Radiotherapy

1. Fast Neutron Beam
Therapy
Prof Amin E AAmin
Dean of the Higher Institute of Optics Technology
Prof of Medical Physics
Radiation Oncology Department
Faculty of Medicine
Ain Shams University

2. What Is Radiotherapy?
❖ Radiotherapy is the
medical use of
ionizing radiation in
the treatment of
malignant cancers.
❖ Most radiation
therapies utilize
photons -- lightweight
particles that damage
cancerous cells.

3. Aim of Radiotherapy
• The aim of radiotherapy is to kill tumor cells and
spare normal tissues
Patient
Tumor
Beam 3
Beam 2
Beam 1

4. What is Radiation Therapy?
(External Beam Therapy)
• Radiation directed at the tumor from outside the body
• Two critical components
• Where the energy is deposited
• The type of damage produced

5. Where is the Energy
Deposited?
0
20
40
60
80
100
0 5 10 15 20 25 30 35
)Depth in Phantom (cm
Dose,NormalizedtoDmax(%)
SAD = 190 cm
SSD = 180 cm
Photons
Neutrons
Protons

6. Neutrons
❖ Neutrons are particles with mass similar to proton but are
chargeless and cannot be accelerated in an electrical device.
❖ They are produced if charged particle like deuterium is
accelerated to high energy and made to hit on a suitable
target.
❖ They are also emitted as a by-product if radioactive atoms
undergo fission.

7. Neutron Beam Therapy
• Neutron beam radiation therapy (NBRT) is a specialized type of
EBRT that uses high energy neutrons which are much heavier
than photons and appear to be more effective in destroying very
dense tumors..

8. Neutron Beam Characteristics
• Compared to X ray, neutrons are characterized by several
properties:
(i) reduced oxygen enhancement factor,
(ii) less or no repair of sub-lethal or potentially lethal cell damage,
and
(iii) less variation of sensitivity through cell cycle.

9. Neutron Radiotherapy
Fast Neutron Therapy Beams
Boron Neutron Capture Therapy

10. NBT vs BNCT
• It should be noted that NBT is different from boron neutron capture
therapy (BNCT), which is a radiotherapy based on the preferential
targeting of tumor cells with non-radioactive isotope B-10 and
subsequent activation with thermal neutrons to produce a highly
localized radiation, and is often used to treat brain tumors.
• In BNCT, the patient is given a drink containing boron, which is
taken up by tumor cells.
• The tumor is then irradiated with a neutron beam, causing the
boron to split into two highly energetic particles (helium and
lithium) that destroy the cancerous cells while largely sparing
adjacent healthy cells.

11. Fast Neutrons Methods Of Production
• Neutrons can be produced in a cyclotron by accelerating
deuterons or protons and impinging them on a beryllium
target.
• Protons or deuterons must be accelerated to ≥50 MeV to
produce neutron beams with penetration comparable to
megavoltage x-rays.

12. Neutrons Production
• Neutron beam therapy entails the use of a particle accelerator;
protons or deuterons from the accelerator are deflected by a magnet
to a target which creates the neutron beam.

13. ❖ Accelerating deuterons to
≥50MeV
❖ Requires very large
cyclotron, too large for
hospital.
❖ Accelerating protons to
≥50MeV
❖ Much smaller cyclotron b/c
proton has ½ the mass of
deuteron.
Fast Neutrons Methods Of Production

14. P+
n
Fast Neutrons From Deuteron
Bombardment Of Be
•Stripping Process –
• Proton is stripped from the deuteron.
• Recoil neutron retains some of the incident kinetic energy of the
accelerated deuteron.
• For each neutron produced, one atom of Be is converted to B.
9
Be4 n
+ 
10
B5

15. • Knock-out Process
• Protons impinge target of beryllium, where they
knock-out neutrons.
• For each neutron “knocked-out”, one atom of Be is converted
to B.
99
Be4 nP+
+ 
5 B
Fast Neutrons From Proton
Bombardment Of Be

16. Fast Neutrons Methods Of Production

17. Why Are Neutrons Needed?
❖Large radioresistant tumors are not well controlled by
photon (or proton) therapy.
❖Resting cells are radioresistant
❖Hypoxic (low oxygen) cells are radioresistant
❖Neutron therapy is less affected by cell cycle or oxygen
content

18. Fast Neutron Interactions
➢ Elastic scattering - neutrons interact with particles of
approximately the same mass such as protons (billiard
ball analogy)
➢ Occurs in materials rich in hydrogen such as water,
wax, concrete
➢ Accounts for about 80% of fast neutron dose to
tissue

19. Elastic Scattering
• Elastic scattering is the most likely interaction between fast
neutrons and low-atomic numbered absorbers. This
interaction is a “billiard ball” type collision, in which kinetic
energy and momentum are conserved.
• Up to neutron energies of the order of 10 MeV, the most
important interaction of fast neutrons with matter is elastic
scattering.

20. Elastic Scattering
In collision with protons, neutrons
lose half their energy on average.

21. Inelastic Scattering
Inelastic scattering – neutrons interact with particles of
much greater mass (e.g. iron)
(analogy of ping pong ball striking bowling ball)
For fast neutrons of energies of about 1 MeV, inelastic
scattering can become appreciable. Inelastic scattering
occurs primarily with high-Z absorbers.

22. Fast Neutron Interactions
• In inelastic scattering, kinetic energy and momentum are not
conserved.
• Rather, some of the kinetic energy is transferred to the target
nucleus which excites the nucleus.
• The excitation energy is then emitted as a gamma-ray photon.
• In human tissue, and for fast neutron energies in excess of 10
MeV, inelastic scattering and nuclear reactions (frequently with
the emission of several particles) become comparable in
frequency with elastic scattering.

23. Inelastic Scattering
• This interaction is best described by the compound nucleus model,
in which the neutron is captured, then re-emitted by that target
nucleus together with the gamma photon.
• This is a threshold phenomenon; the neutron energy threshold
varies from infinity for hydrogen (I.e. inelastic scattering cannot
occur with H) to about 7 MeV for oxygen to less than 1 MeV for U.
• This reaction is not very significant from a tissue dose standpoint,
since tissue is composed of relatively low-Z materials.
• Iron has a particularly strong probability of fast neutron inelastic
scattering.

24. Inelastic Scattering
The neutron is captured, then re-emitted by the target nucleus
together with the gamma photon. It has lesser energy

25. Neutron Cross Sections
➢ Probability that neutron will interact with a given material
➢ Unit is “barn” where 1 barn = 10-24 cm2
25

26. Neutron Cross Sections
• Neutron cross sections are strongly energy dependent.
• The barn is an almost legendary unit in the history of neutron
physics.
• The story says that when neutron cross sections were first being
measured, the cross section for a given material (maybe boron?)
was said to be “as big as a barn!”
• A “shed” is equal to 10-24 barns or 10-48 cm2.
• The shed is used for particle interactions where the cross section
is extremely small, e.g. neutrino interactions.

27. Neutron Cross Sections
• Neutrons can be removed from a beam by the absorber
material generally in three ways:
• Scatter
• Capture
• Fission
• The total removal cross section is the sum of the three cross
sections for these processes.

28. Microscopic Cross Section
Sum of separate cross sections for all processes
which may occur with a given atom. Unit is cm2
total = scatter + capture + fission
28

29. Macroscopic Cross Section
Product of microscopic cross section and the total number of atoms
per cm3 in the material. Unit is cm-1
 total = N total
where N = number of atoms/cm3
Note the macroscopic cross section is used for neutrons, in place of
the linear or mass absorption coefficients that are used in photon
attenuation.

30. Neutron Removal by an Absorber
• Neutron removal is exponential.
I = I0 e- N total x
where
• I = neutrons passing through the absorber
• I0 = neutrons incident on the absorber
• N total = total macroscopic cross section
• x = absorber thickness
30

31. Neutron Therapy
• Radioresistant – not well controlled by conventional photon
(x-ray) therapy
• Depends on the type of tissue that is cancerous
• Location & type

32. Advantages Of Neutron Radiation
Therapy
• Fast neutrons are one type of radiation used and, for certain
types of cancer, offer improved benefits over other types of
radiation therapy such as photons (x-ray), electrons, protons
and other heavy particles.

33. Neutron Beam Therapy
• The neutrons are targeted toward tissue masses that are
characterized by lower tumor oxygen levels and a slower cell cycle,
since neutrons require less oxygen and are less dependent on the
cell’s position in the cell division cycle.
• Neutrons impact with approximately 20 to 100 times more energy
than conventional photon radiation and may be more damaging to
surrounding tissues.
• For that reason, the radiation is delivered utilizing a sophisticated
planning and delivery system.

34. Radiobiological Aspects Of Neutron
Therapy
• Neutrons are more effective per unit dose
than x-rays
• Cell survival curves for neutrons are
more nearly exponential than those of
x-rays
• The modifying effect of hypoxia is smaller
for neutrons than for photons
• Cell sensitivity to neutrons is much less
dependent on cell growth stage than cell
sensitivity to photons

35. Advantages Of Neutron Radiation
Therapy
• The basic effect of ionizing radiation is to destroy the ability
of cells to divide by damaging their DNA strands.
• One measure of this destructive ability is called linear energy
transfer (LET).
• Fast neutrons are high LET radiation and the damage is done
primarily by nuclear interactions.
• Photons, electrons and protons are low LET radiation and
their damage is done by activated radicals produced from
atomic interactions.

36. LET
 Linear energy transfer (LET) is the average energy
transferred per unit length of the track of radiation.
 Its unit is : kiloelectron volt per micrometer (keV/µm).
 The International Commission on Radiological Units
(ICRU) (1962) defined as:
◦ The linear energy transfer(L) of the charged particles in the
medium is the quotient of the dE/dl where dE is the average
energy locally imparted to the medium by a charged particle of
specified energy in traversing a distance of dl. That is
◦ L=dE/dl

37. High and Low LET Radiations
 High LET Radiation:
◦ This is a type of ionizing radiation that deposit a large
amount of energy in a small distance.
◦ Eg. Neutrons , alpha particles
 Low LET Radiation:
◦ This is a type of ionizing radiation that deposit less
amount of energy along the track or have infrequent or
widely spaced ionizing events.
◦ Eg. x-rays, gamma rays

38. High Vs Low LET Radiations
•High LET radiation ionizes water
into H and OH radicals over a very short
track. In fig. two events occur in a single
cell so as to form a pair of adjacent OH
radicals that recombine to form peroxide,
H2O2, which can produce oxidative
damage in the cell.
•Low LET radiation also ionizes water
molecules, but over a much longer track.
In fig. two events occur in separate cells,
such that adjacent radicals
are of the opposite type: the H and OH
radicals reunite and reform H2O.
38

39. High Vs Low LET Radiations
 High-LET radiations are more destructive to biological material than low-
LET radiations.
 The localized DNA damage caused by dense ionizations from high-LET
radiations is more difficult to repair than the diffuseDNA damage caused by
the sparse ionizations from low-LET radiations.
 High LET radiation results in lower cell survival per absorbed dose than low
LET radiation.
 High LET radiation is aimed at efficiently killing tumor cells while
minimizing dose to normal tissues to prevent toxicity.
 Biological effectiveness of high LET radiation is not affected by the time or
stage in the life cycle of cancer cells, as it is with low LET radiation.

40. High Vs Low LET Radiations
• Both examples produce
the same total number
of ionizations, thus
represent the same
dose, but with different
effects by low LET and
high LET.
40

41.  Track Average: calculated by dividing the track into equal
lengths and averaging the energy deposited in each length.
 Energy Average: calculated by dividing the track into equal
energy intervals and averaging the lengths of the track that
contain this amount of energy.
41
Track Average And Energy Average

42. LET And Cell Repair
• If a cancer cell is damaged by low LET radiation it may
repair itself and continue to grow.
• With high LET radiation, the chance for a damaged cancer
cell to repair itself is very low.

43. Biological Effectiveness Of Neutrons
• In general fast neutrons can control large tumors because,
unlike low LET radiation, neutrons do not depend on the
presence of oxygen to kill the cancer cells.
• In addition, the biological effectiveness of neutrons is not
affected by the stage in the life cycle of cancer cells as it is
with low LET radiation.

44. Relative Biologic Effectiveness(RBE)
44
 The National Bureau of Standards in 1954 defined RBE as:
◦ The RBE of some test radiation(r) compared with x-rays is defined by
the ratio D250/Dr, where D250 and Dr are, respectively, the doses of x-
rays and the test radiation required for the equal biologic effects.
 Eg.A comparison of neutrons with 250kV x-rays in lethality of
plant seedlings. The end point of observation being death of half
of plants(LD50). Suppose if LD50 for x-rays is 6Gy and for
neutrons is 4Gy then RBE of neutrons compared with x-rays is
6:4 or 1.5

45. Factors Determining RBE
45
 Radiation quality
 Radiation dose
 Number of dose fractions
 Dose rate
 Biologic system or end point

46. Survival Curves For Mammalian Cells
Exposed To X-rays And Fast Neutrons
❖ X-ray survival curve has large initial
shoulder and neutron curve has smaller
shoulder and steeper final slope
❖ RBE increases with decrease in dose
❖ RBE for fractionated regimen with
neutrons is greater than for single
exposure.
❖ The little or no shoulder of neutron curve
indicates less wastage of dose whereas
wide shoulder of x- ray curve indicates
wastage of a part of dose each time in
fractionated regime
46

47.  The intrinsic radiosensitivity among
the various types of cells differ from
each other.
 The curves demonstrate the variation
of radiosensitivites for x-rays and
markedly less variation for neutrons.
 X-ray survival curves have large and
variable initial shoulder whereas for
neutrons, it is small and less variable
 Hence RBE is also different
for different cell lines. 47
RBE For Different Cells And Tissues

48. RBEAs A Function Of LET
❖ As the LET increases from about
2keV/µm for x-rays upto 150
keV/µm for α-particles, the survival
curve becomes steeper and the
shoulder of the curve becomes
progressively smaller.
❖ Larger shoulder indicates the
accumulation and repair of the large
amount of sub-lethal radiation
damage
48

49. RBE As A Function Of LET
❖ As the LET increases, the RBE
increases slowly at first, and then
more rapidly as the LET increases
beyond 10 keV/µm. Between 10.
and 100 keV/µm, the RBE increases
rapidly with increasing LET and in
fact reaches a maximum at about
100 keV/µm.
❖ Beyond this value for the LET, the
RBE again falls to lower values.
49

50. Survival of Clonogenic DU 145 Prostate Cancer Cells
0.000001
0.00001
0.0001
0.001
0.01
0.1
1
0 5 10 15 20 25 30
Dose in Gray
Photons in 2.00 Gy
fractions
Neutrons in 1.75 Gy
Fractions
Blazek, et al
Factor of 3
Relative Biological Effectiveness
Neutrons
Photons
Relative
Biological
Effectiveness -
RBE - is the
reason for
pursuing
Neutron Therapy

51. The Optimal LET
51
❖ LET of about 100keV/µm is optimal in terms of
producing biologic effect
❖ At this density of ionization the average separation between
the ionizing events just about coincides with the diameter of
DNA double helix(2nm) and has highest probability of
causing DSBs by passage of a single charged particle.

52. ❖ In x-rays, probability of
a single track causing a
DSB is low and requires
more than one track.
❖ Much more densely
ionizing radiations (eg.
LET of 200keV) readily
produce DBSs but energy
is wasted as events
coincide with each other
52
The Optimal LET

53. The Oxygen Effect and LET
53
 Oxygen enhanced ratio(OER) is the ratio of doses of
radiation administered under hypoxic to aerated
conditions needed to achieve the same biologic effect.
 OER for different types of radiations are as follows:
 X-rays: 2.5
 Neutrons: 1.6
 2.5-MeV particles:1
 4-MeV particles: 1.3

54. Survival curves for
cultured cells of
human origin in
hypoxic and aerated
conditions determined
for four different
types of radiation.
54
The Oxygen Effect and LET

55. OER As A FunctionOf LET
At low LET (x- or -rays) with
OER between 2.5 and 3, as the
LET increases, the OER falls
slowly until the LET exceeds
about 60 keV/µm, after which the
OER falls rapidly and reaches
unity by the time the LET has
reached about 200keV/µm.
55

56. OER and RBEAs A Function Of LET
❖ The rapid increase in RBE
and the rapid fall of OER
occur at about the same LET
100keV/µm .
❖ Two curves are virtually
mirror images of each
other.
56

57. The Cell Cycle
•Interphase (90% of cycle)
• G1 phase growth
• S phase synthesis of DNA
(Replication)
• G2 phase preparation for cell
division
•Mitotic phase
• • Mitosis nuclear division
• • Cytokinesis cytoplasm
division

58. Radiosensitivity In Different Phases Of
Cell Cycle
5
• Cells exhibit differential radiation sensitivity while in the
different phases of the cell cycle.
• Cells in mitosis are most sensitive to DNA damaging agents
and cells in late S-phase being most resistant.

59. Protons vs. Neutrons
• However, slow-growing tumors spend a
relatively short time in the dividing phase of
the cell cycle, when they are most sensitive
to ionizing radiation (as that of protons and
photons).
• These tumors are more-effectively treated
with neutrons.
Bragg peak

60. Clinical Use of NBT
• Neutron beam therapy has been employed mainly for the treatment
of the salivary gland cancers and found to be more effective than
low LET radiation.
• It has also been used to treat other malignancies such as soft tissue
sarcoma (STS) as well as lung, pancreatic, colon, kidney, prostate
cancers and malignant melanomas.
• Nevertheless, NBT has not gained wide acceptance because of the
clinical difficulty in generating neutron particles.

61. Neutron Dose
• Because of the high biological effectiveness of fast neutrons,
the required dose of neutrons to kill the same number of
cancer cells is about one third the dose required with low
LET radiation.
• A full course of treatment consists of 12 treatments, three
times a week for four weeks, compared to 30-40 treatments,
five times a week for six weeks with photons, electrons, or
protons.

62. Side Effects
• Acute side effects for fast neutron therapy are similar to those of
low LET therapy.
• The severity depends on the total dose delivered and the general
health of the patient.
• Careful, computerized treatment planning minimizes effects on
normal tissues.
• Most of the acute side effects are temporary and normal tissue
recovery occurs with time.
• Some permanent late effects may be anticipated.