redistribution after irradiation
b. Molecular signaling
b. Molecular signaling
i. Main signaling pathways and critical proteins involved (e.g., PI3K/AKT, RAS/ERK, TGF-β,
i. Main signaling pathways and critical proteins involved (e.g., PI3K/AKT, RAS/ERK, TGF-β,
Wnt,Notch,
Wnt, Notch,NFkB)NFkB)
a)a) Receptors/ligand
Receptors/ligand (e.g.,
(e.g., EGFR,
EGFR, VEGFR,VEGFR, c-MET,
c-MET, HER2,HER2,
FGFR,FGFR,
ALK) ALK)
b)b) Kinases
Kinases
1).Definition
1). Definition of of kinases
kinases (e.g.,
(e.g., STKs, STKs, TKs/RTKs,
TKs/RTKs, DSKs)DSKs)
2).Common
2). Common kinases
kinases in cancer
in cancer (e.g.,
(e.g., ATM,ATM,
ATR,ATR,
Chk1,Chk1,
Chk2,Chk2, PI3K, MAPK)
PI3K, MAPK) and and
corresponding
corresponding phosphatases
phosphatases (e.g.,(e.g.,
PTEN)PTEN)
ii.
ii. Molecular
Molecularsignaling
signalingpathways
pathways activated
activatedby IRby IR
iii.
iii. Transcription
Transcriptionfactors
factorsinvolved
involvedin cancer
in cancerregulation (e.g.,(e.g.,
regulation MYC,MYC,
TP53 and
TP53associated
and associated
proteins)
proteins)
iv. Cell death pathways and main associated
iv. Cell death pathways and main associated players players
a). Intrinsic vs extrinsic apoptosis (caspases)
a). Intrinsic vs extrinsic apoptosis (caspases)
b). BCL-2 family member proteins (pro- vs anti-apoptotic)
b). BCL-2 family member proteins (pro- vs anti-apoptotic)
c. Mechanisms of cancer development
c. Mechanisms of cancer development
i. Hallmarks of cancer and how they could affect 4/5 Rs of radiobiology
i. Hallmarks
ii. Common oncogenes of cancer(e.g.,
andHER2/neu,
how they Ras, could affect
Myc) 4/5 Rssuppressors
& tumor of radiobiology
(Rb, p16, p53,
ii. BRCA1/BRCA2,
Common oncogenes APC, NF1) (e.g., HER2/neu, Ras, Myc) & tumor suppressors (Rb, p16, p53,
BRCA1/BRCA2, APC, NF1)
iii. Telomeres and pathways in cancer to overcome telomere shortening (e.g., TERT
iii. promoter
Telomeres and pathways
mutations in cancerlengthening
and alternative to overcome telomere[ALT])
of telomeres shortening (e.g., TERT
promoter
iv. Signaling mutations and
abnormalities and alternative
association with lengthening
treatmentofresponse
telomeres [ALT])
iv. CancerSignalingas aabnormalities
genetic diseaseand association with treatment response
v.
iv. Multistep
Cancer asnature of carcinogenesis
a genetic disease
vi. Signaling abnormalities
v. Multistep nature of carcinogenesis in carcinogenesis
vii.
vi. Signaling abnormalities insignificance
Prognostic and therapeutic carcinogenesis of tumor characteristics
d. Cancer [Link]/genomics
Prognostic and therapeutic significance of tumor characteristics
i. Types of epigenetic regulation (e.g., DNA methylation (DNMTs/TETs), histone
d. Cancer genetics/genomics
modifications (e.g. HDACs/HATs), chromatin remodelers)
i. Types of epigenetic regulation (e.g., DNA methylation (DNMTs/TETs), histone
ii. Main epigenetic alterations (e.g., CpG island methylator phenotype [CIMP]) in
modifications
cancer
(e.g. HDACs/HATs), chromatin remodelers)
ii. Maina). epigenetic alterations
IDH1/2 mutations (e.g., CpG
in glioma and AML island methylator phenotype [CIMP]) in
cancer
b). TET2 mutations in AML
6/3/2022 a). IDH1/2 mutations in glioma and AML 3
b). TET2 mutations in AML
6/3/2022 3
iii. Epigenetic targets in cancer (DNMTi, HDACi, IDHi, EZH2i)
iv. Omics approaches in cancer (next-gen sequencing/arrays) and newer methods (ctDNA)
v. Biomarkers in cancer (e.g., BCR-ABL, EGFR, ALK)
vi. Molecular profiling of cancer

VII. Radiobiology of normal tissues

a. Clinically relevant normal tissue responses to radiation
i. Responses in early versus late responding tissues
ii. Reirradiation
b. Mechanisms of normal tissue radiation responses
[Link]
i. Molecular and cellular responses in slowly and rapidly proliferating tissues
ii. Mechanisms underlying clinical symptoms
iii. Tissue kinetics
c. Total body irradiation
i. Prodromal radiation syndrome
ABR Exam Results
Physics Students Radiation Oncology Residents
 ARRO Lectures

You can watch videos and download mp3

[Link]
ASTRO Study Guide

Study guide from last few years on Canvas

ABR Exam Calculator
For the convenience of our candidates, a calculator is included in the exam interface.

For the purpose of the in-class exams, a scientific calculator is required

Using smart phone during exam is NOT allowed!!!

Chapter 1

Physics and Chemistry of Radiation

Absorption
Outline

n Brief Historical Overview

n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons, Protons and Heavy Ions
Milestones in History of Radiation Physics

n ???? – Roentgen discovered X-ray

n 1896 – Becquerel discovered

radiation emitted by uranium Wilhelm Conrad Roentgen
compounds (1845-1923)

n 1898 – Pierre and Marie Curie

isolated the radioactive elements
polonium and radium

Pierre Curie (1859-1906)

Marie Curie (1867-1934)
Wilhem RÖentgen & First X-rays

Wilhelm Conrad Roentgen First publically taken radiograph

(1845-1923) Left hand of his wife Anna (hand of a prominent Swiss
Bertha Ludwig professor of anatomy. Jan 1896)
 Context
Many Unnecessary Exposures
• The first unnecessary exposure took place several weeks earlier
- soon followed by many more

Nationellt möte om sjukhusfysik

13-14 nov 2013, Varberg

International work in
radiation protection of patients at the IAEA:
IAEA
Therapeutic, diagnostic and interventional procedures 8

Ola Holmberg, Ph.D.

Head, Radiation Protection of Patients Unit
Radiation Safety and Monitoring Section
Division of Radiation, Transport and Waste Safety
International Atomic Energy Agency
Vienna, Austria

IAEA
International Atomic Energy Agency
Antoine Henri Becquerel (1852-1908)

n French physicist
n Discovered radioactivity along with Marie Curie and Pierre Cure
n All three won the 1903 Nobel Prize in Physics
n The SI unit for radioactivity, the Bq, is named after him
First Medical Use of X-ray
n 1896 – X-ray was used to
locate a broken part of a knife Diagnostic Radiology
in a drunken sailor

n 1896 – Leopold Freund

demonstrated the Therapeutic Radiology
disappearance of a hairy mole
following treatment with x-rays
Leopold Freund (1868-1943)
n Austrian-Jewish radiologist
n Founder of medical radiology and radiotherapy
n The first physician known to have used ionizing radiation for
therapeutic purposes
n Successfully treated a 4 yo patient in Vienna suffering from
hairy moles covering her whole back
n The case was published by the girl’s local physician in 1901

§ Skin scarring
Skin/soft tissue
§ Keratosis
§ Kyphosis
§ Osteoporosis Skeletal

What could be another significant late effect?

Picture taken at age 74
Early Medical Use of X-rays
n 1896 – Emil Grubbe, a Chicago electrician and metallurgist, first
treated the recurrent breast cancer of a 55-year-old woman
n 1898 – William Pusey reported beneficial effects on hypertrichosis
and acne
n 1898 – Leopold Freund pioneered the use of the x-rays in pediatric
nevus and lupus vulgaris
n 1901 – Frands Williams published on the X-ray cure of a cancer of
the lower lip

Heber Robarts editor could list over 100 different surface and deep-
seated conditions treated by 1902
Early Recorded Biologic Effect of
Radiation the removal of
hair by the
roots

n 1896 – Becquerel reported skin erythema caused by

radium left in vest pocket
n 1896 – John Daniel described scalp epilation during a
diagnostic exposure
n 1901 – Pierre Curie deliberately produced a radium
“burn” on his forearm

Radiobiology = the study of the action of ionizing radiations on living things

Contemporary Radiobiologists
Some of the 20th century radiobiologists
whose work advanced our understanding
of radiation biology and formed the basis
of modern radiotherapy
Rod Withers

Strandquist
Lester
Peters

Frank
Ellis Mort
Elkind

Eric Hall
Outline

n Brief Historical Overview

n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons, Protons and Heavy Ions
Case 1
n 60 yo female w/ early-stage breast cancer
n Underwent surgery and radiation therapy, completed July 2013

4240 cGy / 16 fx + 1000 cGy / 4 fx boost

Oct 2013 (3 mo after Radiation)
n Dry cough, fever 100.8°F, chest tightness
n Symptoms did not improve with antibiotics

Radiation Pneumonitis

What are the factors predisposing this lady to developing radiation pneumonitis?

What are the underlying mechanism of radiation lung injury?

Are there any predictive assays that may allow us to identify the subset of patients with such
predisposition?
Preview
Case 2
n 47 yo F with FIGO IIB cervical cancer treated with definitive
chemoradiotherapy with brachytherapy boost
Gynecology

EQD2 = D x [(d + a/b)/2 + a/b]

D = Total dose
d = dose per fraction
50 a/b = 3 (late normal tissue)
A.N. Viswanathan et al. / Brachytherapy 11 (2012) 47e52
a/b = 10 (tumor)
Table 1 Ring CT/MR Applicator Set
Examples of regimens frequently
The used in the
optimal solution United States forOrder
for volume-based tandem and ovoid or tandem and ring brachytherapy
information
intracavitary cervical brachytherapy Ring CT/MR applicator set (4 mm)
EBRT, dose to ICRU 52 The ring CT/MR applicator uses the ring to create a EQD2 (Gy) to the tumor
Part number Description EQD2 (Gy) with 90% of the EQD2 (Gy) with 70% of the
pear-shaped dose to match the anatomy of the cervix 110.669 Ring CT/MR applicator set complete, 4 mm
point or median dose in case Fractionation to point
and endometrium. (point A dose with
110.670 Ring CT/MR applicator set, 30°, 4 mm target dose to the OAR using target dose to the OAR using
a/b 5 10 Gy)a
What is a/b ?
110.671 Ring CT/MR applicator set, 45°, 4 mm
of IMRT TheA (Gy)
applicator uses strong fiber composite tubing and
110.672 Ring CT/MR applicator set, 60°, 4 mm
a/b 5 3 Gy a/b 5 3 Gy
can be used in combination with CT and MR imaging for
volume-based treatment planning. The fixed geometry of
25 ! 1.8 Gy the4 !and7theGy
ring intrauterine tube provide a reproducible 83.9
Ring CT/MR applicator set, 6 mm, part # 101.035 90.1 74.2
applicator geometry. With the use of the Applicator Part number Description
25 ! 1.8 Gy 5 ! 6 Gy
Modeling module in Oncentra Brachy, reconstruction of the
84.3
101.060 Ring applicator set, 30°, CT/MR
88.6 73.4
applicator takes only a few mouse clicks.

82.6 How do you calculate BED and EQD2?

25 ! 1.8 Gy 6 ! 5 Gy 81.8
101.061

101.062
Ring applicator set, 45°, CT/MR

Ring applicator set, 60°, CT/MR

83.7 70.5
Intended for:
25 ! 1.8 Gy 5 !
· Cervix
5.5 Gy 79.8
101.038

101.044
Ring tube, d = 34 mm, 30°

Ring tube, d = 34 mm, 45°

69.6
101.050 Ring tube, d = 34 mm, 60°
· Endometrium
ICRU 52 5 International Commission of Radiation Units Report 52; IMRT 5 intensity modulated radiation therapy; EBRT 5 external-beam radio-
101.054 Perineal bar

Note:
therapy; EQD2 5 normalized therapy dose; OAR 5 organs at Ring
· This applicator can be sterilized using steam sterilization
risk.
CT/MR applicator set, 6 mm, 30°, part # 101.060
Part number Description
a and ethylene oxide
Preview
Immune Checkpoint Therapy
December 2015

Jimmy Carter announced this week he is

free of melanoma.
In addition to surgery and radiation, Mr.
Carter was treated with a new
immunotherapy drug called
pembrolizumab.
 Abscopal Effect
Brief Report

A B C D E
The patient had a response in hilar nodes
and spleen after localized radiotherapy to
paraspinal mass while receiving ipilimumab

August 2009 November 2010 January 2011 April 2011 October 2011

F
Recurrence of
Abscopal effect is a phenomenon in
which local radiotherapy is associated
Unresectable Ipilimumab
Cancer

with the regression of metastatic

Induction Maintenance Radiation Maintenance

cancer at a distance from the

Stable Slow Progression Response Stable
December 2010

irradiated site
Figure 1. Results of Diagnostic and Radiotherapy Simulation Imaging throughout the Disease Course.
Axial CT images are shown, corresponding to the timeline showing therapy and disease status. White arrows indicate the paraspinal
mass, red circles indicate the right hilar lymphadenopathy and spleen, and black arrows indicate an incidental hepatic hemangioma.
Panel A (top) represents the status before treatment with ipilimumab. Panel B shows enlargement of the paraspinal mass (top), stable
right hilar lymphadenopathy (middle), and new splenic lesions (bottom). Panel C shows images 1 month after radiotherapy, when the re-
sponse to radiotherapy had not yet occurred, with apparent continued worsening disease at all three sites. Several months after radio-
therapy, the targeted paraspinal mass showed a response (Panel D, top). Furthermore, disease response outside of the radiation field
Postow
was seen 2012; NEJM
with decreased right 366:925-931
hilar lymphadenopathy (middle) and resolution of splenic lesions (bottom). The response was durable, as
shown in Panel E. Panel F shows the CT simulation image for radiotherapy planning, with the target volume (indicated in purple) encom-
passing the right paraspinal metastatic mass. The isodose lines represent total doses of 2850 cGy (pink), 2000 cGy (orange), 1000 cGy
(green), and 200 cGy (blue). Disease regression was confirmed by means of three-dimensional volumetric assessment (Table 2 in the
Mechanism of the Abscopal Effect

The use of smart radiotherapy

biomaterials (SRBs) and
nanoparticles provides
promising avenues to boost
abscopal response rates.

§ Radiation generates neoantigens from tumor cells.

§ Antigens from damaged tumor cells can be taken up by antigen-presenting cells
(APCs), which travel to the lymph node to prime the T cell-mediated abscopal effect.
§ Activated T cells directed against tumor-specific antigens then infiltrate the primary
tumor and non-irradiated tumor metastases.
 Types of
Immunotherapy
Preview Treatments in
Oncology
b. Radiosensitizers, bioreductive drugs, and radioprotectors
i. Definition of therapeutic window
ABR Study Guide
ii. Tumor radiosensitizers (e.g., oxygen) and mimics (e.g., nitromidazole)
iii. Normal tissue radioprotectors (e.g., amifostine)
iv. Biological response modifiers (e.g., IL-2 and IFN)
v. DNA repair inhibitors (e.g., PARPi, ATMi, ATRi, Chk1/2i)
c. Immune therapeutics
i. Types of immunotherapy treatments in oncology (Markman and Shiao 2015)
a) Monoclonal antibodies (MABs)
b) Checkpoint inhibitors
c) Cytokines
d) Vaccines
e) Adoptive cell transfer types (chimeric antigen receptors [CARs], tumor
infiltrating lymphocytes [TILs], and T cell receptors [TCRs])
ii. Combination of immune therapies and radiation
a) Recently published trials (e.g., PACIFIC, KEYNOTE)
b) Known predictors of response/biomarkers
d. Hyperthermia
Cytokines for
X. Late effects and radiation protection
a. Radiation carcinogenesis Therapy
i. Dose response for radiation-induced cancers
Dr. Sloan will
ii. Importance of agepresent most
at exposure, time sinceup to date
exposure, sex, and tissue
iii. Second tumors in radiation therapypatients
information
iv. Risk estimates on these topics.
in humans
b. Heritable effects of radiation
i. Relative vs absolute mutation risk
ii. Doubling dose (Dranoff 2004)

iii. Heritable effects in humans

iv. Risk estimates for hereditable effects
c. Radiation effects in the developing embryo
Outline

n Brief Historical Overview

n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons, Protons and Heavy Ions
Excitation and Ionization

n Absorption of energy from radiation in biological material

may lead to excitation or to ionization

Excitation – electron from atom or molecule

raised to a higher energy level but not ejected

Ionization – ejection of one or more

electrons
Ionizing Radiation vs. Non-ionizing
Radiation
n Energy of ionizing radiation is deposited unevenly in
discrete packets

n Energy in the form of heat or mechanical energy is

absorbed uniformly and evenly

n The critical difference b/w nonionizing and ionizing

radiations is the size of the individual packets of energy,
not the total energy involved
Ionizing Radiation
n An important characteristic of ionizing radiation is the
localized release of large amounts of energy

n The biologic effect of radiation is determined not by the

amount of the energy absorbed but by the photon size, or
packet size, of the energy
Ionizing Radiation
n Avg energy dissipated per ionizing event ≈ 33 eV
n Typical energy required to break a chemical bond = 2-5 eV
Energy Absorption – Ionizing Radiation
LD50/60: Dose at which 50% of
the irradiated population will die
by day 60
6 | Section I •=For Students
Lethal Dose 4 Gy of Diagnostic Radiology, Nuclear Medicine, and Radiation O
50/60

used in radiation therapy and have

diagnostic radiology not yet explore
Electrons are small, negatively
ticles that can be accelerated to hig
speed close to that of light by mea
trical device, such as a betatron o
erator. They are widely used for ca
Protons
1 Gy = 1 J/kgare positively charged
are relatively massive, having a mas
times greater than that of an electr
 trical device, such as a betatron or lin
erator. They are widely used for cance
Protons are positively charged pa
Energy Absorption – Heat are relatively massive, having a mass alm
times greater than that of an electron.
their mass, they require more complex
expensive equipment, such as a cyclotr
celerate them to useful energies, but th
Equal to energy
creasingly usedabsorbed
for cancer treatment in
centers because of their favorable dos
§ Drinking one sip of warm
tion (see Chapter 25).
coffee or
§ A In
tempnature,
rise of the earth oris showered
0.002°C
tons from the sun, which represent a c
of natural background radiation. We
tected on earth to a large extent by
atmosphere. In addition, the earth be
a giant magnet so that charged part
solar events on the sun are deflected
the equator by the earth’s magnetic fi
miss the earth altogether while other
 centers because of their favorable d
tion (see Chapter 25).
In nature, the earth is showere
tons from the sun, which represent a
Energy Absorption – Mechanical Energy of natural background radiation. W
tected on earth to a large extent b
atmosphere. In addition, the earth
a giant magnet so that charged pa
solar events on the sun are deflecte
the equator by the earth’s magneti
Work done in lifting a person
16miss the
inches earth
from altogether while oth
the ground
neled into the polar regions. This is
the “aurora borealis,” or northern l
by intense showers of charged particl
down the lines of magnetic field in
ionizing the air as they do so (see
Protons are a major hazard to astrona
FIGURE 1.4 The biologic effect of radiation is de-
duration space missions.
termined not by the amount of the energy absorbed
but by the photon size, or packet size, of the energy.
!-particles are nuclei of helium
A: The total amount of energy absorbed in a 70-kg consist of two protons and two neut
human exposed to a lethal dose of 4 Gy is only 67 cal. association. They have a net positive
Absorption of Energy
4Gy = Lethal Dose 50/60

Total Energy
A temp rise of 0.002°C or = 67 cal
Drinking one sip of warm coffee

Work done in lifting a person 16

inch from the ground

Energy of ionizing radiation is deposited unevenly in discrete packets

The biologic effect of radiation is determined not by the amount of the energy absorbed
but by the photon size, or packet size, of the energy
Outline
n Brief Historical Overview
n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons
n Summary
Electromagnetic Radiation
n X-rays may be thought of as waves of electrical
and magnetic energy
n Velocity (c) = 3 x 1010 cm/sec in vacuum
n Wavelength (l)
n Frequency (n)

ln=c
Electromagnetic Radiation
n Alternatively, x-rays may be thought of as
streams of photons, or “packets” of energy

E = hn = h (c/l) h = Planck’s constant

= 6.626068 × 10-34 m2 kg / s
l (Å) = 12.4/E (keV)

short l ® large n ® large E

long l ® small n ® small E

Electromagnetic Spectrum

All have same c, but different l, and thus different n

Ionizing Radiation

Electromagnetic radiations are usually considered ionizing if they have a

photon energy > 124 eV (or l < 10-6 cm)

Biological change
X-ray vs. Gamma-ray
X-rays or g -rays do not differ in nature or properties but are produced in different ways

n X-rays – produced extranuclearly (from orbital electrons)

n g -rays – produced intranuclearly (from decay of an unstable nucleus –

radioactive element)
Particulate Radiations
n e- – small, - charge, accelerated to high energy

n p+ – 2000 x mass of e-, +charge

n a – nuclei of He atoms; 2p+/2n; +charge

n n – mass = p+, no charge; cannot be accelerated (no charge); by-

product of fission

n Heavy charged particles – nuclei of elements (C, Ne, Ar,Fe), +

charge; can be produced by accelerating ions
Electron
n Negatively charged particles
n Very light – mass = 9.10938291 × 10-31 kilograms
n Accelerated by betatron or linear accelerator
n Most commonly used in the treatment of superficial tumors
Proton
n Positively charged
n Mass = ~ 2000x of electron
n Accelerated by cyclotron
n Increasingly used in clinic – favorable dose distribution (Bragg peak)
n A component of natural background radiation
n Major hazard to astronauts on long-duration space missions
a Particles
n Nuclei of helium atoms
n Consists of 2 protons and 2 neutrons
n Positively charged
n Accelerated by cyclotron
n Used in radioimmunotherapy – short range
n Major source of natural background radiation – radon gas
2 Computational and Mathematical Methods in Medicine

(3) Nonuniform distribution of radioisotopes. The hetero-

geneous antigen expression and tumor uptake leads
Alpha emitter to variable spatial microdosimetric distributions of
Kill the cell
the AIC [17]. Spatial and temporal changes of the
source activity in the target can also occur [4]. When
Chelator the distribution of radio-labeled antibody is nonuni-
Binding form, techniques of dose averaging over volumes
greater in size than the individual target volumes can
become inadequate predictors of the biological effect
Antibody [18].
Target cancer cell
Antigen
The specific energy is the most important quantity for micro-
dosimetry as it can be used to calculate the cancer cell sur-
vival rate. Specific energy (z Gy) is the ratio of the energy
Cell nucleus deposited (ε Joule) to the mass of the target (m kg) (1) and
has the same units as absorbed dose [19]. The mean specific
Cancer cell energy equals the absorbed dose [15]. Although microdosi-
metry is concerned with the same concept of energy depo-
Figure 1: Schematic diagram of an AIC targeting a cell. sition per unit mass as dosimetry, the difference in the length
of alpha particle and small size of the target volume intro-
duces stochastic effects which are negligible in conventional
dosimetry [20].
depletion of oxygen and nutrition, is the likely cause of can-
cer cell death and tumor regression [8, 9]. ε
z= Gy. (1)
m
2. Microdosimetry The stochastic quantity of specific energy z can be used to
investigate biological effects [21]. The cell survival fraction
Neutrons
n Mass similar to proton
n Electrically neutral
n Generated via accelerated proton impinging on berylium targets or as
a byproduct of nuclear reaction
n UW Seattle is the only facility in the US that offers neutron therapy
Heavy Charged Particles
n Nuclei of element such as C, Ne, Ar, Fe
n Positively charged
n Accelerated by synchrotron
n A major hazard to astronauts on long missions
Outline

n Brief Historical Overview

n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons
Direct vs. Indirect Ionization
n Directly Ionizing:
¨ Directly disrupt atomic structure of the absorber through
which they pass, thereby produce chemical and biologic
changes
¨ All charged particles are directly ionizing

n Indirectly Ionizing:
¨ Do not produce chemical and biologic damage themselves
¨ Instead, they give up their energy to produce fast-moving
charged particles that in turn are able to produce damage
¨ Electromagnetic radiations (x- and g-rays) are indirectly
ionizing
Direct vs. Indirect Radiation
Direct Indirect
n Able to directly alter n Uncharged particles
atom ¨ Gamma rays
n Charged particles ¨ X-rays
n Generates a fast-moving
¨ Alpha particles
electron when interacts with
¨ Electrons electron shell
¨ b particles ¨ Neutrons
¨ Heavy charged particles n Sets nuclear particle in motion
(proton, alpha particle,
¨ Protons spallation products)
Absorption of X-rays
n The way photons are absorbed depends on the energy of
the photon and the chemical composition of the absorbing
material

n 5 major types of interaction

¨ Photoelectric effect
¨ Compton effect
¨ Pair production
¨ Coherent scattering
¨ Photodisintegration
Photoelectric Process

Little biological
consequence
b/c energy ~ 0.5
kV

E = hn - EB

n Dominates at energies characteristic of diagnostic

radiology
n Mass absorption coefficient ∝ Z3
Compton Effect

KV film MV film

n Compton Process dominates at energies characteristics for radiotherapy

n Independent of Z
Pair Production
Photo-induced Disintegration

Only important at photon

energies > 10 MeV Example:
63Cu + g ® 62Cu + n
Absorption of X-ray

n Although the differences among the various absorption

processes are of practical importance in radiology, the
consequences for radiobiology is minimal
n Regardless of the absorption process, much of the energy
of the absorbed photon is converted to the kinetic energy
of a fast electron
n What we are concerned about is the biological effects of
radiation
Outline

n Brief Historical Overview

n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons
Critical Target of Ionizing Radiation

n The biologic effects of radiation

result principally from damage to
DNA
n Main problem = strand breaks
n Non-rejoined breaks ® cell death
n Incorrectly rejoined breaks ®
mutations
n Damage of bases ® mutations
Direct vs. Indirect Action
n Direct Action
¨ Radiation interacts directly with critical targets in the cell (DNA)

n Indirect Action
¨ Radiation interacts first with other atoms or molecules in the cell
(usually H2O) to produce free radicals, which in turn diffuse and
damage DNA

These terms are defined with respect to the way IR interacts with DNA
Direct Action
n The atoms of the target (DNA)
itself may be ionized, thus
initiating the chain of events
that leads to a biologic change

n Is the dominant process for

radiations with high linear
energy transfer (LET, e.g.,
neutrons or a particles)

We will discuss LET in Chapter 7

 Indirect Action
Ion radical
H2O ® H2O+ + e-

H2O+ + H2O ® H3O+ + OH× Free radical – an atom or

free radical molecule carrying an unpaired
orbital electron in the outer
shell

n ~ 2/3 of the x-ray damage to DNA in mammalian cells is

caused by OH×
Free radical can diffuse a short
distance (2x of the diameter of
n Can be modified by chemical means (protectors or sensitizers)
the DNA double helix)
Direct vs. Indirect Action
n For Low LET radiation, 2/3
photon
damage is indirect action
n Critical distance of indirect
action is within 2nm radius
from DNA

n For High LET radiation, most

(all?) damage is direct action
Chain of Events Leading to Biologic
Effects
X-ray is an ionizing radiation
10-15 sec The physics of radiation
X-ray is indirectly ionizing is short-lived

X-ray interact with DNA 10-10 sec

mainly via indirect action OH×

10-9 sec

10-5 sec

Will I glow in
the dark after
The biologic effect may
radiation take hours, days,
therapy? months, years, or
generations to express
What Biological Effects?

n Cell killing
n Acute (early) tissue and organ damage
n Late (delayed) tissue and organ damage
n Carcinogenesis
n Genetic (hereditary) effects
Outline
n Brief Historical Overview
n Examples of clinical application of radiation biology
n Types of Ionizing Radiations
¨ Electromagnetic Radiations
¨ Particulate Radiations
n Absorption of X-rays
n Direct and Indirect Action of Radiation
n Absorption of Neutrons, Protons, and Heavy Ions
Absorption of Neutrons

n Neutrons are uncharged particles

n Like x- and g-rays, neutrons are indirectly ionizing
n Unlike x- and g-rays, which interact with the orbital
electrons of atoms, neutrons interact with the nuclei of
atoms and set in motion fast recoil protons, a-particles,
and heavier nuclear fragments
Elastic Scattering – Proton Recoil
Reaction
n Neutron collides with proton
(e.g., hydrogen nucleus)
and shares its kinetic energy

n Dominant process with fast

neutrons of energy < 6 MeV
Inelastic Scattering

n Fast neutrons (energy ≥ 6

MeV) interacts with
nucleus and causes
disintegration

n C ® 3 a-particles
n O ® 4 a-particles

Spallation
products
Neutron interact with DNA Predominantly
via Direct Action
n Unlike x- or g-rays, which are Neutron Interaction with DNA

sparsely ionizing, neutrons are

densely ionizing

n Direct Action dominates

n Chemical sensitizers and

protectors are ineffective
modifiers
 Absorption of Proton

[Link]
Review Questions
Review of Chapter 1 – Question 1

Which of the following ionization processes represents the principal

interaction with tissue for X-rays used in radiotherapy?

A. pair production
B. photoelectric effect
C. Compton process
D. photodisintegration
E. coherent scattering
Review of Chapter 1 – Question 1

Which of the following ionization processes represents the principal

interaction with tissue for X-rays used in radiotherapy?

A. pair production
B. photoelectric effect
C. Compton process
D. photodisintegration
E. coherent scattering
Review of Chapter 1 – Question 2

In terms of radiation-induced damage to mammalian cells, the most

important radiolysis products of water are:

A. aqueous solvated electrons

B. hydrogen atoms
C. superoxide radicals
D. hydrogen peroxide
E. hydroxyl radicals
Review of Chapter 1 – Question 2

In terms of radiation-induced damage to mammalian cells, the most

important radiolysis products of water are:

Ion radical
A. aqueous solvated electrons
H2O ® H2O+ + e-
B. hydrogen atoms
C. superoxide radicals
D. hydrogen peroxide H2O+ + H2O ® H3O+ + OH×
E. hydroxyl radicals free radical
Review of Chapter 1 – Question 3

How far out from the center of the DNA molecule can the creation of
hydroxyl radicals affect the DNA?

A. 0.1 mm
B. 10 nm
C. 2 nm
D. 1 nm
Review of Chapter 1 – Question 3

How far out from the center of the DNA molecule can the creation of
hydroxyl radicals affect the DNA?

A. 0.1 mm
B. 10 nm
C. 2 nm
D. 1 nm
Review of Chapter 1 – Question 4

Which of the following are directly ionizing radiations?

A. alpha particles, neutrons, beta particles, protons

B. x-rays, gamma rays, neutrons
C. neutrons, heavy charged particles, beta particles
D. alpha particles, beta particles, protons, heavy charged
particles
Direct vs. Indirect Ionization
n Directly Ionizing:
¨ Directly disrupt atomic structure of the absorber through
which they pass, thereby produce chemical and biologic
changes
¨ All charged particles are directly ionizing

n Indirectly Ionizing:
¨ Do not produce chemical and biologic damage themselves
¨ Instead, they give up their energy to produce fast-moving
charged particles that in turn are able to produce damage
¨ Electromagnetic radiations (x- and g-rays) are indirectly
ionizing
Review of Chapter 1 – Question 5

The approximate minimum photon energy required to cause

ionization is:

A. 10-25 eV
B. 100-250eV
C. 1-2.5keV
D. 10-25 keV
E. 100-250 keV
Ionizing Radiation
n Avg energy dissipated per ionizing event ≈ 33 eV
n Typical energy required to break a chemical bond = 2-5 eV
Review of Chapter 1 – Question 5

The approximate minimum photon energy required to cause

ionization is:

A. 10-25 eV
B. 100-250eV
C. 1-2.5keV
D. 10-25 keV
E. 100-250 keV

On average, about 25 eV is required to create an ion pair in water, although the

minimum energy needed to eject an electron is only 12.6 eV.