DEVELOPMENT AND TEST OF SEGMENTED ELECTRODE IONIZATION CHAMBERS AS BEAM MONITOR FOR HADRONTHERAPY

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15 Νοε 2013 (πριν από 3 χρόνια και 8 μήνες)

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Università degli studi di Torino

Facoltà di Scienze Matematiche Fisiche e Naturali




DOTTORATO DI RICERCA IN FISICA


XVII CICLO






DEVELOPMENT AND TEST

OF SEGMENTED
ELECTRODE IONIZATION

CHAMBERS AS BEAM
MONITOR FOR HADRONTH
ERAPY












Advis
or:
Prof. Cristiana Peroni





Candidate:
Alberto Boriano







1

Index


Index
................................
................................
................................
................................
.................

1

Introduction

................................
................................
................................
................................
......

6

1

The cure of cancer with radiation

................................
................................
................................

7

1.1

The significance of radiobiology in radiotherapy

................................
................................

7

1.1.1

The role of radio
therapy in the management of cancer

................................
...............

7

1.1.2

The role of radiation biology

................................
................................
.......................

7

1.1.3

The time
-
scale of effects in radiation biology

................................
.............................

8

1.1.4

Response of normal and malignant tissues to radiation exposure

...............................

9

1.1.5

Response curve, dose
-
response curves and isoeffect relat
ionship

...............................

9

1.2

DNA damage and cell killing
................................
................................
.............................

11

1.2.1

Initial process of radiation damage

................................
................................
............

11

1.2.2

Radiation damage to DNA

................................
................................
.........................

12

1.2.3

Cell death in mammalian tissues

................................
................................
................

15

1.3

The oxygen effect

................................
................................
................................
...............

15

1.4

Particle beams in radiotherapy

................................
................................
...........................

18

1.4.1

Biological effects depend upon LET

................................
................................
.........

19

1
.4.2

The biological basis for high
-
LET radiotherapy

................................
........................

21

2

Radiotherapy with hadrons

................................
................................
................................
........

22

2.1

Proton interactions with matter

................................
................................
..........................

22

2.1.1

Introduction

................................
................................
................................
................

22

2.1.2

Proton interactions with electrons: energy loss

................................
..........................

2
2

2.1.3

Proton interaction with electrons: energy loss distribution

................................
........

25

2.1.4

Proton interactions with nuclei: scattering

................................
................................
.

29

2.1.5

Pr
oton interactions with nuclei: nuclear reactions

................................
.....................

31

2.1.6

Proton dose distribution

................................
................................
.............................

32

2.1.7

Fragmentation

................................
................................
................................
............

35

2.2

Accelerators for hadrontherapy

................................
................................
..........................

37

2.2.1

Introduction

................................
................................
................................
................

37

2.2.2

Cyclotron

................................
................................
................................
....................

37

2.2.3

Synchrotron

................................
................................
................................
................

38

2.2.4

Example of dedicated designs

................................
................................
....................

38

2.3

Beam spreading

................................
................................
................................
..................

40

2.3.1

Passive spreading

................................
................................
................................
.......

40

2.3.2

Scanning

................................
................................
................................
.....................

41

2.4

Monitoring of hadronther
apy beam

................................
................................
...................

43

2.4.1

Passive scanning systems

................................
................................
...........................

43

2.4.2

Active scanning systems

................................
................................
............................

43

2.4.3

Development of segmented anode ionization chambers

................................
............

44

2.4.4

Electronic read
-
out: the VLSI chip

................................
................................
............

46

3

The GSI test: exp
erimental setup and results

................................
................................
.............

48

3.1

The GSI facility in Darmstadt

................................
................................
............................

48

3.2

The experimental setup

................................
................................
................................
......

49

3.3

The data acquisition system

................................
................................
...............................

50

3.3.1

The operating system VxWorks and the integrated environment TornadoII

.............

50

3.3.2

The data acquisition system: hardware

................................
................................
......

51

3.3.3

The detector read
-
out

................................
................................
................................
.

52

3.4

Results

................................
................................
................................
................................

53

3.4.1

Charge collection efficiency

................................
................................
......................

53

3.4.2

Calibration

................................
................................
................................
..................

54


2

3.4.3

Space coordinates resolution with
a steady beam

................................
......................

55

3.4.4

Space coordinates and fluence measurements with a scanning beam

.......................

57

3.4.5

Performance with a Treatment Plannin
g System (TPS)

................................
............

58

Conclusions

................................
................................
................................
................................
....

61

4

The IBA test: experimental setup and results

................................
................................
............

62

4.1

The CRC facility at Louvain
-
la
-
Neuve

................................
................................
..............

62

4.2

The Pencil Beam Scanning (PBS)

................................
................................
.....................

63

4.2.1

Low Level Regulation

................................
................................
................................

63

4.3

The experimental setup

................................
................................
................................
......

65

4.3.1

The beam line setup

................................
................................
................................
...

65

4.3.2

The structur
e of the data acquisition

................................
................................
..........

66

4.4

Results

................................
................................
................................
................................

68

4.4.1

Time synchronization between PIXEL/STRIP data taking and IBA control system

68

4.4.2

Homogeneity of the dose distribution

................................
................................
........

71

4.4.3

Dimension of the irradiated field

................................
................................
...............

74

4.4.4

Detailed spatial behavior of the scanning beam.
................................
........................

75

4.4.5

Scanning speed

................................
................................
................................
...........

78

4.4.6

Beam shape

................................
................................
................................
................

80

Conclusions

................................
................................
................................
................................
....

82

5

The CATANA test: experimental setup and results
................................
................................
...

83

5.1

Development o
f a dedicated kind of strip detector as monitor of passive scanning beam

83

5.2

The CATANA facility

................................
................................
................................
.......

85

5.3

The experimental setup

................................
................................
................................
......

86

5.3.1

The beam line setup

................................
................................
................................
...

86

5.3.2

Data acquisition structure

................................
................................
...........................

87

5.4

Experimental Results

................................
................................
................................
.........

88

5.4.1

Calibration

................................
................................
................................
..................

88

5.4.2

Fluence measurements and homogeneity of dose distribution

................................
..

91

5.4.3

A mathematical method for the evaluation of the beam structure

.............................

93

Conclusions

................................
................................
................................
................................
..

102

Bi
bliography
................................
................................
................................
................................
.

103


Table of figure



Figure 1.1: Time scale of the effects of radiation exposure on biological systems.

............................

8

Figure 1.2: Four types of chart leading to the construction of an isoeffect plot. (A) Time
-
course of
radiation damage in a normal tissue. (B) The cumulative response. (C) A dose
-
response
relationship, constructed by measuring the response (R)
for varius radiation doses (D). (D)
Isoeffect plot for a fixed level of normal tissue damage.

................................
...........................

10

Figure 1.3
: (A) Computer
-
simulated tracks of 1 KeV electrons. Note the scale in relation to the 2
.3
nm diameter of DNA double helix. (B) Illustrating the concept of a local multiply damaged site
produced by a cluster of ionizations impinging on DNA

................................
..........................

12

Figure 1.4 The structure of DNA, in whi
ch the four bases (G,C,T,A) are linked through sugar
groups to the sugar
-
phospate backbone.

................................
................................
....................

13

Figure 1.5 Types of damge to DNA produced by radiation and chemical agents.

............................

14

Figure 1.6 Survival curves for culturaed mammalian cells exposed to x
-
rays under oxic or hypoxic
conditions, illustrated the radiation dose
-
modifying effect of oxygen. Note that the broken line
extrapolate back to
the same point on the survival axis (n=5.5).

................................
...............

16

Figure 1.7 Variation of oxygen enhancement ratio (OER) with oxygen tension. The horiziontal
arrows indicate the range of physiological blood oxyge
n tensions on the lower scale

.............

17


3

Figure 1.8 The oxygen fixation hypothesis. Free radical produced in DNA either by direct or
indirect action of radiation can be rapired under hypoxia but fixed i
n the presence of oxygen.
17

Figure 1.9

The structure of particle tracks for low
-
LET radiation (above) and


particle (below).
The cricles indicate the typical syze of mammalian cell nuclei. Note the tortuos tracks of low
-
energy secondary electrons.

................................
................................
................................
.......

18

Figure 1.10

Survival of human kidney cells expos
ed in vitro to radiations of different LET

...........

19

Figure 1.11

Dependece of RBE on LET and the phenomenon of overkill by very high
-
let radations.

................................
................................
................................
................................
....................

20

Figure 1.12: The oxygen enhancement ratio (OER) decreases with increasing LET. Closed circles
refer to monoenergetic a
-
paritcles and deuterons; the open triangle to 250 kVp x
-
rays.

..........

20

Figure 1.13: response of 20 human tumour cell lines to (A) 4MVp photons, or (B) p(62.5)
-
Be
neutrons. The vertical lines show the photon (2Gy) and the neutrons (0.68 Gy) doses that give
the same mediam cell survival; the average RBE is therefore 2/0.68=2.
94.

.............................

21

Figure 2.1: Range
-
energ y relationship according to ICRU 49 and fit to relation (2.7) for water, air
and gadolinium using the parameters in table 2.2

................................
................................
......

25

Figure 2.2: The Vavilov distribution function


as a function of the scaled energy loss

for 200
MeV protons.

................................
................................
................................
.............................

26

Figure 2.3: Number of


electrons produced per incid
ent proton per cm
2

H
2
O calculated using
equation (2.12)

................................
................................
................................
...........................

28

Figure 2.4: Solid line (scale on right axis): ratio between total elastic cross section of 180 MeV
protons incident on
16
O and Coulomb
contribution (using equation (2.17)) as a function of
deflection angle. Dotted line: ratio = 1. Dashed line (scale on left axis): Coulomb contribution.

................................
................................
................................
................................
....................

30

Figure 2.5: Total nonelastic nuclear cr
oss section for proton incident
16
O. The line represent a fit to
the experimental data

................................
................................
................................
.................

31

Figure 2.6: Proton flux reduction due to inelastic nuclear reaction for a 80 and a 180 MeV beam in a
wat
er medium calculated using equation (2.21) and the cross sections in figure 2.5.

...............

32

Figure 2.7: The dose per fluence as a function of depth in water calculated with (2.28) for 80 and
180 MeV pro
ton beams, with an initial energy spread s increasing from 0% to 1.5% in steps of
0.25%. Entrance dose per fluence is for a 180 MeV beam 5.78 MeV cm
2
/g and for a 80 MeV
beam 9.32 MeV cm
2
/g. R
0

is shown as dashed line.

................................
................................
..

34

Figure 2.8: Contour plot of dose of a 160 MeV, 2 cm radius parallel proton beam in water. The
contour lines go from 1% to 99% of the maximum dose. At the zero depth and on the beam
axis the dose is 21% ofht edose in the Bragg pea
k.

................................
................................
...

35

Figure 2.9: Bragg curve of 270 MeV/u carbon beam in water illustrating the effects of the beam
fragmentation. The colour
-
code lines are calculated dose distribution: red=total dose,
black=
primary particles, blue=secondary particles, gree=fragemnts of the secondary particles.
Circles indicate measured data.

................................
................................
................................
..

36

Figure 2.10: IBA 235 MeV room temperature cyclotron.

................................
................................
.

38

Figure 2.11: Layout of the TERA synchrotron

................................
................................
..................

39

Figure 2.12: schematic layout of a passive beam spreading system consisting of a double scatterer, a

range modulator, and a snout housing the patient
-
specific collimator and bolus. When used
with a fixed energy beam, the first scatterer also acts as energy absorber. The range modulator
is not required when full energy is achieved from the accelerator.

................................
..........

40

Figure 2.13: Schematic irradiation procedure for a tumour conform treatment. The tumour is
dessected in slices of equidistant particle ranges which are covered using a magnetic scanning
system
.
................................
................................
................................
................................
........

41

Figure 2.14: Pixel (right) and raster (left) scan pattern for a rectangular area and a model of a
tumour slice. Additional scan lines that shortcut the standard (rectangular) scan pattern h
ave to
be introduced.

................................
................................
................................
.............................

42

Figure 2.15: An exploded view of the pixel chamber

................................
................................
........

44


4

Figure 2.16: Logic diagram of the TERA chip

................................
................................
..................

47

Figure 3.1: The GSI accelerator facility

................................
................................
.............................

48

Figure 3.2: Sketc of the beam line set
-
up
................................
................................
...........................

49

Figure 3.3: A sketch of the data acquisition
................................
................................
.......................

51

Figure 3.4: (a) Chamer response and (b) the relative deviation from linearity as a function of the
beam intensity

................................
................................
................................
............................

53

Figure 3.5: (a) Lego plot of the raw counts as a function of the pixel position. (b) Normalized
distribution of the gains.
................................
................................
................................
.............

54

Figure 3.6:(a) Lego pl
ot of the corrected counts as a function of the pixel position. (b) Distribution
of the gains.

................................
................................
................................
................................

55

Figure 3.7: Measured position resolution as a function of the integrated number of ions: (a)
x

c
oordinate; (b)
y

coordinate.

................................
................................
................................
......

56

Figure 3.8: Beam position along x (a) and y (b) as measured in time slices of 100 ms during the
spill.

................................
................................
................................
................................
............

56

Figure 3.9: Corrected second moment vs. beam width (mm).

................................
...........................

57

Figure 3.10: (a) Pictorial map of the scanning points; (b) normalized ratio between the number of
ions as measured by the pixel
chamber and GSI system; (c)
x

and (d)
y

resolution.

.................

58

Figure 3.11:
X
-
Y

scatter plot of four slice at different depths.

................................
...........................

59

Figure 3.
12: Coordinate measurements for a small volume tumour treatment: resolution along
x

(a)
and
y

(b).

................................
................................
................................
................................
....

60

Figure 3.13: (a) Pixel chamber vs. GSI flux measurement and (b) the normalized ratio distrib
ution.

................................
................................
................................
................................
....................

60

Figure 4.1: Typical ISEU response observed durign the experimentation at the CRC and the error
between the expected reference and the measured beam current response.

..............................

64

Figure 4.2: Sketc of the beam line setup

................................
................................
............................

65

Figure 4.3: Picture of the IBA nozzle and strip and pixel chambers

................................
.................

66

Figure 4.4: Y position of Center of gravity for strip chambers (red) and data expected from
trajectories files (black)

................................
................................
................................
..............

68

Figure 4.5: ISEU intensity (red curve), exp
ected intensity (black curve), strip counting (green curve,
threshold of 80 counts).

................................
................................
................................
..............

69

Figure 4.6: Y position of center of gravity for strip chambers (black) and data expected from
trajectories

files (red), with a correct time synchronization,at the beginning (top plot) and at the
end (bottom plot) of the run

................................
................................
................................
.......

70

Figure 4.7: Y position of center of gravity for strip chambers (black) an
d data expected from
trajectories files (red), with a correct time synchronization and the correction of the trajectories
data period.

................................
................................
................................
................................
.

70

Figure 4.8: Horizontal
-

vertical strip counting ratio

................................
................................
.........

71

Figure 4.9: Ratio of horizontal to vertical strip count for four different scans

................................
..

72

Figure 4.10: Sum of the counts over all the st
rips for a single acquisition versus the acquisition
number.

................................
................................
................................
................................
......

72

Figure 4.11: A single scan line. Ibeam expected (black curve), ISEU intensity (red curve), strip
counts (green curve).

................................
................................
................................
..................

73

Figure 4.12: Vertical strip detector: mean and sigma of the counts of each acquisition when only the
central part of each scanning line is considered. Each plot contains one point per each one of
the 30

vertical lines of the scan.

................................
................................
................................
.

74

Figure 4.13: Center of gravity measured with horizontal strip chamber for the “edge” of the field.

74

Figure 4.14: Distribution of X components of the center of gravity on the mean value for a single
scanning line

................................
................................
................................
..............................

76

Figure 4.15: Mean X values per scanning line for strip (blue), trajectories e
xpected (gree) and
measured (red) on the detector surface.

................................
................................
.....................

77


5

Figure 4.16: Distribution of Y components of the center of gravity on the expected values for a
single scanning line.

................................
................................
................................
...................

78

Figure 4.17: Computed scanning speed for a scan
................................
................................
.............

79

Figure 4.18: mean FWHM (top plot) and sigma FWHM (bottom plot) for all the runs.
..................

80

Figure 4.19: FWHM X and Y for all the acquired points (top plot) and in a particular scanning line
(bottom plot).

................................
................................
................................
.............................

81

Figure 5.1: An explode
d view of the strip chamber

................................
................................
...........

83

Figure 5.2: Sketch of the CATANA facility

................................
................................
......................

85

Figure 5.3: Sketch of the CATANA beam line

................................
................................
..................

86

Figure 5.4: Picture of the CATANA beam line with the MOPI strip detector

................................
..

87

Figure 5.5: Mean background per second of the two strip chambers

................................
................

88

Figure 5.6: Comparision of the left tail of beam profiles with and without background for the strip
chamber and the film.
................................
................................
................................
.................

89

Figur
e 5.7: (a) Single film profile with (red points) and without (black points) saturation effects
correction. (b) Integrated film profile with (red points) and without (black points) correction.

89

Figure 5.8: (a) Horizontal strip and film profile for a modulated field. (b) Distribution of the point to
point differences between the two profiles

................................
................................
................

90

Figure 5.9: (a) Horizontal strip and film

profile for a not modulated field. (b) Distribution of the
point to point differences between the two profiles

................................
................................
...

90

Figure 5.10: Distribution of the point to point differences between the calibra
tion coefficients
computed with modulated and not modulated beam, for horizontal (a) and vertical (b) strip
detector.

................................
................................
................................
................................
......

91

Figure 5.11: Integrated counts over all the strips with 5 Hz of acquisiti
on rate: (a) first run (b)
eleventh run.

................................
................................
................................
...............................

91

Figure 5.12: Distribution of the vertical and horizontal strip detectors gains ratios; data are referred
to the two curves of Figure 5.11 (b).

................................
................................
..........................

92

Figure 5.13: Distribution of the integrated counts over all the strips (horizontal chamber) with a 5
Hz acquisition rate.

................................
................................
................................
....................

93

Figure 5.14
: Comparison of the fluence integrated over the acquisition run for the vertical and
horizontal strip chambers and for the CATANA ionization chambers, for 8 different runs.

....

93

Figure 5.15: Compa
rison between the skewness and the collected charge.

................................
......

95

Figure 5.16: Skewness vs acquisition number and distribution of the values.

................................
..

96

Figure 5.17: Skewness and c.o.g. vs acquisition number in a beam line configuration with the
modulator wheel

................................
................................
................................
.........................

96

Figure 5.18: Vertical and horizontal beam profiles, for four different magnet s
ettings, in a not
modulated beam condition

................................
................................
................................
.........

97

Figure 5.19: Vertical and horizontal beam profiles, for four different magnet settings, in a
modulated beam condition.

................................
................................
................................
........

97

Figure 5.20: Beam profile at the isocenter, in air, detected with a silicon diod

................................
.

98

Figure 5.21: RT (from vertical diode profile) vs skewness (from horizontal

strip chamber profile)
computed for seven different magnet configurations.

................................
...............................

99

Figure 5.22: ST (from vertical diode profile) vs skewness (from horizontal strip chamber profile)
computed for seve
n different magnet configurations.

................................
.............................

100

Figure 5.23: Comparison between skewness computed for modulated and not modulated beam, for
four different magnet setting.

................................
................................
................................
...

100



6


Introduction



The work I have done during the three years of Ph.D. was mainly aimed at the development and test
of different kind of ionization chambers to be used as beam monitor during hadrontherapy
treatments; it has been done within a collaborat
ion between the University and the INFN of Torino.

The cure of tumours with hadrons (protons and carbon ions) presents, with respect to the
conventional x
-
rays radiotherapy, some advantages, from both the biological and physical point of
view. In the first

chapter the main effects caused by the radiation in the interaction with the
biological matter are explained, discussing in particular way the damages leaded by the use of the
high LET (linear energy transfer) particles to the mammalian cells.

The physica
l description of the interaction between radiation and matter are treated in the first part
of the second chapter; in particular the energy loss by hadrons in function of depth is presented.
There is then a brief overview of the accelerators used in hadron
therapy, followed by the
description of the passive and active beam spreading system. The last part of this chapters presents
the description of the mechanical structure and the electronic read
-
out of the ionization chambers
designed and built by the group

of Torino. My personal contribution given to the development of
these detectors is explained in the following chapters in detail.

The chapters 3, 4 and 5 present the experimental setup and the results of three different tests. The
first (chapter 3) has be
en done in April 2001 at the GSI centre of Darmstadt, in Germany, where
patients are treated with carbon ions. The accelerator is a synchrotron and the beam spread is
obtained with the voxel scanning technique. In particular I have described the acquisitio
n system
dedicated to this scanning method, and the analysis aimed to the characterisation of the detector.

In October 2002 a test within a collaboration with the IBA (Ion Beam Application) was done at
Louvain
-
la
-
Neuve. This test was aimed to check and cha
racterise the raster scanning system

developed by the IBA. In chapter 4

the experimental setup and the analysis done on the data
collected are reported.

The last chapter describes the development of a new strip ionization chamber designed for the
beam line

of CATANA, at INFN LNS Catania. Since four years in fact in Catania patients are
treated for ocular pathologies with protons. Until the end of the 2004 no detectors for the on
-
line
check of the beam structure were present on that beam line. The last part
of my doctorate work was
aimed to design, build and test a detector dedicated to CATANA, for the on
-
line verification of the
beam shape. In chapter five also the mathematical functions used to study the beam stability,
optimizing the computation speed, are

reported. For the end of February 2005 the first treatment
session with the detector placed on the beam line are planned.





7


1


The cure of cancer with radiation


1.1

The significance of radiobiology in radiotherapy

1.1.1

The role of radiotherapy in the management

of cancer

Radiotherapy is one of the two most effective treatments for cancer. Surgery, which of course has
the longer history, is in many tumour types the primary form of treatment and it leads to good
therapeutic results in a range of early non
-
metastat
ic tum
ours. The combination between
radiotherapy and
surgery
often achieve a reasonable probability of control for many tumours, and in
case of tumour of
head and neck, cervix, bladd
er, prostate and skin the only radiotherapy gives
good results
. In additio
n to these examples of the curative role of the radiation therapy, many
patients gain valuable palliation by radiation. Chemotherapy is the third most important treatment
modality at present time. Many patients receive chemotherapy at some point in their m
anagement
and useful symptom relief and diseases arrest are often obtained [1.1].

The following is a brief outline of the role of radiotherapy in six disease sites:



Bladder
: the success of surgery or radiotherapy varies widely with the stage of
disease; bo
th approaches give 5
-
year survival in excess of 50%.



Breast
: early breast cancer, not known to have metastasized, are usually treated by
surgery and this have a tumour control rate in the region of 50
-
70%. Radiotherapy given to
the chest wall and regional
lymph nodes increases control by up to 20%. Hormonal therapy
and chemotherapy also have significant impact on patient survival. In patients who have
evidence of metastatic spread at the time of diagnosis, the outlook is poor.



Cervix
: disease that has devel
oped beyond the in situ stage is often treated by
combination of intracavitary and external
-
beam radiotherapy. The control rate varies widely
with stage of the disease, from around 70% in stage I to perhaps 7% in stage IV.



Lung
: most lung tumours are inope
rable and for them the 5
-
year survival rate for
radiotherapy combined with chemotherapy is in the region of 5%.



Lymphoma
: in Hodgkin’s disease radiotherapy alone achieves a control rate of
around 50% and when combined with chemotherapy this may rise to 80%
.



Prostate
: where there is evidence of local invasion, surgery and radiotherapy have
similar level of effectiveness, with 10
-
years control rates in the region of 50%.
Chemotherapy makes a limited contribution to local control.

Very substantial number of pa
tients with common cancers achieves long
-
term tumour control
largely by the use of radiation therapy. There are three main ways in which an improvement in
radiotherapy might be obtained:



by rising the standard of radiation dose prescription and delivery wi
th respect to
those currently in use.



by improving radiation dose distributions beyond those that are conventionally
achieved, either using techniques of conformal radiotherapy with photons, or by use of
hadronic beams.



by exploring radiobiological initiat
ives.



1.1.2

The role of radiation biology

Experimental and theoretical studies in radiation biology contribute to the development of
radiotherapy at three different levels, moving in turn from the most general to the most specific:


8



Ideas
: providing a conceptua
l base for radiotherapy, identifying the mechanisms and
processes that underline the response of tumour and normal tissues to irradiation and which
help to explain the observed phenomena. Examples are: hypoxia, reoxigenation, tumour cell
repopulation or me
chanism of repair of DNA damage.



Treatment strategy
: development of specific new approaches in radiotherapy.
Examples are hypoxic cell sensitizers, high LET
-
radiotherapy, hyperfractionation.



Protocols
: advice on the choice of schedules for clinical radioth
erapy, for instance
conversion formulae for changes in fractionation or dose rate, or advice on whether to use
chemotherapy concurrently or sequentially with radiation. We may also include under this
heading methods for predicting the best treatment for th
e individual patient (individualized
radiotherapy).

There is no doubt that radiobiology has been very fruitful in the generation of new ideas and in
the identification of potentially exploitable mechanisms. A variety of new treatment strategies have
been p
roduced, but few of these have so far led to demonstrable clinical gains.



1.1.3

The time
-
scale of effects in radiation biology

Irradiation of any biological system generates a succession of processes that differ enormously in
time scale. This is illustrated in

Figure
1
.
1

where these processes are divided into three phases.



Figure
1
.
1
: Time scale of the effects of radiation exposure on biological systems.



The physical phase

consists of

the interaction between charged particles and the atoms of which
the tissue is composed. An high speed electron takes about 10
-
18

seconds to traverse the DNA
molecules and about 10
-
14

seconds to pass across a mammalian cell. As it does so, it interacts
ma
inly with the orbital electrons, ejecting some of them from atoms (ionization) and raising other to
higher energy levels within an atoms or molecule (excitation). If sufficiently energetic, these
secondary electrons may excite or ionize other atoms near wh
ich they pass, giving rise to cascade of
ionizing events. For 1 Gy of absorbed radiation dose there are in excess of 10
5

ionizations within
the volume of any cell of diameter of 10

m.

The chemical phase

describes the period in which the damaged atoms and molecules react with
other cellular components in rapid chemical reactions. Ionization and excitation lead to the breakage
of chemical bonds and the formation of broken molecules, k
nown as ‘free radical’. These are highly
reactive and engage in a succession of reactions that lead eventually to the restoration of electronic

9

charge equilibrium. Free
-
radical reactions take place within approximately 1ms of radiation
exposure. An importa
nt characteristic of the chemical phase is the compensation between
scavenging reactions, for instance with sulphydryl compounds that inactivate the free radical, and
fixation reaction that lead to stable chemical changes in important biological molecules.

The biological phase

include all subsequent processes. These begin with enzymatic reactions that
act on the residual chemical damage. The vast majority of lesions, for instance in DNA, are
successfully repaired. Some rare lesions fail to repair and this i
s what lead eventually to cell death.
Cells take time to die; indeed, after small dose of radiation they may undergo a number of mitotic
divisions before dying. It is the killing of stem cells and the subsequent loss of the cells that they
would have given

rise to, that causes the early manifestations of normal
-
tissue damage during the
first week and month after irradiation exposure. Examples are: breakdown of the skin or mucosa,
denudation of the intestine and haemopoietic damage. A secondary effect of cel
l killing is
compensatory cell proliferation, which occurs both in normal tissue and tumours. At later times
after the irradiation of normal tissue the so called ‘late reactions’ appear. These include fibrosis and
telangiectasia of the skin, spinal
-
cord da
mage and blood vessel damage. An even later manifestation
of radiation damage is the appearance of secondary tumours (i.e. radiation carcinogesis). The time
-
scale of the observable effects of ionizing radiation may thus extend up to many years after
exposu
re.



1.1.4

Response of normal and malignant tissues to radiation exposure

The effects of radiation exposure become apparent during the weeks, month and years after
radiotherapy. These effects are seen both in tumour tissues and normal tissues that surround a
tu
mour and which are unavoidably exposed to radiation. The response of a tumour is seen by
regression
, often followed by
regrowth
, but perhaps with failure to regrow during the normal
lifespan of the patient (which is termed
cure

or
local control
).

The respo
nse of normal tissue to therapeutic radiation exposure range from those that cause mild
discomfort to other that are life threatening. The speed at which a response develops varies widely
from one tissue to another and often depends on the dose of radiatio
n that the tissue receives.
Generally speaking the haemopoietic and epithelial tissues manifest radiation damage within weeks
of radiation exposure, whereas damage to connective tissue becomes important at later times.



1.1.5

Response curve, dose
-
response curv
es and isoeffect relationship

The damage that is observed in an irradiated tissue increases, reaches a peak, and then may
decline (
Figure
1
.
2
A). It could be possible use the measured response at some chosen time after
irradiation,
such at the time of maximum response, but the timing of the peak may change with
radiation dose and this would lead to some uncertainty in the interpretation of the results. A
common method is to calculate the cumulative response by integrating this curve
from left to right
(
Figure
1
.
2
B). The response for some normal tissue gives a cumulative curve that rises to a plateau,
and the height of the plateau is a good measure of the total effect of that radiation dose on the tissue.
Other

normal tissue response, in particular the late responses seen in connective and vascular
tissues, are progressive and the cumulative response continues to rise.



10



Figure
1
.
2
: Four

types of chart leading to the construction of an isoeffect plot. (A) Time
-
course of radiation damage in a
normal tissue. (B) The cumulative response. (C) A dose
-
response relationship, constructed by measuring the response
(R) for varius radiation doses (D
). (D) Isoeffect plot for a fixed level of normal tissue damage.


The next stage in a study of the radiation response of a tissue consist in varying the radiation dose
and thus investigating the dose
-
response relationship (
Figure
1
.
2
C). Radiation dose
-
response curves
have a sigmoid shape, with the incidence of radiation tending to zero as dose goes to zero and
tending to 100% at very large doses. Many mathematical functions could be used with these
properties, but the most standard
formulation used is the Poisson distribution. Munro and Gilbert
published a landmark paper in 1961 in which they formulated the target cells hypothesis of tumour
control: ‘The object of treating a tumour by radiotherapy is to damage every single potentiall
y cell
to such an extent that it cannot continue to proliferate’. From this idea and the random nature of cell
killing by radiation they derived a mathematical formula for the probability of the tumour cure after
irradiation ‘of a number of tumours each co
mposed of N identical cells’. More precisely, they
showed that this probability depends only on the average number of clonogens surviving per
tumour. When describing tumour cure probability (TCP), it is the probability of zero surviving
clonogens in a tumo
ur that is of interest. This is the zero
-
order term of the Poisson distribution and
if


denotes the average number of clonogens after irradiation this is simply:


TPC = e
-







(1.1)


The simple exponential was later replaced by the linear
-
quadratic model and thus we arrived at
what could be called the standard model of tumour con
trol:


TCP=exp[
-
N
0
*exp(
-

D
-

dD)]




(1.2)


Here N
0

is the number of clonogens per tumour before irradiation and the second exponential is
simply the surviving fraction after dose D given with dose per fraction
d
, according to the linear
quadratic model. Th
us when we multiply these two quantities we obtain the average number of
surviving clonogens.

Diagrams similar to
Figure
1
.
2
A, B, C can also be constructed for fractionated radiation
treatment, although the results are easiest to i
nterpret when the fraction are given over a time that is
short compared with the time scale of development of the response. If we change the schedules of
dose fractionation, for instance by giving a different number of fractions, changing the fraction size


11

or radiation dose rate, we can then investigate the therapeutic effects in term of
isoeffect plot

(
Figure
1
.
2
D). Experimentally this is done by performing multiple studies at different doses for
each chosen schedule and calculatin
g a dose
-
response curve. We then select some particular level of
effect (T in
Figure
1
.
2
C) and read off the total radiation dose that gives this effect. For effects on
normal tissues the isoeffect will often be some upper limit of
tolerance of the tissue, perhaps
expressed as a probability of tissue failure. The isoeffect plot show how the total radiation dose for
the chosen level of effect varies with dose schedule. The dashed line in
Figure
1
.
2
D

illustrate
s how
therapeutic conclusion may be drawn from isoeffect curves.



1.2

DNA damage and cell killing

1.2.1

Initial process of radiation damage

As mentioned above the irradiation of a biological system initiates a series of processes that can
be classified in term of t
ime scale over which they act. The physical, chemical and biological phases
of this processes have been described in section
1.1.3
.

An electron with an energy of 1 MeV has a range in soft tissue of a few millimeters [1.2]. In th
e
early part of its track the particle moves very quickly and its rate of energy deposited is low; the
result is a relative straight track in which the ionizations may be separated by distance of around
0.1mm on average. We describe this as radiation with
a low linear energy transfer (LET). As the
electron slows down, it interacts more strongly with the orbital electrons in the medium. Its rate of
energy loss increase, the track becomes more tortuous due to the stronger collision, and the
ionization density

increase.
Figur
e
1
.
3
A shows a computer simulation of the tracks of 1 KeV
electrons, representing a very small part of the tracks of 1 MeV electrons. The important feature is
the tendency towards clustering of the i
onization events at the end of the track, each cluster having
the size of a few nanometers. Within each electron track there is opportunity of interaction between
the products of separate ionization events and it may be, particularly at low dose rate or fo
llowing
acute radiation doses up to few Gy, that the main biological effects of radiation (i.e. cell killing and
mutation) are predominantly due to damage that is produced by these ‘hot spots’. Within perhaps
10
-
10

seconds of exposure to either photon or p
articles beam, the irradiated volume will contain
atoms that have been ionized and a corresponding number of free electrons, all produced by cascade
of atomic reaction just described and with a rather non
-
uniform spatial distribution. The number of
ionizat
ion produced at therapeutic dose levels is very large


approximately 10
5

ionizations per cell
per Gy


but the vast majority of these produce no toxic damage. The biological effect is influenced
by three factors: free radical scavenging processes, the num
ber of ionizations that are closed to
DNA to damage it, and the cellular repair process.



Free
-
radical process

Since biological systems consist largely of water, the bulk of the ionization produced by
irradiation occur in water molecules. Negatively char
ged free electron that are produced by
ionization will rapidly become associated with polar water molecules, greatly reducing their
mobility. The configuration of an electron surrounded by water molecules (a ‘hydrated electron e
-
aq
)
has a degree of stabili
ty and lifetime under physiological condition of few microseconds. The water
molecule that has lost an electron is a highly reactive positive charged ion. It quickly breaks down
to produce a hydrogen ion (H
+
) and an (uncharged) OH radical. OH is a molecule

that normally
doesn’t exit in water, indeed the stable configuration is H
2
O. The uncharged OH radical has an
unpaired electron (‘unattached valence’) that makes it highly reactive. We designate it as a free
radical thus: OH

. Free radicals are simply frag
ment of broken molecules. OH


is different from

12

OH
+

which is positive charged ion: the OH radical has equal number of protons and orbital
electrons but because of unpaired electron is chemical reactive (some ions may also be radical, for
example a water mo
lecule that has lost an electron is actually H
2
0
+
, a radical cation). Similarly, H+
is a bare proton, positively charged, whilst H


is a proton plus an electron (neutral charge) but again
highly reactive because the stable form of hydrogen is H
2
.



Figur
e
1
.
3
: (A) Computer
-
simulated tracks of 1 KeV electrons. Note the scale in relation to the 2.3 nm diameter of
DNA double helix (adapted from Chapman and Gillespie, 1981). (B) Illustrating the concept of a loc
al multiply
damaged site produced by a cluster of ionizations impinging on DNA


Around 10
-
10

seconds after irradiation there will be three principal radiolysis products of water:

e
-
aq
, OH


and H

. These highly reactive species will go on to take part

in further reactions. An
important one is:


OH


+ OH




H
2
O
2


the production of hydrogen peroxide. Oxygen, if present, plays an important part in the free
-
radical
reactions following the irradiation. Molecular oxygen has a high affinity for free
-
radical (
R

):


R


+ O
2



RO

2


giving rise to further reactive products and acting to fix the free
-
radical damage. The oxygen effect
in radiation cell killing has often been explained in term of this type of process.

In biological system the free radicals produced
in water may react with essential macromolecules.
A vast range of reaction takes place, most of which are unimportant for the survival and functioning
of the cell. The most important reactions are those with DNA, because of the uniqueness of many
parts of
this molecule. Damage of DNA by free radicals produced in water is called the
indirect

effect of radiation; ionization of atoms that are part of the DNA molecule is the
direct

effect.



1.2.2

Radiation damage to DNA

The structure of DNA

Deoxyribonucleic acid (D
NA) is a large molecule that has a characteristic double helix structure
consisting of two strands, each made up of a sequence of nucleotides (
Figure
1
.
4
).


13



Figure
1
.
4

The structur
e of DNA, in which the four bases (G,C,T,A) are linked through sugar groups to the sugar
-
phospate backbone.


A nucleotide is a subunit in which a ‘base’ is linked through a sugar group to a phosphate group.
The sugar is deoxyribose, which have five
-
atom ri
ng: four carbons and one oxygen. The ‘backbone’
of the molecules consists of alternating sugar
-
phosphate group. There are four different bases. Two
are single
-
ring group (pyrimidines): thymine and cytosine, and two are double
-
ring group (purines):
adenine
and guanine. It is the order of these bases along the molecule that specifies the genetic
code.

The two strands of the double helix are held together by hydrogen boning between the bases.
These bonds are made between thymine and adenine, and between cytosi
ne and guanine; the bases
are paired in this way along the length of DNA molecule. During the S phase of the cell cycle, DNA
synthesis takes place (the process of
replication
) in which every base pair is accurately duplicated.

The first stage in the manufa
cture of proteins is the construction by the process of
transcription

of
a messenger RNA (i.e. mRNA) that has a similar to a single strand of DNA expect that the sugar
groups are ribose in place of deoxyribose, and the thymine is replaced by uracil. The de
coding is
based on the pairing of bases: A
-
U, C
-
G, G
-
C, U
-
A. Transcription is performed by RNA
polymerases, which bind to DNA and generate the corresponding mRNA.



Radiation damage to DNA


Early experiments showed that irradiation leads to a loss of visco
sity in DNA solutions.
Subsequently this has been shown to result from DNA strand breaks. There are two categories of
DNA strand breaks: single
-
strand (SSB) and double
-
strand (DSB). The detection of these depends
on a study of the size distribution of frag
ments of DNA after extraction from irradiated cells. As
shown in
Figure
1
.
5
, there is a variety of other types of DNA lesion that may have a role in cellular
responses to radiation or chemical damage.



14


Figure
1
.
5

Types of damge to DNA produced by radiation and chemical agents.


There are many sources of evidence to suggest that DNA damage is the critical event in radiation
cell killing and mutation, including the following:



Micro
-
ir
radiation studies show that to kill cells by irradiation of only the cytoplasm
requires far higher radiation dose than irradiation of the nucleus.



Isotopes with short
-
range emission (such as
3
H,
125
I) when incorporated into cellular DNA
efficiently produce

radiation cell killing and DNA damage.



The incidence of chromosomal aberrations following irradiation is closely linked to cell
killing.

The number of lesions induced in DNA by radiation is far greater than those that eventually lead to
cell killing. A do
se of radiation that induces on average one lethal event per cell will kill 63% and
leave 37% still viable (this result from Poisson statistic) and we call this the D
0

dose. D
0

values for
oxic mammalian cells are usually in region of 1
-
2 Gy. The numbers of

DNA lesions per cell that are
detected immediately after such a dose have been estimated to be approximately:


Events per D
0

Base damage

>1000

Single
-
strand breaks

~1000

Double
-
strand breaks

~40


In addition, cross
-
links between DNA strands and betwee
n DNA and nuclear proteins are formed
(
Figure
1
.
5
). Irradiation at clinical used doses thus induces a vast amount of DNA damage, most of
which is successfully repaired by the cell. In a variety of experimental situations it has bee
n found
that the incidence of cell killing fails to correlate with the number of SSB induced, but relates better
to the incidence of DSB. Significantly, a dose of hydrogen peroxide that induces many DDB
produces little cell killing and few DSB unless the n
umber of SSD is so large that they are close
enough to form DSB. On this basis it is generally believed that DSB are the critical lesions for
radiation cell killing in most cell types, although experimental evidences indicate that only some
DSB are importa
nt.







15


Modifier

Cell kill

DSB

SSB

Base

DNA
-
protein cross
-
link

High
-
let rad









†††


y灯楡







0

††††


周楯Ts







0

††††


ye牴r牭楡





0

0

††††
0

y摯rge渠灥爮

0

0





††††









, Increased;

, Decreased; 0 littl
e or no effect;
-
, not know.

See Frankenburg Schwager (1989) for further information

Table
1
-
1

Double
-
strand DNA breaks correlate best with cell killng



1.2.3

Cell death in mammalian tissues


The definition of eff
ective cell death could be described as the loss by the cell of its ability to
produce progeny. This end point is defined as
clonogenic

cell death. But for organized tissue and
tumours the definition of cell death is much more complicated. We recognized th
at clonogenic
potential is the essential element for the maintenance of a cell line, either
in vitro

or in organized
tissue, but there are other important issues in the behavior of complex tissue system. Normal
senescence of cells is one of these important

issues. Another important issue is the removing of the
cells that are in the wrong place at the wrong time. Example of this would be the metastatic arrival
of tumour cells transported from a primary tumour elsewhere or the resolution of inflammatory
proce
sses.

One can define at least two types of cell death that go beyond the end point of clonogenic
potential and involve the actual disappearance of the cells. Acute pathological cell death, which
generally results from cell injury or from lack of oxygen or
essential metabolites, is called
necrosis
.
Necrosis is characterized by a tendency for cells to swell and ultimately to lyse, which allows the
cell’s contents to flow into cellular space. Necrosis is usually accompanied by an inflammatory
response. In the
case of neoplasm, necrosis is most often seen in rapidly growing tumours, where
the tumour mass outgrows its blood supply and regions of the tumour became undernourished in
oxygen and energy sources. In this case inflammation is not a characteristic of the

necrotic process.
For cell death that results from senescence or cell population control, by contrast, the characteristic
process, called
apoptosis
, involves shrinkage of the nucleus and cytoplasm, followed by
fragmentation and phagocytosis of these fragm
ents by neighbouring cells or macrophages. The
contents of cells do not usually leak into extracellular space, so there is no inflammation. Since
there is no inflammation accompanying apoptosis, the process is histologically quite inconspicuous
[1.3].



1.3

Th
e oxygen effect

The response of cells to ionizing radiation is strongly dependent upon oxygen (Gray
et al
., 1953;
Wright and Howard
-
Flanders, 1957). This is illustrated in
Figure
1
.
6

for mammalian cells irradiated
in culture. The c
ell surviving fraction is shown as a function of radiation dose administrated either
under normal aerated condition or under hypoxia, generally achieved by flowing nitrogen gas over
the surface of the cells suspensions for a period of 30 minutes or more. T
he enhancement of
radiation damage by oxygen is dose
-
modifying, i.e. the radiation dose that gives a particular level of

16

survival is reduced by the same factor at levels of survival. This allows us to calculate an oxygen
enhancement ratio (OER):






for
the same level of biological effect. For most cells the OER for x
-
rays is around 3.0. However,
some studies suggest that at radiation dose of 3 Gy or less the OER is actually reduced (Palcic and
Skarsgard, 1984). This is an important finding because this i
s the dose range for clinical
fractionation treatments [1.4].


Figure
1
.
6

Survival curves for culturaed mammalian cells exposed to x
-
rays under oxic or hypoxic conditions,
illustrated the radiation dose
-
modi
fying effect of oxygen. Note that the broken line extrapolate back to the same point
on the survival axis (n=5.5).


It has been demonstrated from rapid
-
mix studies that the oxygen effect only occurs if oxygen is
present either during irradiation or within
a few millisecond thereafter (Howard
-
Flanders and
Moore, 1958). The dependence of the degree of sensitization on oxygen tension is shown in
Figure
1
.
7
. By definition, the OER under anoxic condition is 1.0. As the oxygen level incre
ases, there is a
steep increase in radiosensitivity (and thus in OER). The greatest change occurs from 0 to about 20
mmHg; further increase in oxygen concentration, up to that seen in air (155 mmHg) or even to
100% oxygen (760 mmHg), produces a small thoug
h definite increase in radiosensitivity. Also
shown in
Figure
1
.
7

is the oxygen partial pressure range typically found in arterial and venous
blood. Thus, from a radiobiological standpoint most normal tissues can be considered to b
e well
oxygenated, although it is now recognized that moderate hypoxia is a feature of some normal tissue
such as cartilage and skin.

OER =

dose in O
2

for surviving fraction, S/S
0

dose in N
2

for surviving fraction, S/S
0


17


Figure
1
.
7

Variation of oxygen enhancement ratio (OER) with oxygen tensi
on. The horiziontal arrows indicate the
range of physiological blood oxygen tensions on the lower scale. Adapted from Denekamp (1989).

The mechanism responsible for the enhancement of radiation damage by oxygen is generally
referred to as the oxygen
-
fixat
ion hypothesis and is illustrated in
Figure
1
.
8
. When radiation is
absorbed in a biological material free radicals are produced. These are highly reactive molecules
and can thus break chemical bonds, produce chemica
l changes, and initiate the chain of events that
results in biological damage. They can be produced either directly in target molecule (usually DNA)
or indirectly in other cellular molecules and defuse far enough to reach and damage critical targets.
Most
of the indirect effects occur by free radical produced in water, since this makes up to 70
-
80%
of mammalian cells. It is the fate of the free radicals ultimately produced in critical target,
designated in R


in
Figure
1
.
8
, that is important. If oxygen is present, then it can react with R


to
produced RO
2


which then undergoes further reaction ultimately to yield ROOH in target molecule.
Thus we have a change in the chemical composition of the target and the damage is

chemically
fixed. Subsequently this damage can be processed enzimatically and perhaps repaired. In the
absence of oxygen, or in the presence of reduced species, R


can react with H
+
, thus restoring its
original form.



Figure
1
.
8

The oxygen fixation hypothesis. Free radical produced in DNA either by direct or indirect action of radiation
can be rapired under hypoxia but fixed in the presence of oxygen. Adapted from Hall (1989).




18

1.4

Particle beams in radiothera
py

Figure
1
.
9

shows examples of microdosimetric calculation of ionization tracks from

-
rays or

-
particles passing through a cell nucleus (Goodhead, 1988). At the scale of cell nucleus, the

-
rays
deposit much of t
heir energy as single isolated ionizations or excitations and much of resulting of
DNA damage is efficiently repaired by enzymes within the nucleus. About 1000 of these sparse
tracks are produced per Gy of absorbed dose. The

-
particles produce fewer track
s but the intense
ionization within each tracks leads to more severe damage where the track intersects vital structure
such as DNA. The resulting DNA damage may involve several adjacent base pairs and will be
much more difficult or even impossible to repai
r; this is probably the reason why these radiations
produce steeper cell survival curves and allow less cellular recovery than x
-
rays. At the low doses
that are encountered in environmental exposure, only some cells will be traversed by a particle and
many

cells will be unexposed [1.5].



Figure
1
.
9

The structure of particle tracks for low
-
LET radiation (above) and


particle (below). The cricles indicate
the typical syze of mammalian cell nuclei. Note the to
rtuos tracks of low
-
energy secondary electrons. From Goodhhead
(1988).


Linear energy transfer

(LET) is the physical quantity used to describe the density of ionization in
particle tracks. LET is the average energy given up by a charged particle traversing

a unitary
distance, normally expressed in KeV

m
-
1
. In
Figure
1
.
9

the

-
rays have a LET about 0.3 KeV

m
-
1

and are described as low
-
LET radiation. The

-
particles have a LET of about 100 KeV

m
-
1

and are
an example of high
-
LET radiation.

Also neutrons are descri
bes as high
-
LET radiation, even if they are uncharged. In fact they do not
interact with the orbital electrons in the tissue through which they pass and they do not directly
produce ionization. They do, however, interact with atomic nuclei from which they
eject slow,
densely ionization protons. It is this secondary production of knock
-
on protons that confers high
LET.






19

1.4.1

Biological effects depend upon LET


As LET increases, radiation produces more cell killing per Gy.
Figure
1
.
10

shows the survival of
human T1G cells plotted against dose for high different radiations, with LET varying from 2
keV

m
-
1

(250 kVp x
-
rays) to 165 keV

m
-
1

(2.5 MeV


particles). As LET increases, the survival
curves became steeper; they also
become straighter with less shoulder, which indicates either a
higher ratio of lethal to potentially lethal lesion (in lesion
-
interaction models) or that high
-
LET
radiation damage is less likely to be repaired correctly. For particles of identical atomic
c
omposition, LET generally increases with decreasing particles energy. However, notice that 2.5
MeV


particles are less efficient compared with 4 MeV


particles even though they have a higher
LET; this is due to the phenomenon of overkill indicated in
Figure
1
.
11
.

The relative biological effectiveness (RBE) of
a radiation under test (e. g. a high LET radiation) is
defined as:





to give the same biological effect.




Figure
1
.
10

Survival of human kidney cells exposed in vitro to radiations of different LET. F
rom Barendsen (1968).


The reference low
-
LET radiation is usually 250 kVp x
-
rays.
Figure
1
.
11

shows RBE values for
T1g cells featured in
Figure
1
.
10
. Curves have been calcula
ted at cell survival levels of 0.8, 0.1 and
0.01, illustrating the fact that RBE is not constant but depends on the level of biological damage and
hence on the dose level. RBE rises to a maximum at a LET of about 100keV

m
-
1
, then falls for
higher values of

LET due to overkill. For cells to be killed, energy must be deposited in a number of
critical sites in the cell.


RBE=

dose of reference radiation



dose of test radiation


20


Figure
1
.
11

Dependece of RBE on LET and the phenomenon of overkill by very high
-
let radatio
ns. From Barendsen
(1968).


Sparsely ionizing low
-
LET radiation is inefficient because more than one particle may have to pass
through the cell to kill it. Densely ionizing very high
-
LET radiation is also inefficient because it
deposits more energy than ne
cessary in critical sites. These cells are overkilled and per Gy there is
then less likelihood that other cells will be killed, leading to a reduced biological effect. Radiation
of optimal LET deposits just enough energy per cell to inactivate the critical

targets. This optimum
LET is usually around 100mm
-
1 but it does vary between different cell types and depends on the
spectrum of LET values in the radiation beam as well as the mean LET.

As LET increases, the oxygen enhancement ratio decreases. The measur
ements shown as an
example in
Figure
1
.
12

were also made with T1g cells of human origin. The sharp reduction of
OER occurs over the same range of LET as the sharp increase in RBE (
Figure
1
.
11
).






Figure
1
.
12
: The oxygen enhancement ratio (OER) decreases with increasing LET. Closed circles refer to
monoenergetic

-
paritcles and deuterons; the open triangle to 250 kVp x
-
rays. From Barendsen (1968).




21

1.4.2

The biological basis for high
-
LET radiotherapy


We have seen in
Figure
1
.
12

that the differential radiosensitivity between more oxygenated (mo
re
resistant) cells is reduced with high
-
LET radiation. Therefore, tumour sites in which hypoxia is a
problem in radiotherapy (some head and neck tumour, for example) might benefit from high
-
LET
radiotherapy in the same way as from chemical hypoxic
-
cell se
nsitizers.

The effect of low
-
LET radiation on cells is strongly influenced by their position in the cell cycle,
wit cells in S
-
phase being more radioresistant than cells in G2 or mitosis. Cells in stationary phase
also tend to be more radioresistant than c
ells in active proliferation. Both these factors act to
increase the effect of fractionated radiotherapy on more rapidly cycling cells comparing with those
cycling slowly or not at all, because the rapid cycling cells that survive the first few fractionati
on
are statistically more likely to be caught in a sensitive phase and so killed by a subsequent dose, a
process termed ‘cell
-
cycle resensitization’. This differential radiosensitivity due to cell cycle
position is considerably reduced with high
-
LET radiat
ion and is a reason why we might expect
high
-
LET radiotherapy to be beneficial in some slowly growing, x
-
ray resistant tomours.

A third biological rationale for high
-
LET therapy is based on the observation that the range of
radiation response of different
cells types is reduced with high
-
LET radiation compared with x
-
rays.
This is shown in
Figure
1
.
13
, which summarized the
in vitro

response of 20 human cells lines to
photon and neutron irradiation ( Britten
et al
, 1992). This reduce
d range of response affects the
benefit expected, which is the balance between the tumour and the normal
-
tissue response. Thus, if
tumour cells are already more radiosensitive to x
-
rays than the critical normal
-
cells population,
high
-
LET radiation should n
ot be used since this would reduce an already favourable differential.
Possible examples are seminomas, lymphomas and Hodgking’s disease. However, if the cells are
more resistant to x
-
rays than the critical normal cells, high
-
LET radiation might reduce thi
s
difference in radiosensitivity and thus would effectively ‘sensitize’ the tumour cells population
relative to a fixed level of normal
-
tissue damage. High
-
LET radiation would be advantageous in
this case.



Figure
1
.
13
: response of 20 human tumour cell lines to (A) 4MVp photons, or (B) p(62.5)
-
Be neutrons. The vertical
lines show the photon (2Gy) and the neutrons (0.68 Gy) doses that give the same median cell survival; the average RBE
is therefore 2/0.68=2.9
4.





22

2

Radiotherapy with hadrons


2.1

Proton interactions with matter


2.1.1

Introduction


For an understanding of the dose distribution produced by protons, a knowledge of their energy loss
and scattering is needed. Protons traversing matter lose energy through suc
cessive collision with
atoms and molecules of the material. With respect to energy loss, the most important interaction is
between the protons and the atomic or molecular electrons. The interactions between the protons
and the atomic nucleus effect the pro
tons flux (nuclear reactions), and the proton trajectory
((in)elastic scattering) [2.1].

The most important parameter characterizing the energy loss of an incident proton is the
stopping
power
, which is the mean energy loss per unit path length in material
. A full description of the
proton energy loss process, however, requires more detailed information that is provided by the
stopping power alone. The amount of energy transferred from a proton to an atomic electron, as
well as the number of interactions th
at occur per unit path length has a probabilistic distribution.
Moreover, there is a certain probability that very energetic electrons are produced (

-
electrons
or


-
rays
) which can travel a considerable distance before their energy is deposited.

The most
important contribution to proton scattering comes from the
electromagnetic interaction

with the nucleus. This gives rise to a small scattering angles, but since there are a large number of
collisions, the effect can be considerable. If the impact parameter

is small also the
hadronic
interaction

contributes to elastic scattering. In addition inelastic interaction can occur: these can be
either an inelastic scattering process during which the proton transfer energy to the nucleus (which
will then be in an exc
itated state and decay by

-
emission) or a nuclear reaction process (such as
(p,n), (p,d), (p,2p) or (p,3p)) where the incident proton will disappear. In case of scattering of
protons by very light nuclei, such as protons in hydrogen, also the recoil nucle
us can travel a
considerable length before its energy is fully deposited.



2.1.2

Proton interactions with electrons: energy loss


Within the energy range of importance in proton therapy (from stopping proton to about 250 MeV)
it is convenient to consider two en
ergy intervals separately:



Low energy: below ≈ 0.5 MeV protons can pick up orbital electrons and form hydrogen.
Also energy can be lost to atomic nuclei due to electromagnetic interactions (nuclear
stopping power). These are complicated process, but fortunately they only play a role

at
the very last microns of a proton track. It is important for the subject of microdosimetry,
which deals with the energy loss process on a microscopic scale (for example the study of
the effect of ionizing radiation on DNA).



High energy: for proton ener
gies between ≈ 0.5 MeV and 250 MeV the atoms in the
stopping medium can be excited or ionized. The collision process is well understood and
in principle the stopping power can be calculated theoretically.

The mean energy loss per proton
S

can be described
by the Bethe theory [2.2]

which leads to the
following expression:



23







L
A
Z
K
dz
dE
S
2
1
1
1








(2.1)


with:


K =
2
π
r
2
e

mc
2
N
av

≈ 0.135 MeV cm
2
g
-
1





(2.2)



where
r
e

= e
2
/4

0
mc
2

is the classical electron radius,

0

is the permittivity of the vacuum (w
hich
is introduced by the use of SI units),
mc
2

is the electron rest mass energy,
N
av

Avogadro’s number,


is the particle velocity in unit of velocity of light,
Mc
2

is the proton rest mass ≈ 938.3 MeV,
E

the
proton kinetic energy,
Z

and
A

are the atomic
number and relative atomic mass of the target atom.
The quantity
L
(

) takes into account the fine details of the energy loss process and is written as the
sum of three terms:


L
(

) =
L
0
(

) +
L
1
(

) +
L
2
(

)




(2.3)


The first term is given by:























Z
C
I
T
mc
L
2
ln
2
2
1
2
ln
2
2
max
2
2
0




(2.4)


where I is the
average excitation potential

of the atoms of the medium, C/Z the
shell correction

and


the
density
-
effect correction
. The shell correction plays a role at low velocities and deals with
effects due to the finite

speed of the proton compared to the velocity of bound electrons. It can be as
high as 10% but it is usually implicitly taken into account by the choice of the excitation potential I.
The density correction takes into account the polarization of the medium

to the passage of the
projectile proton. It can be neglected (


« 0.1%)for proton energies below 500 MeV.
T
max

is largest
possible energy loss in a single collision with a free electron, given by:


1
2
2
2
2
2
max
1
2
1
1
2