27 Basics of Radiation Therapy
Elaine M. Zeman, Eric C. Schreiber, and Joel E. Tepper
SUMMARY
O F
K E Y
P O I N T S
Introduction and Historical
Perspective
• X-rays were first discovered
emanating from an energized
Crooke’s tube by Wilhelm Roentgen
in 1895.1 In 1896, Henri Becquerel
discovered that some naturally
occurring elements emitted ionizing
radiation.2 The radioactive elements
radium and polonium were isolated
and characterized by the Curies in
1898.3
• Within a year or two, ionizing
radiation was in use worldwide for
medical imaging and radiation
therapy.
Radiation Physics
• Several types of ionizing radiation
are used to treat patients; most are
of the low linear energy transfer, less
biologically potent varieties.
• Therapeutic x-rays (photons) and
electrons are produced by linear
accelerators but can also be
produced by nuclear isotopes that
undergo radioactive decay. These
form the basis of external beam
radiotherapy and brachytherapy,
respectively.
• Ionizing radiation interacts with
matter via several processes, the
most important of which for clinical
radiation therapy is Compton
scattering.
• Megavoltage photons from linear
accelerators have the desirable
property of delivering their maximum
dose at depth within the patient,
thereby sparing the skin and, to
some extent, other normal tissues.
The Radiobiology of
Radiotherapy
• Ionization of biomolecules from the
deposition of energy by photons or
particles can occur directly and
indirectly. The most important
cellular target for radiation is DNA,
with irreparable or “misrepaired”
double-stranded breaks believed to
be the lesions most responsible for
cell killing.
• Irradiation elicits diverse cellular
responses that include the sensing
of DNA damage, mobilization of DNA
repair proteins, repair (or attempted
repair) of DNA damage, triggering of
cell cycle checkpoints, and, for
irreparable or mis-rejoined damage,
cell death by one of several
mechanisms (e.g., mitotic
catastrophe, apoptosis, and
senescence).
• The most commonly applied model
of cell survival probability is the
linear quadratic (α/β) model, with
the surviving fraction of irradiated
cells described by the equation
2
S = e –( αd+ βd ) . The α/β ratio is a
convenient metric for describing
cellular radiosensitivity and has been
adapted to describe the response of
irradiated tissues as a function of
time, dose, and fractionation.
• DNA damage and repair were initially
inferred by monitoring increases in
cell survival or tissue tolerance with
fractionation. These phenomena
were termed sublethal and
potentially lethal damage repair or
recovery.
• Cells in different cell cycle phases
possess different radiosensitivities;
cells are most radiosensitive in the
G2 and M phases of the cell cycle,
and most resistant in the S phase,
particularly the late S phase. Cells in
the G1 phase are of intermediate
radiosensitivity.
• Well-oxygenated cells are as much
as three times more sensitive to
radiation-induced cell killing than
(severely) oxygen-deprived cells.
Viable hypoxic cells that exist in
many human tumors but that are
mostly absent in normal tissues may
be an impediment to tumor control.
The elimination of such cells has
been a long-standing clinical goal.
Hypoxia may provide avenues for
therapeutic gain through the use of
hypoxia-directed therapies.
• Radiation sensitizers, particularly
cytotoxic chemotherapy and, to a
lesser extent, radiation protectors,
aim to improve the therapeutic ratio.
Clinical Radiation Oncology
• Radiation therapy is used in more
than half of all patients with cancer,
either as an adjuvant or neoadjuvant
treatment in combination with
surgery; as a definitive treatment
alone or in combination with
chemotherapy; as an organ-sparing
therapy; or to palliate symptoms.
• Fractionation of radiation and altered
fractionation schedules, such as
accelerated hyperfractionated
radiation therapy, make use of
differences in the responses of
normal and malignant tissues to
irradiation to achieve higher
therapeutic ratios.
• Radiation produces early effects,
such as mucositis, skin erythema, or
desquamation, and late effects, such
as fibrosis and carcinogenesis.
Planning and Delivery of
Radiation Treatment
• Patient simulation uses multiple
imaging approaches to identify
cancerous and healthy regions within the patient and to select
appropriate beams to deliver a dose to the tumor while minimizing
the dose delivered to surrounding
tissues.
Continued
393
394
Part I: Science of Clinical Oncology
• Three-dimensional conformal
treatment planning and delivery has
permitted escalation of doses and
improved sparing of normal tissues.
• Intensity-modulated radiation therapy
uses varying radiation beam
intensities to precisely sculpt the
dose distribution around the tumor
to improve the therapeutic ratio.
• Image-guided radiation therapy uses
real-time and/or daily imaging to
ensure that the tumor is positioned
such that the radiation beams are
precisely delivered to the appropriate
location within the patient.
Other Modalities in Radiation
• Brachytherapy delivers extremely
high-dose radiation to tumor tissue
with a much lower dose to
surrounding normal tissues.
• Stereotactic radiosurgery and
stereotactic body radiation INTRODUCTION
Radiation therapy, one of the three established cancer treatment
modalities, is used to treat most types of solid tumors and selected
hematologic malignancies. It is used almost entirely to treat malignant disease, although it has a small role in preventing proliferation
in benign disease. Radiation therapy is routinely combined with
surgery, chemotherapy, or both to improve therapeutic results. It is
often used with surgery to destroy microscopic regions of tumor
extension and with chemotherapy to more effectively destroy the
primary tumor. An understanding of the therapeutic use of ionizing
radiation requires a basic comprehension of both the physics of radiation therapy delivery and the biological effects of the interaction of
radiation with matter.
OVERVIEW OF RADIATION PHYSICS
The toxic biological effects of ionizing radiation, although complex,
varied, and incompletely understood, form the basis for the use of
radiation therapy as a cancer treatment. These biological effects are
initiated when packets of energy are deposited in a volume of tissue
and remove electrons from constituent atoms through a process called
ionization. Accordingly, the physics of radiation oncology is focused
on the details of how, where, and how much energy can be deposited
in diseased tissue in the hopes of eradicating it, while simultaneously
minimizing the energy released in healthy tissue. This process requires
an understanding of the nature of the radiation and the matter
through which it passes and how that matter is changed as a result
of the energy deposition events.
The Nature of Matter and Radiation
All matter, biological or otherwise, is composed of atoms. Atoms are
made up of groups of electrons (i.e., small negatively charged particles) orbiting a nucleus consisting of protons (larger positively charged
particles) and neutrons (uncharged particles having mass similar to
that of a proton). The properties of an atom are generally defined by
the number of protons in the nucleus. A matching number of electrons are held in orbit around the nucleus by electrostatic attraction.
A specific, discrete set of possible electron orbits exists for each kind
of atom, with each electron orbit corresponding to a specific energy.
Moving an electron from one orbit to another requires adding or
subtracting the energy difference between the two orbitals, and
removing an electron from the atom entirely, that is, ionization,
requires adding the full energy of the electron orbital.
The properties of a nucleus are defined by the number of protons
and neutrons, with the number of protons defining the type of
element and the number of protons and neutrons together defining
the isotope. Analogously to the arrangement of electrons in an atom,
protons and neutrons are arranged in discrete energy levels specific
to a particular nucleus, and transitioning between energy levels
requires adding or removing a comparable amount of energy. Of the
therapy combine a high dose per
fraction with highly conformal
treatment delivery to increase the
therapeutic ratio while reducing
treatment time.
• Proton therapy has dose distribution
advantages compared with photon
therapy, and it may be used to
deliver high doses of radiation to
tumors in close proximity to sensitive
normal structures.
1400 known isotopes of the 92 naturally occurring elements, approximately 80% are unstable and spontaneously undergo a transition
between energy levels, emitting energy in the process. The phenomenon of spontaneous energy release from a nucleus, called radioactivity, can take many forms, including combinations of the emission of
γ-rays, the ejection of electrons, positrons, or α-particles, and the
transmutation of one element to another.
The term “radiation” refers to energy emitted from a source that
is transmitted through a material or space. This radiation can then
deposit its energy by interacting with the matter through which it
passes. Regardless of the source, most radiation used in radiation
therapy involves electromagnetic interactions. This energy can take
the form of packets of electromagnetic waves called photons or can
be carried as the kinetic energy of freely propagating particulate radiation such as electrons, protons, or α-particles.
Photons are packets of oscillating electric and magnetic fields
propagating through space at the speed of light (3 × 1010 cm/second).
Photons are characterized by their wavelength, which is the distance
traversed by a wave over the course of a single oscillation. The possible
wavelengths of photons have no real limits, but common examples
range in wavelength from AM radio (103 m) to visible light (10−7 m)
to gamma rays (10−12 m). Photons that have a shorter wavelength
oscillate at a higher frequency (i.e., they have more oscillations per
unit time) and are more energetic. Energy and frequency are related
by Planck’s constant (4.135 × 10−15 eV-sec) and are generally expressed
in units of electron volts (eVs), which are equivalent to the kinetic
energy of a single electron accelerated over a potential of 1 volt. The
energy of a photon determines its ability to penetrate matter. Visible
light (~1 eV) can only interact with the surface of objects. Diagnostic
(kilo eV [keV]) and therapeutic (mega eV [MeV]) photons can penetrate much more deeply, permitting therapeutic effects anywhere in
the body. Photons at therapeutic energies can pass through many
centimeters of tissue before experiencing any interactions.
Most particulate radiation consists of energetic charged particles.
The electric fields around these particles cause them to interact with
all the other charged particles in the surrounding medium. Charged
particles are therefore much more efficient at depositing energy in
matter, because the particles will continuously lose their energy as
they attract or repel other charged particles along their path. Many
of these interactions will cause ionization, which correlates with the
amount of biological damage delivered. Heavy particles, such as
protons and α-particles, ionize matter very efficiently, lose energy
more efficiently, and have a higher linear energy transfer (LET), that
is, amount of energy loss per length of the particle’s track (discussed
later in this chapter) than do lighter particles such as electrons and
positrons. Although most particulate radiation is charged, uncharged
neutrons are also capable of depositing energy in a material. Unlike
charged particles, neutrons can only interact with other nuclei. Generally, this interaction takes the form of a collision with a proton. The
proton recoils with some fraction of the neutron’s initial energy. The
positively charged proton then ionizes the surrounding particles,
causing most of the biological damage.
Basics of Radiation Therapy • CHAPTER 27 395
Interactions of Radiation and Matter
Compton effect
e:
In order of roughly increasing energy, photons can interact with:
1. the atom as a whole;
2. tightly bound inner shell electrons;
3. loosely bound outer shell electrons;
4. the extranuclear space surrounding the nucleus; or
5. the nucleus itself.
e:
e:
e:
Compton Scattering
When photon energy is significantly higher than the binding energy
of an electron, the photon can scatter from the electron without being
absorbed, as illustrated in Figure 27-1. The result of this interaction
is a photon with reduced energy and new direction and a recoil
electron with some fraction of the initial photon energy. The energy
of the scattered electron varies with the scattering direction. An electron scattered in the direction of the incident photon claims most of
the initial photon energy, whereas electrons scattered at greater angles
have successively less energy. Compton scattering is only weakly
dependent on Z and is the dominant photon interaction in tissue
between 30 keV and 30 MeV.
Pair Production
Above 1.022 MeV, photons can interact in the presence of a strong
nuclear field. The photon will disappear and spontaneously become
an electron-positron pair (Fig. 27-1). The electron and positron will
divide the initial photon energy between them to create their mass
and kinetic energy. These particles will lose their energy as they
interact with the surrounding materials. Upon losing all their energy,
the electrons will be absorbed into an atom. The positron, on the
other hand, will annihilate by interacting with a local electron, creating two 511 keV photons. (This annihilation reaction is what is
detected during positron emission tomography scanning.) Pair production is the dominant atomic interaction in tissue for photons
above 30 MeV and therefore has only a minor effect in radiation
therapy, where energies are significantly lower.
Photodisintegration
Above a threshold energy, a photon can be absorbed into an atomic
nucleus and cause one of the nucleons (a proton or a neutron) to be
ejected. This process is called photodisintegration. Photodisintegration is more probable in high-Z materials (such as metals), and thus
e: Fast
electron
Scattered
photon
Incident photon
Photoelectric effect
e:
Incident photon
e:
Photoelectric Effect
Photons having sufficient energy to ionize an atomic electron can
undergo the photoelectric effect (Fig. 27-1). In this process, the
photon energy is entirely absorbed. Some energy is lost to breaking
the electron binding energy, and the rest is carried away as kinetic
energy of the ejected electron. The probability of a photoelectric
interaction scales with the cube of the atomic number (Z) and the
inverse cube of the photon energy (E), making the photoelectric effect
very sensitive to material type and much more prevalent for lower
photon energies. The photoelectric effect is the dominant photon
interaction in tissue below 30 keV.
e:
e:
Coherent Scatter
Low-energy photons can be briefly absorbed by the bound electrons
of an atom. If the photon lacks the energy to remove the electron
from the atom, the photon energy will be immediately reemitted as
another photon. The reemitted photon has the same energy as the
incident photon, and close to the same direction of travel. Because
no energy is deposited, coherent scattering does not contribute to
dose deposition, but the small deflections of the photons from coherent scatter can cause blurring in diagnostic images. Coherent scattering accounts for approximately 10% of interactions at 30 keV and is
negligible for most therapeutic energy beams.
p;np;
np; n
np;
np; n
e:
Vacancy in k-shell
e: Fast
electron
p;np;
np; n
np;
np; n
e:
e:
Characteristic x-rays
Pair production
e:
Incident photon
e:
e:
e:
p;np;
np; n
p; np;
np; n
e:
e: Positron
e; electron
pair
e:
Figure 27-1 • Photons interact with atoms through three major mecha-
nisms. Low-energy photons interact through the photoelectric effect, in
which photons are absorbed by an atom, which then ejects an energetic
electron. Higher energy photons undergo Compton scattering, in which both
the photon and an electron are scattered from an atom. At higher energies,
photons can interact with the field around the nucleus and undergo pair
production, in which the photon spontaneously converts into an electronpositron pair.
is more likely to happen during photon generation in a linear particle
accelerator (linac) than in tissue. Neutrons produced in this manner
can contribute a significant background radiation dose to patients
receiving radiotherapy from very high energy machines. However,
photodisintegration is negligible for accelerators operating below
10 MV.
Charged Particle Interactions
Charged particles will lose and transfer their energy to a medium
through two mechanisms: collision and radiation. Collision energy
loss by an energetic charged particle refers to the energy transfer
resulting in ionization, excitation, and molecular damage. In a collision event, energy is absorbed in the medium at or very near the site
of the interaction. Collision energy loss accounts for more than 95%
of energy loss in tissue for therapeutic-energy electrons and is the
major source of absorbed dose along the path of the electrons. Radiative energy loss occurs when particles are accelerated in the electric
field of a nucleus and emit a fraction of their energy as a photon.
This process, called bremsstrahlung, is relatively unimportant in
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Part I: Science of Clinical Oncology
tissue but is fundamental to the production of therapeutic photons
in a linac.
Most electromagnetic interactions result from an interplay
between photons and electrons, because many photon interactions
result in atomic ionization and release of an energetic electron, with
some of the electron energy converted back into photons through the
bremsstrahlung process. Thus the effects of therapeutic beams passing
through tissue can be described as a photon-electron shower, with the
highly penetrating photons carrying energy deeper into tissue until
a scattering event occurs, and the resulting scattered electrons de­­
positing most of the resulting energy locally through collisional
interactions.
The Generation of Therapeutic Radiation
To be useful in radiation therapy, radiation must be generated in a
manner in which it can be directed at the targeted tissues. Radiation
for cancer therapy is predominantly generated through two means:
linacs and radioactive sources.
Linear Accelerators
The most common modality used in radiation oncology is external
beam radiation therapy. Although a small number of radiation
therapy facilities generate external beams using radioactive sources
such as cobalt-60, the vast majority of therapeutic electromagnetic
radiation is generated in a linac. A linac is a device that accelerates
charged particles (electrons) to velocities near the speed of light using
oscillating electric fields to push the electrons through a series of
accelerating cavities. A schematic of a linac is shown in Figure 27-2,
A. Electrons are accelerated to energies typically between 4 and 18
MeV. Electric and magnetic fields focus and steer the high-energy
electrons such that they strike a thin metal target that stops the electron beam, with some fraction of the electron energy converted to a
spray of photons through the bremsstrahlung process. The bremsstrahlung photons, called x-rays, move approximately in the same
direction as the electrons and have an energy spectrum, ranging from
a few 10’s of keV up to the maximum energy of the initial electrons.
The resulting photon beam then passes through a series of filters and
beam-shaping elements that flatten and define the edges of the beam.
The dose from a photon beam is related to its intensity, defined
as the number of photons per unit area. Two major effects serve to
decrease the intensity of a photon beam as it passes through tissue.
First, as with any photon source, the beam intensity decreases with
increasing distance from the source, just as is the case for a light bulb.
In addition, beam intensity decreases as photons are attenuated from
the beam via various scattering and absorption effects. This process
leads to a characteristic decrease in intensity versus depth that varies
based on photon energy. Although the photon intensity begins
decreasing immediately upon entering a material, the energy released
through the photon interactions is spread over a few centimeters as
the electrons scattered by the photons gradually lose their energy as
they pass through the material. The resulting dose distribution is
characterized by a region of rapid increase near the surface, a leveling
off of dose at a depth of 1 to 3 cm, and a gradual dose falloff as depth
increases. The plot of dose versus depth is called a percent depth dose
curve, as shown in Figure 27-3. Because higher energy photons are
more penetrating, higher energy beams will attenuate more slowly,
leading to a more gradual decrease in dose with depth.
Linacs designed to produce photon beams can also be configured
to produce therapeutic electron beams. Removing the photongenerating target and replacing it with a comparatively thinner electron scattering foil allows the transmission of the initial electron
beam, but not without scattering the initially narrow beam into a
broader distribution. Multiple filters and beam-shaping elements, as
shown in Figure 27-2, B, produce an even distribution of customized
shape at the surface of the patient. Electron beams lose their energy
through different types of interactions than photons, leading to a
different pattern of dose versus depth for electron beams. Rather than
periodically removing photons from the beam through attenuation,
electrons lose their energy gradually and at a relatively constant rate
until the entire kinetic energy of the electron is expended and the
particles simply stop. Ideally, this phenomenon would lead to a region
of constant dose with increasing depth until the depth of full energy
loss is reached, at which point the dose would drop abruptly to zero,
with the depth of the dose drop-off being dependent on the initial
electron energy. In practice, scattering and redirection of electrons
within the beam lead to a mildly peaked dose plateau region and a
somewhat more gradual dose falloff, as shown in Figure 27-3.
Electron beam
Electron beam
X-ray target
X-ray target
Primary collimator
Forward peaked
x-ray beam
Carousel
Flattening filter
Primary collimator
Scattering foil
Scattering foil
Flattening filter
Carousel
Ion chamber
Ion chamber
Secondary
collimator
Secondary
collimator
Slot for wedges,
blocks, compensators
Accessory
mount
Flattened
x-ray beam
Electron applicator
A
Patient
B
Patient
Figure 27-2 • Schematic of the treatment head of a modern linear accelerator operating in photon-production mode (A) or electron-production
mode (B).
Figure 27-3 • Dose deposited versus increasing
depth for photon beams (110 KV, cobalt-60, 6 MV
and 18 MV) and electron beams (6 MeV, 12 MeV, and
20 MeV).
100
90
80
70
60
50
40
30
20
10
0
18 MV
6 MV
60Co
12 MeV
6 MeV
0
Radioactive Sources
Unstable isotopes can spontaneously decay to lower energy states,
releasing energy in the process. This radioactive decay can result in
the emission of therapeutically useful photons, electrons, or other
decay products. The degree to which a sample is radioactive is called
its activity and is defined as a number of decays per unit time. The
activity of a sample depends both on how much of the isotope is
present and how quickly the isotope decays. The historic unit of
activity is the Curie (Ci), which is defined as 3.7 × 1010 atomic decays/
second, corresponding to the decay rate of 1 g of radium-226. Activity is also specified in Becquerel (Bq), defined as 1 decay/second.
Because the rate of disintegration is proportional to the number
of nuclei present, the absolute number of radioactive nuclei will decay
exponentially. Activity is proportional to the number of nuclei, and
thus a sample’s activity, and therefore its ability to deliver dose, will
decay with the same exponential behavior. The decay is described by
A(t) = Aoe−λt, where A is the current activity, Ao is the activity at time
zero, and λ is a decay constant for the isotope in question. The decay
rates for various isotopes are more commonly given as the time
required for half of the sample to decay away; this period is called
the half-life of the isotope.
Therapeutically useful isotopes vary in half-life and in energy of
emitted particles, as shown in Table 27-1. Isotopes emitting higher
energy particles can deliver significant amounts of dose farther from
the radioactive source than those emitting lower energy particles. One
type of radioactive source, 60Co, emits photons with an average
energy of 1.25 MeV, which is sufficiently similar to photon energies
found in linacs that 60Co can be used as an external source to treat
targets deep in a patient. Most other therapeutically useful radioactive
sources emit lower energy radiation with less penetrating power and
must be placed in close proximity to the area to be treated. Sources
are formed into small sealed seeds, typically 1 to 5 mm in size, and
can be inserted into the treatment area on a temporary or permanent
basis. The dose rate falls off very quickly with distance from a seed,
both because of rapid attenuation and the rapid spread of photons as
they move away from the source.
Delivery of Therapeutic Radiation
The cytotoxic properties of ionizing radiation provide an opportunity
for tumor control but also require that care be exercised to limit the
exposure of healthy tissue to radiation. For external beam radiation
therapy, linacs are typically mounted on rotating gantries (Fig. 27-4)
that allow beams to pass through the patient and the target from a
variety of directions. By placing the area to be treated at or near the
center of rotation, multiple beams can be made to overlap in the
region of the tumor, delivering a high dose to the overlap area and a
comparatively low dose to other areas. For treatment based on
implanted radioactive sources, a procedure known as brachytherapy,
proper dose delivery consists of designing and delivering a
5
10
20 MeV
Depth dose (%)
Depth dose (%)
Basics of Radiation Therapy • CHAPTER 27 397
100
80
60
40
20
0
0 2 4 6 8 10121416 18 20
Depth (mm)
110 KV
15
20
Depth (cm)
110 KV
6 MV
18 MV
25
30
Table 27-1 Therapeutically Useful Radioisotopes
Isotope
PHOTON
226
Ra
Half-Life Average
Energy (keV)
1620 y
830
137
30 y
662
198
2.7 d
412
192
73.8 d
370
125
60 d
28
Cs
Au
Ir
I
103
Pd
Isotope
BETA
16.97 d
21
Half-Life
Maximum Energy (keV)
32
14.3 d
1710
90
28.5 y/2.7 d
550/2280
188
69.4 d/17 h
350/2120
186
3.8 d
1070
P
Sr/90Y
W/188Re
Re
62
62
9.3 h/9.7 min
660/2930
133
Zn/ Cu
5.2 d
360
131
I
8.0 d
600
89
Sr
50.5 d
1495
26.8 h
1850
Xe
166
Ho
From Cox JD, Ang KK, editors. Radiation oncology: rationale, technique, results.
8th ed. St Louis: Mosby; 2003.
keV, Kiloelectron volt.
three-dimensional (3D) distribution of radioactive seeds within the
volume to be treated, creating a high-dose region that decreases
rapidly beyond the treatment volume. Both of the aforementioned
treatment modalities require a 3D understanding of the patient
anatomy and require:
1. precise location of the tumor within the patient anatomy;
2. customization of a treatment plan for an individual patient; and
3. reliable and reproducible positioning of the patient relative to the
radiation sources such that the intended radiation pattern can be
precisely delivered.
THE RADIOBIOLOGY OF RADIATION THERAPY
Mechanisms of Radiation Damage to Cells
As discussed previously, ionizing radiation (in the form of photons
or particles) deposits energy as it traverses the absorbing medium
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Part I: Science of Clinical Oncology
through which it passes, with the most salient feature of this interaction being the random and discrete nature of the energy deposition
events. Energy is deposited in increasingly energetic packets called
quanta, each of which leaves anywhere from a handful to several
dozen ionized atoms in its wake. Assuming the absorbing medium
is a biological system, a mammalian cell for example, any and all
biological molecules contained in that cell are potential targets for
these highly localized energy deposition events. Secondary particles
set in motion by the original ionization event can themselves go
on to produce additional damage. This chain reaction continues
until all the energy deposited by the incident photon or particle is
consumed.
The total amount of energy imparted to a cell during the passage
of ionizing radiation (expressed in units of dose, Gray, which in turn
is expressed in units of energy deposited, joules per kilogram) is by
itself insufficient to describe its biological consequences. For example,
1 Gy of x-rays and 1 Gy of neutrons deliver the same total energy to
Collimator (C)
Gantry (G)
C
G
Isocenter
T
Table (T) (patient support assembly)
Figure 27-4 • Layout for gantry-based radiotherapy machines. The
linear accelerator rotates around a single point called the isocenter. Patients
are placed on a movable table to align the area to be treated with isocenter.
(From Bourland JD. Radiation oncology physics. In: Gunderson LL, Tepper
JS, editors. Clinical radiation oncology. 3rd ed. Philadelphia: Saunders;
2012.)
a cell macroscopically speaking but do not produce equivalent biological effects because it is the microscopic pattern of that energy
deposition, the spacing or density of the discrete ionization events
along the track of the photon or particle, that is key to determining
biological effectiveness. In this example, the 1 Gy of neutrons is
much more potent biologically because the average energy deposited
locally along the length of each neutron’s track is higher than for
x-rays. This quantity of ionization density, typically expressed in units
of keV/µm, is termed the radiation’s LET. The concept of ionization
density is illustrated graphically in Figure 27-5 for radiations of differing LET, using a strand of DNA drawn to scale as a representative
“biomolecule.” Although most radiation therapy is performed using
low LET x-rays, γ-rays, or electrons, a few institutions do use high
LET neutrons or even higher LET heavy charged particles (heavy
ions), such as carbon ions, for treatment. Lower total doses of these
radiations are used to achieve tumor control in keeping with their
greater biological potency, and especially stringent limits are placed
on the amount of normal tissue incidentally irradiated out of justifiable concern for an increased frequency of complications. The use of
protons for radiotherapy is also gaining in popularity; protons behave
like other high LET particles in terms of their physical properties,
although somewhat surprisingly, they are only marginally more
potent biologically than x-rays or electrons.
Whether the ionization of a particular molecule results in a measurable biological effect depends on a number of factors, including
how important the molecule is to the continued survival and function
of the cell, how many copies of the molecule are normally present in
the cell, and to what extent and how the cell responds to the loss of
working copies. DNA is arguably the most important cellular macromolecule and one that is present only as a single, double-stranded
copy, and thus an energy deposition event occurring directly in DNA
certainly could affect a cell’s continued survival and functioning.
Accordingly, much attention has been focused historically on understanding radiation-induced DNA damage and its repair and the
consequences when that damage is either irreparable or “misrepaired.”
That said, many other molecules in the cell may be less crucial to
survival yet are much more abundant than DNA and therefore have
a much higher probability of being ionized. By far, the most abundant
molecule in the cell is water. Free radicals formed by the radiolysis of
water (the hydroxyl radical, •OH, in particular) are capable of adding
to the DNA damage resulting from direct energy absorption by
migrating to the DNA and damaging it indirectly, as illustrated in
Figure 27-6. This mechanism is referred to as “indirect radiation
action” to distinguish it from “direct radiation action”4 previously
described. Approximately 30% of the total DNA damage produced
by a given dose of x-rays is from the direct effect, and 70% is from
the indirect effect.4
Incident particle track
DNA
helix
“Spur”: 0–100 eV
10 nm
Short track: 500–5000 eV
“Blob”: 100–500 eV
Figure 27-5 • A charged particle track through an absorbing medium, illustrating the random and discrete energy-deposition events along the track.
Each event can be classified according to the amount of energy deposited locally, which determines how many ionized atoms will be produced. A segment of
a DNA double helix is shown approximately to scale. (From Zeman EM. Biologic basis of radiation oncology. In: Gunderson LL, Tepper JS, editors. Clinical
radiation oncology. 3rd ed. Philadelphia: Saunders; 2012.)
Basics of Radiation Therapy • CHAPTER 27 399
Direct
photon-DNA
interaction
H2O2
eaq
H2O
O•
Indirect
interaction
Figure 27-6 • DNA damage that occurs after radiation exposure is a
result of two types of ionization interactions. The “direct effect” occurs when
an incident photon deposits energy directly into the DNA, ionizing it. The
“indirect effect” occurs when water molecules are ionized and the reactive
species that are created damage DNA indirectly.
Complex macromolecules like DNA that have been ionized and
converted to free radicals undergo a series of chemical transmutations
in an attempt to rid themselves of unpaired electrons, many of which
involve the further breakage of chemical bonds. These broken bonds
can result in the modification or loss of a DNA base or an entire
nucleotide, a cross-linking of the two DNA strands, or a scission of
the sugar phosphate backbone involving either one or both strands.
Luckily, DNA is unique in that it is the only cellular macromolecule
with its own repair system, and most of this damage can be repaired
efficiently and typically with very high fidelity. Under certain circumstances, however, the cell’s attempts to repair these lesions may result
in large segments of DNA being lost, rearranged, exchanged, or
rejoined in inappropriate ways, so-called “misrepair.” In other cases,
repair is impossible because of the complex nature of the damage
itself, particularly when both DNA strands are involved (e.g., a DNA
double-stranded break), or its location in the genome in time and
space. It is this residual DNA damage that manifests itself as chromosome aberrations the next time the cell attempts to go through mitosis
and that usually leads to cell death. In fact, the radiation dose response
for the production of asymmetrical, exchange-type chromosome
aberrations mirrors the shape of the corresponding cell survival
curve.5
Historically, much of what radiobiologists learned (or inferred)
about DNA damage and repair, its time course, and its implications
for cell survival and radiotherapeutic response came at least two
decades before the complex molecular underpinnings and processes
involved in the different types of mammalian DNA repair were
elucidated.
We now know that several different DNA repair pathways exist
in mammalian cells, including single-step reactions that directly
reverse certain simple types of damage, single and multistep base
excision and resynthesis processes, and multistep pathways to “clean
up,” resynthesize, and ligate single or double-stranded breaks in the
DNA backbone.6 Which one (or more) of these repair pathways is
activated depends on a number of factors, including the type of lesion
produced, the physical location of the lesion in the genome (e.g., in
the coding region of a gene versus in apparently noncoding DNA),
the functional/temporal location of the lesion (i.e., in an actively
replicating or transcribing gene versus an inactive one), and, critically,
the overall repair competence of the cell in which the lesion was
created.7
For a more in-depth discussion of the molecular biology, biochemistry, and regulation of DNA repair, please refer to Chapter 10.
Many bacterial, yeast, rodent, and human genes involved in DNA
repair processes have been identified and cloned,8 with many of the
encoded proteins functioning as components of large repair complexes. Some of these proteins are interchangeable and participate in
different DNA repair and replication pathways, whereas others are
unique to specific types of repair. In fact, some are not directly
involved with repair per se but rather link DNA repair to other cellular functions, including damage sensing, cell cycle checkpoint
control, chromatin remodeling, and apoptosis.9 Inactivation or loss
of any of these myriad proteins can lead to dysfunction of the DNA
damage response, which in turn can precipitate diverse clinical syndromes of varying severity including immunodeficiency, neurodegenerative disorders, infertility, premature aging, hypersensitivity to
DNA damaging agents, and cancer proneness.10
It is of particular interest that most cancer cells harbor one or
more defects in the DNA damage response. Further, because different
DNA repair pathways can share common components and functions
under normal circumstances, and in some cases compensate for
defects in other pathways, it may be that the clinical strategy of DNA
repair inhibition will have a greater effect on the tumor than on
normal tissues.10 The approach of combining DNA repair inhibitors
with radiation to produce selective tumor radiosensitization is discussed further later in this chapter.
The Molecular Biology of Cellular
Radiation Responses
Much more has been learned about the radiation response of cells at
the molecular level since the molecular biology and biotechnology
revolutions beginning in the early 1980s. In fact, many of the radiobiological phenomena carefully characterized decades ago but necessarily couched in operational terms (e.g., clonogenic survival, sublethal
damage recovery, and the cell cycle age response) now have solid
molecular underpinnings. Of particular interest to radiation biologists
is the molecular basis of radiation sensitivity, the pertinent aspects of
which will be summarized here. An important ramification of our
ever-growing understanding of the molecular workings of cells is the
promise of being able to identify and target specific genes, proteins,
or pathways for therapeutic gain, such as to render tumors cells more
radiosensitive or normal cells more radioresistant.
A cell’s (normal or tumor) radiation response represents a complex
interplay between intrinsic properties and extrinsic factors imposed
by the cell’s microenvironment. Properties intrinsic to the cell include,
for example, its capacity to recognize and repair DNA damage, its
position in the cell cycle, and its response to being damaged, that is,
to either adapt and grow or to die. However, extrinsic, environmental
factors also can contribute to cellular radiosensitivity. Examples
include the availability of nutrients and oxygen, the ability to eliminate waste, and the presence or absence of cytokines, growth factors,
or other signaling molecules that instruct the cell how to respond to
its radiation injury.
Normal mammalian cells have in common key molecular signaling pathways that regulate growth, death, and differentiation, many
of which are activated in response to radiation exposure. Many of
these pathways also exist in tumor cells but are typically dysregulated—
that is to say, hyperactive or hypoactive—secondary to the activation
of oncogenes and/or the inactivation of tumor suppressor genes. Not
surprisingly, the activity (or lack thereof ) of these pathways can influence both cellular radiosensitivity and other radiation responses of
intact tissues.
The first activated oncogene identified to confer radiation resistance was NRAS (see references 11 and 12). Ras proteins, products
400
Part I: Science of Clinical Oncology
of RAS family member genes, are small guanosine triphosphatases
activated by upstream receptor tyrosine kinases. They transduce
signals to a complex downstream cascade of protein kinases that have
the net effect of promoting cell survival (for example, by the suppression of apoptotic cell death pathways) and unlimited proliferation
(secondary to, for example, the downregulation of antiproliferative
proteins), two of cancer’s hallmark phenotypes. When the ras protein
is mutated, however, as is the case in approximately 30% of all human
cancers, these pathways become overactive and no longer responsive
to the normal regulatory mechanisms that antagonize the ras pathway
and reign in excessive proliferation. This situation is exacerbated in
many tumors by the concurrent loss of function of tumor suppressor
proteins.
Ras became, accordingly, a desirable target for molecular cancer
drug development.13 The general approach to targeting ras focused
on its need for posttranslational modification through prenylation to
become activated.14 Despite encouraging preclinical results with a
class of prenylation-inhibiting agents known as farnesyl transferase
inhibitors—drugs that, when used alone or combined with radiation,
produced sensitization of tumor cells with constitutively active ras
pathways—these drugs did not meet expectations in clinical trials
because of alternative prenylation pathways.13
Subsequent drug development focused on inhibiting proteins
upstream of ras, in particular, members of the human epidermal
growth factor receptor (EGFR) family of receptor tyrosine kinases
that transduce growth signals through ras and other signaling proteins.15,16 These transmembrane glycoproteins are activated through
binding of ligands belonging to the EGF family of peptide growth
factors.
Cetuximab, a human-murine chimeric immunoglobulin G1
monoclonal antibody raised against the EGFR, is among the more
successful molecularly targeted drugs, yielding improved outcomes in
squamous cell head and neck cancers when combined with radiation
therapy.17 Details of its mechanism of action and clinical use are
discussed later in this chapter. Other classes of drugs that target
EGFR include the small molecule tyrosine kinase inhibitors gefitinib
and erlotinib, which inhibit EGFR phosphorylation and its downstream cascade by blocking the intracellular catalytic domain of the
receptor.18 These drugs have shown some efficacy in selected patients
with treatment-refractory, advanced non–small cell lung cancer
(NSCLC).19
A second molecular target of interest is vascular endothelial
growth factor (VEGF) and/or its cell surface receptor. VEGF is the
most potent of the proangiogenic endothelial cell proliferation stimulators and chemoattractants and plays a pivotal role in promoting
tumor survival by stimulating the growth of new blood vessels derived
from the host vasculature. This phenotype of sustained angiogenesis
is a hallmark property of cancer. Several isoforms of VEGF bind
to the corresponding receptors VEGFR1, VEGFR2, and VEGFR3
(encoded, respectively, by the genes FLT1, KDR, and FLT4).20
Bevacizumab, a recombinant humanized monoclonal antibody, is
the first molecularly targeted antiangiogenic drug to gain approval
for clinical use by the U.S. Food and Drug Administration. This
antibody binds to VEGF, with the net effect of eliminating signaling
to vascular endothelial cells to initiate angiogenesis.21,22 The clinical
use of bevacizumab in combination with radiation therapy is discussed later in this chapter.
Cell Survival and Tissue Dose-Response
Curves
Tumor control is achieved only when essentially all clonogenic cells
(the putative “tumor stem cells”) are killed or otherwise rendered
unable to sustain tumor growth indefinitely. To estimate the likelihood of cure, it is necessary to know, at least to a first approximation,
how radiosensitive or resistant these cells are—that is, some measure
of cell killing efficiency per unit radiation dose.
Death as a permanent, irreversible cessation of vital functions is
not the same as what constitutes “death” to the radiation biologist or
oncologist. For proliferating cells, including those maintained in vitro
and the stem cells of both normal tissues and tumors in vivo, cell
death in the radiobiological sense refers to a loss of reproductive
integrity or clonogenicity, that is, an inability to sustain proliferation
indefinitely. It is important to note that the term “clonogenic death,”
as first described more than 50 years ago, is operationally defined and
today serves as a catch-all term encompassing various mechanistic
ways that cells die, all of which culminate in a cell losing its ability
to divide indefinitely. These modes of cell death include mitotic
catastrophe (the most common form of cell death after radiation
exposure), apoptosis, autophagy, necrosis, senescence, and, strictly
speaking, differentiation as well, to the extent that differentiated cells
lose their ability to divide.23 Another noteworthy feature of clonogenic death is that it does not necessarily preclude the possibility that
a cell may remain physically intact, metabolically active, continue its
tissue-specific functions, and even divide a limited number of times
after irradiation.
The first report of a quantitative measure of intrinsic radiosensitivity for a human cell line (HeLa, derived from a cervical carcinoma)
was published by Puck and Marcus in 1956.24 For different doses of
x-rays, the reproductive integrity of HeLa cells was measured by their
ability to form macroscopic colonies of at least 50 cells (corresponding to approximately six successful postirradiation cell divisions) on
Petri dishes. The HeLa cell survival curve, in which the log of the
surviving fraction of cells was plotted as a function of the radiation
dose, was characterized by a roughly exponential dose response at
intermediate to high doses and a bending, “shoulder” region at low
doses where cell killing was less effective. This phenomenon is illustrated graphically in the upper panel of Figure 27-7. Radiation survival curves for hundreds of cell types derived from mammalian
tumors and normal tissues have been generated in the years since the
pioneering work of Puck and Marcus,24 and most are qualitatively
similar to the original HeLa survival curve (see lower panel of
Fig. 27-7).
Mathematical models were developed to fit the cell survival data,
with survival curve theory originating in a consideration of the
physics of energy deposition in matter by ionizing radiation. An
assumption inherent to target theory was that a biological response
(cell killing in this case) resulted from critical “targets” receiving
random “hits”25 in a probabilistic manner. Further, for cell survival
curves with shoulders, each target was envisioned as requiring more
than one hit to elicit the response, that is, that “sublethal” damage
had to accumulate first before the cell would be killed. One mathematical expression derived from target theory that provided a fairly
good fit to survival data was:
S = 1 − (1 − e − D/D0 )n
In this equation, S is the fraction of cells that survive a given
dose (D), D0 is the dose increment that reduces the cell surviving
fraction to 37% (1/e) of some initial value on the exponential
portion of the curve, and n, the extrapolation number, is the back
extrapolation of the exponential portion of the survival curve to
zero dose.
Over time, it became apparent that some features of this model
were inadequate,26 not the least of which was that its basis was the
probabilistic nature of energy deposition in matter by ionizing radiation and not anything biologically based. For example, target theory
was not concerned per se with which biomolecules in the cell were
the purported “targets” of radiation damage, what the nature of the
damage was in a molecular sense, or how the cell responded to it.
(Of course, it was not lost on radiation biologists of the day that at
least one cellular target was likely to be the DNA contained in
chromosomes.24)
A different and more biology-based interpretation of the dose
response for radiation-induced cell killing was proposed by both
Basics of Radiation Therapy • CHAPTER 27 401
Y=
Surviving fraction
100
αD
+
βD2
e–
10:1
e–
10:2
e–
10:3
0
200
A
400 600 800 1000 1200
Exposure (R)
+
Surviving fraction
100
10:1
10:2
10:3
0
B
200
400 600 800 1000 1200
Dose (cGy)
Hewitt and Wilson: CBA mouse leukemia
Puck and Marcus: human carcinoma
McCulloch and Till: mouse bone marrow
Mutants (e.g., A-T)
Figure 27-7 • X-ray or γ-ray acute-dose radiation survival curves for
mammalian cells. A, The first such survival curve (for HeLa cells, obtained
from a patient with cervical adenocarcinoma) was published in 1956 by Puck
and Marcus.24 (Note that the dose is expressed in Roentgens (R), which for
cells x-irradiated while adherent to glass Petri dishes, must be multiplied by
approximately 1.4 to obtain the dose in cGy.) B, A family of survival curves
for other types of mammalian cells. The dashed lines encompass the radiosensitivity range for wild-type cells, whereas the steepest curves show the
range more typical of hypersensitive mutants, such as cells from patients with
the disease ataxia-telangiectasia.
Kellerer and Rossi27 and Chadwick and Leenhouts.28 The linearquadratic (LQ) or “alpha-beta” equation,
2
S = e − ( αD + β D )
was shown to fit cell survival data quite well, particularly in the
low-dose region of the curve where the target theory model often
failed.26 In this expression, S is again the fractional cell survival
following a dose (D), α is the rate of cell kill by a single-hit process,
and β is the rate of cell kill by a two-hit mechanism. Implicit in
the LQ model was that (borrowing the language of target theory
for comparative purposes only) DNA (or a chromosome) was the
target, and the hits corresponded to irreparable or misrepaired lesions
produced by either one or two radiation tracks traversing the cell
nucleus (Fig. 27-8).
A comparison of the features and parameters of the target theory
and LQ survival curve models is shown in Figure 27-9.
To bridge the gap between the radiation responses of single cells
grown in culture and tissues or tumors in a laboratory animal or
human patient, several ingenious methods were developed to measure,
or at least estimate, the radiation sensitivity of intact normal tissues
Figure 27-8 • Chromosome aberration production can be modeled
using the relationship Y = αD + βD2, where Y is the average chromosome
aberration yield per cell and D is the dose delivered. The single-track αD
component is shown on the left, where a single electron track is envisioned
as producing a break in each of two different chromosomes, which, if rejoined
incorrectly, produce a dicentric chromosome and an acentric fragment. These
exchange-type chromosome aberrations can also be formed as a consequence
of two different electron tracks, which accounts for the βD2 component, as
shown on the right. (From Wilson PF, Bedford JS. Radiobiologic principles.
In: Hoppe RT, Phillips TS, Roach M, editors. Leibel and Phillips textbook
of radiation oncology. 3rd ed. Philadelphia: Saunders; 2010.)
and tumors in vivo.29-31 Some of these assays used the reproductive
integrity of cells as an end point, similar in principle to the in vitro
survival curve assay, but in which the animal essentially served as its
own Petri dish. One classic example of an in vivo clonogenic assay is
the spleen colony assay of Till and McCulloch,30 which originally was
developed as a model system for the study of bone marrow transplantation. These authors determined that lethally irradiated mice could
be “rescued” by a bone marrow transplant and that the transplanted,
viable bone marrow stem cells were noted to form discrete nodules
or colonies in the spleens of irradiated animals. By extension, then,
a mouse’s spleen could be used as a pseudo Petri dish, with the
number of clonogenic bone marrow colonies countable as a function
of the radiation dose that the donated bone marrow received prior
to transplantation. Assays such as this showed that the radiosensitivity
of individual cells (tumor cells or normal cells) was largely unchanged
whether the cells were irradiated in relative isolation in Petri dishes
or as parts of a more complex tissue containing many different,
interacting cell types in 3D contact.
Unfortunately, in vivo clonogenic assays necessarily involved the
sacrifice of the animal and thus obviously are not applicable for clinical use. Further, such assays are labor intensive and involve long
waiting periods before results are obtained, adding to their impracticality. A second type of in vivo radiosensitivity assay is nonclonogenic,
using a tissue structural or functional end point as a surrogate for cell
survival. Data derived from nonclonogenic assays and plotted as a
function of radiation dose are properly called dose-response curves
rather than cell-survival curves, because cell survival is not the end
point being assessed. Regardless, cell-survival curves and doseresponse curves are often analyzed and interpreted similarly; for
example, a mathematical model is commonly used to fit the data and
survival curve parameters are calculated.
Two examples of nonclonogenic assays, one for normal tissues and
one for tumors, are worth mentioning, especially because aspects of
both are used routinely in the clinic, if not in the exact same way as
the laboratory assay. One of the first nonclonogenic methods developed to assess normal tissue radioresponse was the skin reaction
Part I: Science of Clinical Oncology
S=1– (1–e-D/D0)n
n
Dq
Surviving fraction
0.01
Surviving fraction
α Cell kill
1/e
0.0037
β Cell kill
S=e – (αD + βD2)
D0
α/β ratio
A
Dose (Gy)
B
Dose (Gy)
Figure 27-9 • Comparison of two mathematical models commonly used to fit cell survival curve data. A, The single-hit, multitarget model is shown
with its associated parameters, D0, n, and Dq. B, The linear-quadratic model and its associated parameters, α and β. This model also forms the basis for
current isoeffect formulas used in radiation therapy treatment planning. (From Zeman EM. Biologic basis of radiation oncology. In: Gunderson LL, Tepper
JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saunders; 2012.)
assay.32 (Pigs were used in the original studies because their skin is
similar to that of humans in several key respects, although rodents
have also been used.) An ordinate scoring system was used to quantify
the severity of the skin reaction; for example, a skin score of “1” might
correspond to mild erythema, whereas a score of “4” might correspond to confluent moist desquamation over more than half of the
irradiated area. Then, when comparing different time, dose, and
fractionation schedules, any combination that resulted in the same
skin reaction score was assumed to correspond to an equivalent
amount of cell killing. In this way, and by collecting information for
different severities of skin reactions, a dose-response curve could be
generated. A common nonclonogenic assay of tumor response to
radiotherapy is the regrowth delay assay.33 In this assay, the tumor’s
dimensions (or volume) are measured periodically as a function of
time after irradiation, with the degree of tumor shrinkage assumed
to be a reflection of the fraction of clonogenic tumor cells killed.
Dose-response curves are generated by plotting the amount of growth
delay (in days) as a function of radiation dose.
Modifiers of Radiation Sensitivity
As discussed previously, factors both intrinsic and extrinsic to the cell
can alter its radiosensitivity. In addition to the intrinsic, genetic
determinants of radiation sensitivity, other physical and chemical
modifiers can also play important roles. The type of radiation used
for treatment can be considered a physical modifier of radiosensitivity
to the extent that high LET types of radiation (e.g., neutrons and
heavy ions) are more biologically effective for a given unit of dose
than low LET types (e.g., x-rays and electrons). Representative doseresponse curves for radiations with different LETs are shown in Figure
27-10. In light of these differences in biological potency, the term
relative biological effectiveness (RBE) has been coined to compare and
contrast two radiation beams of different LET. RBE is defined as the
ratio of doses of a known type of low LET radiation (historically,
250 kVp x-rays were the standard, but others can also be used) to
that of a higher LET radiation to yield the same biological end point.
RBE is highly variable and depends on several irradiation parameters,
100
Surviving fraction
402
10–1
10–2
10–3
0
2
4
6
8
10
12
14
Dose (Gy)
High LET (alpha particles)
Intermediate LET (15 MeV neutrons)
Low LET (250 kvp x-rays)
Figure 27-10 • Dose response curves for radiations of differing linear
energy transfer (LET). The relative biological effectiveness (RBE) of neutrons
or alpha particles relative to that of x-rays is defined as the ratio of doses
(x-rays/neutrons) to yield the same biological effect. (From Wilson PF,
Bedford JS. Radiobiologic principles. In: Hoppe RT, Phillips TS, Roach M,
editors. Leibel and Phillips textbook of radiation oncology, 3rd ed. Philadelphia: Elsevier-Saunders; 2010.)
including the type of radiation, total dose, dose rate, dose fractionation pattern, and the biological effect being assessed. An example of
how RBE values are obtained from cell survival curves is shown in
Figure 27-11.
Chemical modifiers of radiation response are also important, and
perhaps the “chemical” of greatest significance in this regard is molecular oxygen, a potent radiosensitizer. Mechanistically speaking, the
Basics of Radiation Therapy • CHAPTER 27 403
1.0
100
10–1
RBE0.05~3.6
10–2
Neutrons
Surviving fraction
Surviving fraction
OER=2 at
doses below 2 Gy
RBE0.5~5.6
X-rays
10–3
RBE0.0005~2.8
10–4
0.1
OER=3 at
large doses
10–5
0
2
4
6
8
10
12
14
Dose (Gy)
Figure 27-11 • Representative cell survival curves for x-rays and neu-
trons, illustrating the increase in relative biological effectiveness (RBE) with
decreasing dose. This phenomenon occurs because higher linear energy transfer (LET) radiations preferentially decrease or eliminate the shoulder on cell
survival curves. (From Zeman EM. Biologic basis of radiation oncology.
In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology. 3rd ed.
Philadelphia: Saunders; 2012.)
reason that well-oxygenated cells are more sensitive to radiation than
cells relatively lacking in oxygen is that oxygen readily participates in
the free radical reactions that occur in the micro- to milliseconds after
irradiation and has the net effect of enhancing the radiation damage
to cellular macromolecules. Poorly oxygenated cells experience less
enhancement of radiation injury and are therefore more radiation
resistant. This phenomenon is termed the oxygen effect. The relative
resistance of poorly oxygenated cells compared with well-oxygenated
ones can be expressed in terms of an oxygen enhancement ratio
(OER). The OER is the ratio of doses to produce the same biological
effect under low versus normal conditions of oxygenation. The OER
typically ranges between 2.5 and 3.0 for large single doses of x-rays
or γ-rays and 1.5 to 2.0 when multiple small dose fractions are used.34
Further, the oxygen effect is reduced or eliminated as the LET of the
type of radiation increases; OERs of 1.5 to 2.0 are obtained for radiations of intermediate LET, and an OER of 1.0 (i.e., no oxygen effect)
is obtained for high LET radiations. Representative radiation survival
curves generated in the presence or relative absence of oxygen are
shown in Figure 27-12.
Hypoxic cell radiosensitizers, exogenous chemicals that mimic the
radiation damage–enhancing effects of oxygen, have been used clinically in an attempt to combat the relative radiation resistance of
tumors that contain a clonogenic fraction of poorly oxygenated,
hypoxic cells. A second approach to the problem posed by tumor
hypoxia is to combine radiotherapy with a drug that, rather than
sensitizing hypoxic cells, kills them outright. These drugs are called
“bioreductive” because their toxic effects only occur secondary to the
reductive metabolism common in cells relatively lacking in oxygen.35,36
These drugs are discussed further later in this chapter.
With few exceptions, clinical trials over several decades involving
such hypoxia-directed therapies have been unsuccessful, in no small
part because there was no way to preselect patients whose tumors
contained sizeable hypoxic fractions and therefore might be expected
to reap the most benefit from the use of a hypoxic cell radiosensitizer.
In fact, there was no way to directly measure hypoxia in human
tumors at all until the late 1980s.
One of the first studies demonstrating an association between
directly measured oxygen tension in tumors and clinical outcome
was published in 1988 by Gatenby et al.37 An oxygen-sensing electrode was inserted into patients’ tumors (advanced squamous cell
0.01
0
2
4
6
8
10 12 14 16 18 20 22 24
Dose (Gy)
Figure 27-12 • For x-rays, cells irradiated in the presence of oxygen are
more radiosensitive than cells that are maintained under hypoxic conditions
(where the partial pressure of oxygen is greater than zero but less than about
10 mm Hg). The ratio of doses that produce the same level of biological
damage in the absence of oxygen versus the presence of oxygen is known as
the oxygen enhancement ratio (OER). At high doses, the OER has a value
of approximately 3.0; however, its value is close to 2.0 for doses (or doses per
fraction) below about 2 Gy.
carcinomas of the head and neck), and multiple readings of partial
pressure of O2 were taken at different depths along the probe’s track;
the arithmetic mean pO2 value for each tumor positively correlated
with local control rate, as did the tumor volume–weighted pO2 value.
A high tumor oxygen tension was associated with a high complete
response rate and vice versa. Several years later, comparable oxygen
electrode results for uterine cervix cancers were obtained by Höckel
et al.38 They made the important discovery that tumor hypoxia was
a negative prognostic indicator in general, regardless of whether the
patient had received radiation therapy, suggesting that radiation resistance was only one aspect of the hypoxia problem. A large metaanalysis of the relationship between tumor oxygenation status
measured with oxygen electrodes and clinical outcome was published
more recently for advanced head and neck tumors,39 with comparable
findings of improved overall survival in patients whose tumors were
less hypoxic.
Another method of directly identifying and quantifying hypoxic
cells in tumors is through the use of “hypoxia markers.” Both exogenous and endogenous markers for tumor hypoxia are available and
can be studied in relation to each other, the tumor vasculature, or
other “markable” features of the tumor microenvironment (e.g., the
proliferation status of tumor cells). Exogenous markers consist
of injectable drugs or chemicals that are bioreducible only under
hypoxic conditions, causing them to bind to cellular proteins. These
bound metabolites can be marked radioactively or with antibodies
and can be visualized using several different techniques, such as
autoradiography40 or fluorescence immunohistochemistry.41 Two
exogenous markers studied extensively in both preclinical cell and
animal systems, as well as in human patients, are pimonidazole hydrochloride42,43 and EF-5.44 Both are of the chemical class known as
nitroimidazoles that were originally studied as possible radiosensitizers of hypoxic cells (e.g., see references 45 and 46, as well as the
discussion later in this chapter) but were serendipitously found
to also have the property of bioreduction and binding to cellular
macromolecules under hypoxic conditions. This facilitated their
use as hypoxia markers. Endogenous markers, on the other hand,
consist of genes and proteins that are upregulated as part of the
404
Part I: Science of Clinical Oncology
cellular stress/adaptive response to hypoxic conditions and whose
expression levels can, with caveats, be used as surrogates for tissue
oxygenation status.47,48 Commonly studied endogenous hypoxia
markers include the hypoxia-inducible factor 1–alpha (HIF-1α, a
transcription factor),48 the enzyme carbonic anhydrase IX (CA-9 or
CAIX),49 glucose transporter–1 (GLUT1),50-52 and osteopontin.53
Figure 27-13 illustrates the potential of deriving “geographic”
information about the extent and location of hypoxia in six different
human tumors, using the exogenous marker pimonidazole hydrochloride. Simultaneously marking other tumor features, the location
of blood vessels and proliferating cells in these examples, provides
additional information about the tumor microenvironment.
CLINICAL RADIATION ONCOLOGY
Therapeutic Ratio
The use of radiation therapy is heavily dependent on the concept of
the therapeutic ratio. Given a high enough dose, virtually any cancer
will be destroyed with radiation therapy. Increasing the dose of radiation increases the likelihood of tumor control within the radiation
therapy field. However, if an excessive dose of radiation therapy is
delivered, it will produce an unacceptably high rate of normal tissue
complications. The likelihood of a complication increases as the
radiation dose increases and as the volume of normal tissue irradiated
A
B
C
D
N
E
F
Figure 27-13 • Microscopic images of tissue sections from six different squamous cell carcinomas of the head and neck (A-F), immunofluorescently
labeled with markers for tumor blood vessels (red, anti-PAL-E capillary endothelial cell marker), tumor cell proliferation (blue, anti-iododeoxyuridine marker
only incorporated by cells in the S phase of the cell cycle), and hypoxia (green, antipimonidazole marker only metabolized by cells under hypoxic conditions).
Differences are evident between the tumors in terms of the amount, intensity, and pattern of staining with the hypoxia marker and its location relative to
proliferating cells, regions of necrosis (N), and blood vessels. (From Wijffels K, Marres HAM, Peters JPW, et al. Tumor cell proliferation under hypoxic conditions in human head and neck squamous cell carcinomas. Oral Oncol 2004;44:335–44.)
Basics of Radiation Therapy • CHAPTER 27 405
The Biology of Fractionation
Response (%)
100
Tumor
Normal tissue
0
Radiation dose (Gy)
Figure 27-14 • Graphical illustration of the concept of therapeutic
ratio, which describes the relationship between the normal tissue tolerance
and tumor control dose-response curves. In this example, very good tumor
control can be achieved for total dose D (corresponding to the vertical dotted
line); however, that same dose produces an unacceptably high normal tissue
complication rate. Optimizing this therapeutic ratio as much as possible
through manipulation of the radiation physics and/or radiobiology for each
patient being treated with curative intent is the major goal of radiation
therapy. (From Horsman MR, Lindegaard JC, Grau C, et al. Dose-response
modifiers in radiation therapy. In: Gunderson LL, Tepper JS, editors. Clinical
radiation oncology, 3rd ed. Philadelphia: Saunders; 2012.)
increases. The technical aspects of radiation therapy are designed to
deliver the radiation therapy so as to avoid or minimize the amount
of radiation delivered to selected normal tissues while maximizing the
dose of radiation to the tumor. The biological discussion is all directed
to developing means to produce a differential effect between the cell
killing in the tumor and that in the normal tissues.
The concept of therapeutic ratio reflects the ability to estimate the
likelihood of complication and tumor control in a given situation.
At a given dose, these probabilities can be estimated (although usually
not very accurately in clinical practice). Advances in radiation oncology can be made by moving the normal tissue complication curve to
the right (as illustrated in Figure 27-14) so as to produce fewer complications at the same radiation dose, or by moving the tumor control
curve to the left, so that less physical dose is needed to control the
tumor (while also producing fewer complications).
Historically we have made much progress in moving the normal
tissue complication curve to the right by improving radiation delivery
techniques and taking advantage of the biology associated with dose
fractionation. The use of modern radiation therapy techniques
(described later in this chapter), along with improved imaging to
enhance tumor localization, has made a major difference in decreasing the morbidity of therapy while improving tumor control. The
ability to move the tumor control curve to the left can be accomplished primarily by the use of radiation-sensitizing compounds that
are given concurrently with radiation therapy or by altering fractionation. Although a huge amount of effort has been expended in this
area, the major sensitizers that have been effective are chemotherapeutic drugs that have both a radiation-sensitizing ability and an
independent cytotoxic effect on the tumor. Examples include drugs
such as 5-fluorouracil, cisplatinum, and mitomycin C that are used
to treat, among others, head and neck squamous cell carcinomas,
uterine cervix cancers, and multiple gastrointestinal (GI) tumors.
Although great interest has been expressed in using biological agents
as radiation sensitizers, with the exception of the EGFR inhibitor
cetuximab (discussed earlier), these approaches have not made their
way into standard clinical practice.
In the earliest days of radiotherapy, around the turn of the twentieth
century, both x-rays (generated by applying an electric current across
an x-ray tube1) and radium (a naturally occurring radioactive
element2,3) were used for cancer treatment. Because of the greater
availability and radiation output of x-ray tubes, delivering one or a
few large single doses in short treatment times was convenient and
efficient. This “massive dose technique”54 was a common way of
administering radiation therapy from about 1900 through the 1920s.
Unfortunately, normal tissue complications were severe, and to make
matters worse, the rates of local tumor control were poor.
Meanwhile, radium therapy was used more extensively in France.
Because of the low activity sources available, radium applications
involved longer overall treatment times to reach comparable total
doses as used in x-ray therapy. Although extended treatment times
were less convenient, clinical results were frequently superior. Perceiving that the lengthening of the overall time was the critical factor and
armed with animal experiments convincingly demonstrating the
superiority of longer treatment times,55 French physicians began to
experiment with the use of multiple, smaller x-ray doses delivered
over extended periods in human patients.56 Clinical outcomes were
improved to such an extent that fractionated radiation therapy using
many small dose increments spread over several weeks’ time became
the standard of care and has largely remained so to the present day.
Therapy using radioactive sources (such as the aforementioned
radium therapy pioneered by the French) also has continued to the
present day, evolving into today’s practice of brachytherapy using
both high and low activity radioactive sources capable of delivering
a range of dose rates.
What was lacking in these early days of radiotherapy, however,
and arguably for decades thereafter, was a biological basis for doserate/dose-fractionation effects. Radiobiologists studied dose-rate
effects extensively in the laboratory in an attempt to better elucidate
the biological factors involved in radiotherapy response; however, the
clinical community was often unaware of these laboratory studies.
This lack of cross talk between biologists and clinicians began to
change with the publication in 1975 of a seminal book chapter
entitled The Four R’s of Radiotherapy.57 The chapter was an attempt
to explain the biological basis of fractionation by describing in simple
terms the key radiobiological phenomena thought to affect the
outcome of fractionated radiotherapy: Repair, Repopulation, Reoxygenation, and Redistribution.
Repair
The tenets of target theory suggested that the shoulder region of the
radiation survival curve indicated that “hits” had to accumulate prior
to cell killing. Elkind and Sutton58 sought to better characterize how
this damage accumulated and how the cell processed it. Even in the
absence of detailed information about DNA damage and repair at
that time—the structure of DNA had only been elucidated a few
years earlier—a few facts could be gleaned. First, the hits that were
part of the damage accumulation process, yet did not in and of
themselves produce cell killing, were, by definition, sublethal. Further,
this sublethal damage (SLD) only became lethal if and when it interacted with additional SLD. Elkind and Sutton conducted experiments that deliberately interfered with the damage accumulation
process by delivering part of the intended radiation dose, inserting a
radiation-free interval, and then delivering the remainder of the dose
in what was called a “split-dose” experiment.
The overall surviving fraction of cells after a moderate to high
radiation dose was higher if that dose was split into two fractions
with a time interval in between than if it was delivered as a single
dose. This phenomenon is illustrated graphically in the right panel
of Figure 27-15. This finding suggested that the cells that survived
the initial dose fraction had “repaired” some of the damage during
the radiation-free interval. Therefore this damage was no longer
Part I: Science of Clinical Oncology
1
D/2
Surviving fraction
406
D
Proliferation
0.1
D/2-+-D/2
0.01
Reassortment
in fastcycling cells
Single dose
Split dose
Repair SLD
Dose
A
0
B
2 4 6 8 10 12
Time between split doses
Cell
cycle
Figure 27-15 • Sublethal damage repair or recovery (SLDR) is operationally defined as the increase in cell survival observed when delivering part (D/2)
of an intended total dose (D), inserting a radiation-free interval, and then delivering the remainder of the dose, compared with delivering D as a single fraction. A, The shoulder of the radiation survival curve is regenerated during the radiation-free interval between the first and second D/2 doses. B, SLDR
demonstrated in a plot of surviving fraction after the total dose, D, as a function of the time between the two dose fractions, D/2. Most SLDR occurs within
the first two hours of the “split” time. If the cell population is not proliferating, there is no further increase in cell survival with increasing time. If the cells
are proliferating rapidly, cell cycle redistribution or reassortment can occur, leading the SLDR curve to appear to oscillate. If the time between the two dose
fractions is very long, a proliferating cell population would be constantly increasing its numbers, making it appear that more repair was occurring.
available to interact with the damage inflicted by the second dose
fraction, and thus a higher cell-surviving fraction resulted. Had the
total dose been delivered as a single fraction, more damage in total
would have accumulated, some SLD would have been converted to
lethal damage, and the cell-surviving fraction would have been lower.
The results of split-dose experiments turned out to be crucial to the
understanding of why and how fractionated radiation therapy works
the way it does, that is, that fractionation/protraction of a total radiation
dose reduces its toxicity, in large part because of SLD repair. This
phenomenon is termed the dose-fractionation or dose-rate effect, and
it occurs after low LET radiation exposure in an undiminished
manner regardless of the number of dose fractions.
When considering complete cell survival curves, SLD repair
manifests itself as a return of the low-dose, shoulder region of the
radiation survival curve. After an initial radiation dose and an adequate time interval for repair to occur, the response of surviving cells
to graded additional doses is nearly identical to that obtained from
cells without previous radiation exposure (illustrated in the left panel
of Fig. 27-15).
Bedford and Hall59,60 generated in vitro survival curves for HeLa
cells irradiated at various dose rates and found that the killing effectiveness per unit dose decreased as the dose rate decreased, to a point.
A limit to this dose rate effect was reached; that is, further lowering
of the dose rate did not produce a further decrease in toxicity. This
finding is consistent with the idea that survival curves have negative
initial slopes, as described by the “αD” component of the LQ survival
curve equation. A further implication is that small differences in
initial slopes of survival or dose-response curves for different tissues
could be magnified into large differences when many small dose fractions or continuous low dose rates were used.
Repopulation
The sparing effects of fractionated external beam and brachytherapy
are largely attributed to the repair of SLD; however, other factors can
be involved as well. Repopulation is defined as a compensatory
increase in cell proliferation in tissues in response to an injury that
results in a large amount of cell killing. Stem cells (known or suspected) of normal tissues and tumors can begin to proliferate during
and after a course of radiation therapy,61 although the mechanism(s)
the tissue uses to affect this process and the time it takes to commence
varies with the tissue. Some tissues, however, do not seem to be able
to mount a repopulation response, or at least, not a prompt or robust
one, presumably because they only possess very small numbers of
stem cells, if any.
Repopulation is desirable in normal tissues because it facilitates
the healing of common radiotherapy complications that can develop
during or soon after treatment (e.g., oral mucositis in patients receiving radiotherapy for head and neck cancer). Repopulation of tumor
cells, on the other hand, is quite undesirable because it has the net
effect of counteracting the toxicity of ongoing radiation therapy. After
radiation therapy is complete, repopulation also can lead to tumor
recurrence.
In intact tissues, it can sometimes be difficult to tease apart the
relative contributions of repair and repopulation to the overall dose
rate effect, although generally speaking, repair-related effects occur
over a time scale of hours to a day, whereas proliferative effects usually
do not come into play for days or weeks (or more) after the start of
radiotherapy. In normal tissues capable of mounting a proliferative
response, molecular signals associated with the radiation injury seemingly need to reach a certain threshold before the repopulation begins
in earnest, and for most tissues, this process takes a minimum of
a week, and more commonly, several weeks. Tissues that exhibit a
prompt and robust response to radiation injury (during or within a
couple of months of treatment) and begin to repopulate are called
“early responding,” and those that show a delayed proliferative
response (more than 6 to 9 months after irradiation), if any, are
referred to as “late responding.”
For tumors, especially carcinomas, the prevailing view (although
it is not without its detractors) is that compensatory repopulation
does not begin until approximately a month into the course of treatment.62 One clinical implication of this view is that overall treatment
times should be kept as short as practically possible, because
Basics of Radiation Therapy • CHAPTER 27 407
type and extent of hypoxia present in the tumor. Slower reoxygenation might be expected to occur in cases in which the type of hypoxia
is chronic, such as might occur in cells that are multiple cell diameters
away from vasculature and near or beyond the diffusion distance of
oxygen (approximately 70  µm34,44). Physiologically speaking, the
main ways that reoxygenation could occur under these circumstances
is for aerobic cells closer to vasculature to decrease their oxygen consumption, which would occur if such cells are killed in large numbers
by the radiation, or for the tumor mass as a whole to shrink in size,
which would have the net effect of bringing the chronically hypoxic
cells closer in to the existing vasculature. Some, although not all,
human tumors shrink at least somewhat during the course of radiotherapy. Conversely, in cases in which hypoxia is intermittent or
cyclic, reoxygenation could occur on the order of minutes to hours,
as has been noted for many experimental rodent tumors.69,70
treatment time much longer than a month would allow for more
tumor cell repopulation and therefore less treatment effectiveness.
Some clinical data (mostly culled from fractionation studies involving
treatment of head and neck cancers) suggest that up to a third
of a typical 1.8 to 2.0 Gy daily dose fraction is wasted as a result
of repopulation62 and that for each day of treatment beyond the
time that repopulation begins, as much as 1% of local tumor control
is lost.
Reoxygenation
Tumor blood vessels tend to be abnormal both structurally, functionally, and physiologically as a consequence of the dysregulated angiogenesis characteristic of tumors63,64 (see also Chapter 8). One
consequence is that tumors can develop microregions relatively
lacking in nutrients and oxygen. And although prolonged oxygen
deprivation, that is, anoxia, will eventually kill even the hardiest of
tumor cells, hypoxia—a state of very low tissue oxygenation on the
order of 0.5% oxygen or less (corresponding to a partial pressure of
oxygen of about 10 mm Hg)65—is potentially survivable, particularly
when it is intermittent or cyclic in nature. In contrast, the structure
and function of the vasculature of normal tissues is such that it
specifically avoids (in nearly all cases) the development of such
gradients of oxygen and nutrients. Thus hypoxia has a built-in specificity for tumors, which, ironically, is an attractive feature clinically,
where differences between normal tissues and tumors might be
exploitable.
Unfortunately, as previously discussed, maintenance under
hypoxic conditions renders cells more radiation resistant by upward
of a factor of three (i.e., three times the total dose would be required
to achieve the same biological end point). Thus a tumor containing
even the smallest fraction of clonogenic, hypoxic cells could easily
make or break the success of radiation therapy that is necessarily
limited by the response of the aerobic, and therefore more radiosensitive, normal tissues.66 Many types of experimental solid tumors in
laboratory rodents and spontaneous tumors in veterinary patients and
humans studied to date show an average pretreatment hypoxic fraction of approximately 15% to 20%, although the range of values is
quite broad,45,67 as might be expected given intra- and intertumor
heterogeneity.
Of course, tumor hypoxia would not constitute a barrier to clinical
success if, during the course of fractionated radiotherapy, the fraction
of hypoxic cells decreased, ideally to zero. This process is called reoxygenation, and it has been studied extensively in experimental rodent
tumors (e.g., see reference 68), and to a limited extent in human
tumors as well (e.g., see reference 64).
The reoxygenation process can be either slow (days to weeks) or
fast (hours), and it can be complete or incomplete, depending on the
Redistribution
Tumors that contain a sizeable fraction of actively proliferating cells
will necessarily contain subsets of cells in different phases of their cell
cycle, much more so than for some normal tissues in which cells are
differentiated, no longer able to proliferate, and reside in G0 phase.
Furthermore, even for the normal tissues that do contain stem cell
compartments consisting of undifferentiated, proliferating cells, these
tend to be few in number compared with the tissue as a whole, nor
do they necessarily proliferate rapidly. Thus tumors are much more
heterogeneous than normal tissues with respect to cell cycle phase
distribution.
It was the pioneering work of Terasima and Tolmach71 during the
1960s that led first to the development of a relatively simple method
of obtaining populations of cells synchronized with respect to cell
cycle phase, followed by the generation of radiation survival curves
for each phase.
After a single dose of approximately 7 Gy of x-rays, Chinese
hamster V79 cells in culture were noted to be most radioresistant in
(late) S phase. Cells in G1 phase were of intermediate radiosensitivity
(i.e., more resistant at the beginning of the phase but somewhat more
sensitive toward the end of the phase), and G2 cells were increasingly
sensitive as they moved toward the most radiosensitive M phase. This
phenomenon was termed the cell cycle “age response” for ionizing
radiation71 and is a general feature of mammalian cell radiation
response.72 (The original work by Terasima and Tolmach71,73 also
showed this feature to be true for human HeLa cells.) Differences in
radiosensitivity for cells in each phase were largely attributable to
changes in the shoulder regions of their respective survival curves,
with late S-phase cells characterized by broad survival curve shoulders, and mitotic cells showing strictly exponential cell killing with
no survival curve shoulders (Fig. 27-16). It should also be noted that
1.0
7.1 Gy
Figure 27-16 • The age response through
the cell cycle. A, Cell survival curves for synchronized populations of Chinese hamster cells irradiated in different phases of the cell cycle. B, An
illustration of how these radiosensitivity differences translate into age response patterns. Cells in
the S phase (especially the late S phase) are the
most radiation resistant, and cells in the G2 and
M phases are the most radiosensitive.
Surviving fraction
0.2
0.1
0.1
0.05
0.02
0.01
0.01
0.005
0.001
Late S
Early S
G1
G2/M
5.0
A
M
G1
S
Cell cycle phase
10.0
Dose (Gy)
15.0
B
G2
408
Part I: Science of Clinical Oncology
when high LET radiations such as neutrons are used in place of
x-rays, the age response variation through the cell cycle is significantly
reduced or eliminated.
Because of the age response through the cell cycle for low LET
radiations, an initially asynchronous population of cells surviving a
dose of radiation becomes enriched with more resistant cells (S-phase,
and to a lesser extent, G1-phase cells). This partial synchrony decays
rapidly, however, in part because of radiation-induced perturbations
in cell cycle progression and also because of natural variations in cell
cycle phase durations. Such cells are said to have “redistributed,”74
with the net effect of sensitizing the population as a whole to subsequent dose fractions compared with what would have been expected
had the cells remained in their resistant phases. The redistribution
process can be demonstrated in rapidly growing cells in vitro but
tends to be dampened in vivo because of the longer (and dispersed)
cell cycle times and lower fractions of actively proliferating cells in
tumors. Attempts to take advantage of redistribution clinically,
however, such as by carefully timing each dose fraction to correspond
to times when tumor cells would be expected to be most radiosensitive, have been unsuccessful.75 In fact, it has been difficult to demonstrate that redistribution has occurred in tumors (or normal tissues,
for that matter) at all, other than by indirect inference, that is, that
increasing resistance to each subsequent dose fraction during radiotherapy does not occur.
Radiosensitizers and Radioprotectors
The use of radiosensitizing or radioprotective compounds in combination with radiation therapy is predicated on the idea that tumors
contain one or more radioresistant (or effectively so) subpopulations
of cells that threaten the success of treatment. Historically, three such
subpopulations in tumors that fit this description are inherently
radioresistant cells, hypoxic cells, and rapidly proliferating cells.
The latter may not be radioresistant per se, but rather have the net
effect of making the tumor seem less responsive to treatment because
the production of new cells outpaces the cytotoxic action of
radiotherapy.
Radiosensitizers and radioprotectors can be defined generically as
any chemical or pharmacologic agent that increases or decreases,
respectively, the cytotoxicity of ionizing radiation. “True” radiosensitizers and protectors meet the stricter criterion of being relatively
nontoxic in and of themselves, acting only to potentiate or ameliorate
radiation toxicity. “Apparent” radiosensitizers and protectors still
produce the net effect of making tumors more sensitive or normal
tissues less so, yet their mechanisms of action are not necessarily
synergistic, nor are the agents necessarily nontoxic when given alone.
Finally, it is important to realize that the use of any chemical
modifier of radiation response is only as good as it is selective, or at
minimum, partially selective, for either tumors or normal tissues;
agents that show little or no differential effect between tumors and
normal tissues do not improve the therapeutic ratio, and therefore
may not be of much clinical utility.
Traditional Radiosensitizers
Sensitizers of Proliferating Cells
Halogenated analogs of the DNA precursor thymidine, such as bromodeoxyuridine (BrdUdR) and iododeoxyuridine (IdUdR), can be
incorporated into the DNA of actively proliferating S-phase cells in
place of thymidine because of close structural similarities between the
compounds. Cells that contain DNA substituted with these compounds are more radiosensitive than their unsubstituted counterparts,
with the amount of sensitization directly proportional to the fraction
of thymidine replaced.76 In general, the radiosensitization takes the
form of a decrease in or elimination of the shoulder region of the
radiation survival curve. The molecular basis of the ability of BrdUdR
and IdUdR to radiosensitize the cells that incorporate the drugs into
their DNA remains somewhat unclear. However, it is likely that both
the formation of more complex radiation-induced lesions caused by
the presence of the halogen atoms and an interference in DNA repair
are involved.77
The clinical use of halogenated pyrimidines began in the late
1960s, with a major clinical trial in persons with head and neck
cancer.78 Although BrdUdR did improve the tumor response to radiotherapy, it also produced severe oral mucositis as, in retrospect, might
have been expected given that the mucosa also contains rapidly proliferating cells that would have been radiosensitized. As a result, the
therapeutic ratio did not improve. Subsequently, these drugs were
evaluated in more appropriate disease sites such as brain tumors and
sarcomas, which consist of rapidly growing tumor cells against a
background of slowly proliferating or nonproliferating cells of the
surrounding normal tissues.79,80 Unfortunately, these drugs did not
improve outcomes sufficiently to warrant their adoption for routine
clinical use.
Sensitizers of Hypoxic Cells
The increased radiosensitivity of cells in the presence of oxygen is due
to oxygen’s affinity for the electrons produced by the ionization of
biomolecules. Molecules other than oxygen also have this chemical
property, known as “electron affinity,”81 some of which are not consumed by the cell for other purposes, as is oxygen. Assuming that
such an oxygen-mimetic compound is not otherwise used by the cell,
it should diffuse further from capillaries and reach hypoxic regions
of a tumor, sensitizing the hypoxic cells to radiation.
One class of compounds that represented a reasonable trade-off
between efficiency as a radiosensitizer (i.e., compared with oxygen)
and diffusion effectiveness was the nitroimidazoles, which include the
drugs misonidazole, etanidazole, and nimorazole, all of which were
the subjects of intensive preclinical and clinical studies over several
decades. Unfortunately, the nitroimidazoles were found to cause
adverse effects in normal tissues (in particular, peripheral neurop­
athy), which curtailed their clinical utility.82,83 In fact, the only one
of this class of compounds currently approved for clinical use is
nimorazole, which is used in Europe for subgroups of patients with
advanced head and neck cancer.84
Another class of hypoxic cell radiosensitizers does not sensitize
cells per se but rather kills them outright. This action produces the
net effect of (apparent) sensitization of the tumor because of the
elimination of an otherwise radioresistant subpopulation of cells.
Agents selectively toxic to hypoxic cells are termed “bioreductive
drugs,” with the organic nitroxide tirapazamine (formerly SR
4233)34,85 being the lead compound.
In preclinical models, tirapazamine has been shown to outperform
the nitroimidazole radiosensitizers using clinically relevant fractionated radiotherapy86 and with some chemotherapy drugs either alone
or in chemoradiotherapy regimens.87 In humans, more than 20 clinical trials are ongoing or complete, including randomized phase 2 and
3 trials with tirapazamine combined with radiotherapy and/or chemotherapy (particularly, cisplatinum) for advanced head and neck,
cervix, and lung cancers. Although tirapazamine has improved outcomes for some standard regimens, results overall have been mixed
(e.g., see references 88 and 89). Thus although the drug has in no
way become a staple of clinical practice, its activity against some
tumors warrants further investigation, as does the search for more
effective agents from the same or similar chemical classes.
Traditional Radioprotectors
In theory, if normal tissues could be made to tolerate higher total
doses of radiation through the use of radioprotectors, then the relative
radioresistance of hypoxic tumor cells would no longer limit treatment. One such agent, amifostine, is a compound containing thiol
moiety that was developed by the U.S. Army for use as a radiation
protector for soldiers on a nuclear battlefield. It subsequently was
Basics of Radiation Therapy • CHAPTER 27 409
repurposed for clinical use. Chemically, amifostine is an analog of
naturally occurring radioprotective sulfhydryl compounds found in
cells, such as cysteine, cysteamine, and glutathione.90 Like those antioxidant compounds, amifostine’s mechanism of action involves either
the scavenging of free radicals produced by ionizing radiation, radicals that otherwise could go on to damage other cellular macromolecules, or reacting with oxygen, thereby preventing “fixation” of
damage that has already been registered. Amifostine can also detoxify
other reactive species, and because of this mechanism, the drug can
also be used as a chemoprotective agent.91
Amifostine is approved for use in patients receiving radiotherapy
for head and neck cancer to reduce xerostomia as a result of exposure
of the parotid glands.92 It is also indicated for the reduction of renal
toxicity associated with cisplatin chemotherapy in patients with
advanced ovarian and NSCLC.93
Chemotherapy Drugs as Radiosensitizers
One of the major changes that has occurred in the clinical practice
of radiation therapy during the past two decades is the large percentage of patients who are treated with concurrent radiation therapy and
chemotherapy. This combination is used in two ways: chemotherapy
used independently for its cytotoxic effect on the tumor, and chemotherapy used to enhance the effect of the radiation therapy through
a drug sensitization effect. It is this second approach that will be
discussed here. As mentioned earlier in this chapter, the value of
radiation sensitization is dependent on producing a differential sensitization of the tumor compared with the adjacent normal tissue
(therapeutic ratio). A drug has little value if its only effect is to
decrease the amount of time the radiation therapy machine is
turned on.
It has been known for decades that certain pharmaceutical agents
can increase the tumor cell kill produced by radiation therapy.94 One
of the earlier approaches used in this manner, and one that is still
very commonly used, is the combination of a fluoropyrimidine (typically 5-fluorouracil or, more recently, capecitabine) with radiation
therapy for a variety of tumors, but especially those of the GI tract.95
The underlying mechanism(s) of action of these fluorinated pyrimidines as radiation sensitizers is still not completely clear, but it most
likely involves some combination of the drug’s selective toxicity to
otherwise radioresistant S-phase cells, interference with DNA synthesis and repair, and ability to dysregulate the cell cycle.94 At present a
fluoropyrimidine is used routinely in the therapy of most tumors of
the GI tract, including esophageal, gastric, pancreatic, rectal, and anal
cancers. In the past, the combination had been used in head and neck
and uterine cervix squamous cell carcinomas, although that practice
is much less common at present. The details of these combinations
are described more fully in the individual disease site chapters in this
book. However, it should be noted that local control has been consistently improved by this approach and has had a beneficial effect
on survival in some of these diseases.
Another drug commonly used with concurrent therapy is cisplatinum, an inorganic compound consisting of a coplanar complex
capable of producing both inter- and intrastrand DNA and protein
cross-links.94 The cross-linking produced by cisplatinum most likely
interferes with cellular repair of radiation damage, particularly DNA
double-stranded breaks, resulting in radiation sensitization,96 although
as in the case of the fluoropyrimidines, additional mechanisms of
action have also been proposed.94 This combination is routinely used
for head and neck and uterine cervix cancers (e.g., as described in
references 97 and 98), with a major impact on long-term outcome.
Mitomycin C is routinely used in the therapy of anal cancer,99 temozolomide is in standard use in the therapy of high-grade gliomas,100
and various other combination therapies have also been explored.
Molecularly Targeted Drugs and Biologics
Investigators have a great interest in the use of biological therapies in
combination with radiation therapy. Although preclinical data have
been generated for quite a few of these agents, with even newer
compounds constantly being developed, the only two that have gone
through substantial clinical testing and entered the treatment mainstream are anti-EGFR inhibitors used to treat squamous cell carcinomas of the head and neck17 and anti-VEGF therapies in the treatment
of GI tract tumors.101
The use of cetuximab, a monoclonal antibody raised against the
EGFR, has been shown to improve outcomes in head and neck
cancers when combined with radiation therapy17 and is being explored
in a variety of other clinical situations. Cetuximab competitively
binds to the extracellular domain of EGFR, preventing activation of
the receptor by endogenous ligands, which abrogates its near-constant
signaling to cancer cells to proliferate. The antibody-receptor complex
is then internalized and degraded, resulting in a downregulation of
EGFR expression relative to the overexpression often displayed by
diseases such as squamous cell cancers of the head and neck.
Bevacizumab exploits a different cancer hallmark, namely the
ability of tumors to continuously recruit new blood vessels from surrounding normal tissues. This recruitment is accomplished through
the production and release into their microenvironment by tumor
cells of large quantities of (among other proangiogenic factors) VEGF,
the principal stimulant of endothelial cells of the host vasculature to
reproduce and migrate into the tumor mass, forming new—if immature and aberrant—blood vessels. The observation that tumors
cannot grow beyond a size of approximately 2 mm3 without the
support of neovascularization102 has led to accelerated development
of angiogenesis-inhibiting agents, many of which target either VEGF
or its endothelial cell surface receptor.103,104
Bevacizumab is a humanized monoclonal antibody raised against
VEGF.105 The binding of the antibody to VEGF prevents it from
binding to its receptor on the surface of vascular endothelial cells,
which has the net effect of inhibiting the downstream signaling events
that cause these cells to begin proliferating and forming vessel
“sprouts” that migrate toward the tumor mass. At first blush, therapy
that blocks new blood vessel formation might be expected to create
more tumor hypoxia, and therefore more radiation resistance.
However, findings of both preclinical and clinical studies with bevacizumab and related inhibitors of angiogenesis show that they most
often promote radiation (and chemotherapy) sensitivity, not resistance. One hypothesis to explain this observation is that antiangiogenic therapy actually “normalizes” tumor vasculature106 by selectively
pruning away small, immature, abnormal tumor blood vessels,
leaving the larger, most “normal-like” vessels behind. This process
would lead to improved tumor oxygenation and better access of
chemotherapy agents.
Bevacizumab had been shown to prolong both overall survival and
progression-free survival in patients with advanced colorectal cancer
when added to a standard chemotherapy regime consisting of irinotecan, 5-fluorouracil, and leucovorin.107,108 In persons with rectal
cancer,109 bevacizumab has been evaluated in combination with radiation therapy, and although initial reports were encouraging, with
excellent early responses, it remains unclear whether the combination
will improve clinical efficacy. Also, despite prolonged progression-free
survival, no clear overall survival benefit of bevacizumab was seen in
large clinical trials for NSCLC,110 renal cell carcinoma,111 and metastatic breast cancer.112 In response to the disappointing results in
persons with metastatic breast cancer, the U.S. Food and Drug
Administration has recently withdrawn its approval of bevacizumab
as a first-line therapy, concluding that the drug’s benefit did not
outweigh its adverse effects, which can include hypertension, proteinuria, bleeding episodes, and thrombotic events.113 Continued interest
exists in trying to explore the vascular normalization hypothesis in a
variety of tumor types.
Because many newer biological agents have been shown to have
radiation-sensitizing properties in vitro and in animal systems, investigators have a great interest in translating this information to the
clinic. For example, one class of drugs currently in clinical trials is
410
Part I: Science of Clinical Oncology
the poly(adenosine diphosphate–ribose) polymerase or “PARP”
inhibitors. The PARP family of proteins participate in a number of
cellular functions, including detecting the presence of DNA strand
breaks and activating signaling pathways that recruit and mobilize
DNA repair proteins to the site of the damage.114 PARP1 is by far
the most abundant member of this family and has been the most
frequently targeted for inhibition. PARP inhibitors have been evaluated in preclinical models as potential radiation sensitizers, given that
unrepaired or mis-rejoined DNA double-strand breaks are considered
the lethal lesions with respect to the cytotoxic effects of radiation and
that PARP inhibition might be expected to enhance this damage and
increase toxicity.
DNA repair inhibition will only be clinically useful insofar as it
is selective for tumors, because inhibiting repair in irradiated normal
tissues could have adverse results. Fortuitously, PARP inhibition was
found to be selective for tumors, in particular the tumors whose cells
were already defective in at least one DNA repair pathway, as is the
case for cells that carry mutations in the BRCA1 or BRCA2 genes,
for example.115,116 Because cells from normal tissues have intact alternate or “salvage” pathways for DNA repair, the PARP inhibitors
should be less toxic. Phases 1 and 2 clinical trials of PARP inhibitors
are currently under way for brain tumors.
Normal Tissue Toxicity
In the delivery of radiation therapy, an understanding of the biology
of normal tissue response to injury is critical. Normal tissue complications that arise during or after radiotherapy are the result of the killing
of critical target cells crucial to the tissue’s continued functional and/
or structural integrity. The loss of these target cells can occur either
as a direct consequence of the cytotoxic action of the radiation, or
indirectly because of the loss of other cells that support them. Further,
especially in the case of late-responding tissues, the response to the
depletion of the tissue’s target cells involves a long, complex, and
somewhat cyclic process that can actually exacerbate the injury. For
example, the hyperproliferation of fibroblasts and deposition of collagen after a tissue injury can culminate over time in the replacement
of a large proportion of that tissue’s parenchymal cells, resulting in
fibrosis, a common complication of radiation therapy.
Tolerance Doses
Several important considerations in determining tolerance doses for
different tissues include the radiosensitivity of the tissue’s component
cells, the proliferative organization of the tissue (which determines
the earliness or lateness of the tissue response to radiation), the
volume of the tissue irradiated, and the tissue’s fractionation sensitivity. As such, it follows that tolerance doses for particular complications in particular tissues are necessarily average values that take all
of these factors into consideration. That tolerance doses are average
values is reinforced by the fact that these doses have been determined
by pooling clinical outcomes data on thousands of patients over long
periods (decades, generally). Bearing this in mind, several general
findings about normal tissue tolerance are worth mentioning.
First, because tissues and organs contain, by definition, more than
one cell type (each with its own inherent radiosensitivity), it follows
that one tissue could manifest more than one complication after
radiation therapy, with the severity of each determined by the radiosensitivity of the particular target cell whose death precipitates the
complication and by the time-dose-fractionation schedule used. In
addition, the severity of one complication does not necessarily predict
for the severity of another complication, even within the same tissue.
Using skin as an example, an early effect of treatment might consist
of dry or moist desquamation (killing of basal cells of the epidermis),
whereas late effects might include fibrosis (loss of tissue parenchymal
cells and some dermal fibroblasts, resulting in overproliferation of
survivors) or telangiectasia (damage to small blood vessels in the
dermis, resulting in abnormal regrowth).
Second, although it is generally true that tissues known to be
composed of radiosensitive cells have lower tolerance doses (e.g.,
the tolerance dose for a 5% risk of radiation-induced bone marrow
aplasia within 5 years of treatment, the “TD5/5,” is ≈2.5  Gy) compared with the tolerance doses for tissues containing more radioresistant cells (e.g., the TD5/5 for rectal stenosis or fistula formation
is ≈60  Gy),45 this situation is not universally the case because radiosensitivity is not the sole determinant of radiation response. Early
and late effects in irradiated normal tissues do result from the killing
of critical target cells either directly or indirectly; however, the
“process” that culminates in the complication is both complex and
dynamic, involving radiation-inducible gene expression (including
production of cytokines and growth factors), cellular signaling cascades, different modes of cell death, and compensatory proliferative
responses.
Tolerance dose data for representative early- and late-responding
normal tissues are shown in Table 27-2. Data are included for select
normal tissues from three seminal publications (each about 20 years
apart) that compiled such information based on exhaustive reviews
of the literature and updated to reflect new knowledge about the
etiology of normal tissue complications and changes in treatment
technique over the years.
Radiation Carcinogenesis
With increasing numbers of long-term cancer survivors, one late
normal tissue complication of radiotherapy that is of particular
concern is the production of second malignancies. Leukemia accounts
for about 20% of these second cancers, with the remainder presenting
as solid tumors that develop in and around the previously irradiated
site.117,118 Large epidemiological studies have assessed the breast and
lung cancer risk in Hodgkin lymphoma survivors119 and leukemia
and sarcomas in cervical cancer survivors.120 Certain subpopulations
of previously irradiated patients are at an even higher risk than the
majority, including children and young adults (who would be
expected to live long enough for such second cancers to develop, and,
in the case of children, who are more radiosensitive than adults to
begin with), immunocompromised individuals, and persons with a
known genetic predisposition to cancer. Large studies of previously
irradiated patients demonstrate that the risk of late cancer developing
in an incidentally irradiated organ will very roughly double the baseline risk.121 Fortunately, the baseline risk in an individual organ is
quite low, and thus the absolute impact of a radiation-induced cancer
is also low, assuming there is clinical benefit in the original therapy.
However, the impact of a second cancer occurring many years after
a prior cancer developed can be severe.
Volume Effects
By convention, normal organs have been divided into what are called
“serial” and “parallel” organs, by analogy with electrical circuits.122 A
serial organ is one in which a severe injury at any anatomic point in
the normal structure will produce a severe functional loss. The classic
example of a serial organ is the spinal cord. If there is major damage
to the cord at any level, from a small dosimetric hot spot, for example,
all function can be lost below that level. Examples of parallel organs
are the kidneys and the liver. Radiation injury to a portion of one of
these organs will generally just decrease its function by an amount
approximately equal to the percent of the organ that is destroyed but
often will not produce a major functional deficit unless the irradiated
volume is large.
Some organs behave as if they have both a serial and a parallel
component. The liver can be viewed in this manner because the
hepatic parenchyma functions as a parallel structure, but the biliary
system near the hilum functions as a serial structure; obstruction of
the common bile duct is a major complication affecting the entire
organ. Thus the radiation oncologist can design radiation therapy
fields that totally destroy portions of the parenchyma of the liver
without a clinical problem to the patient, whereas damage to any
Basics of Radiation Therapy • CHAPTER 27 411
Table 27-2 Radiation Tolerance Dose and Complication Frequency Data for Select Normal Tissues
Tissue
Early/Late
End Point
Lung
Early
Pneumonitis
Rectum
Spinal Cord
Late
Late
Ulcer/perforation/
fistula/stricture
Myelopathy
Irradiation and Volume
Details
Tolerance Dose or Complication
Frequency
Conventional fractionation;
>½ of organ irradiated
Conventional fractionation;
1/3 or whole organ irradiated
Conventional fractionation;
3D-CRT; whole organ
irradiated
TD5/5 ≈20 Gy
TD5/5 (1/3) ≈45 Gy
TD5/5 (whole) ≈17.5 Gy
7 Gy ≈5% complication frequency
20 Gy ≈20% complication frequency
27 Gy ≈40% complication frequency
Conventional fractionation
TD5/5 ≈65 Gy
Conventional fractionation;
100 cm3 field
Conventional fractionation;
3D-CRT
TD5/5 ≈60 Gy
Conventional fractionation;
5- to 10-cm field
Conventional fractionation;
5- or 20-cm field
Conventional fractionation;
3D-CRT; partial organ
irradiation, including full
cord cross section
Author
Rubin and
Casarett (1968)
Emami (1991)
QUANTEC (2010)
Rubin and
Casarett (1968)
Emami (1991)
V50 <50%: <15% complication frequency
V65 <25%: <15% complication frequency
V75 <15%: <15% complication frequency
QUANTEC (2010)
TD5/5 ≈50 Gy
Rubin and
Casarett (1968)
Emami (1991)
TD5/5 (5 cm) ≈50 Gy
TD5/5 (20 cm) ≈47 Gy
Dmax = 50 Gy: <1% complication frequency
Dmax = 60 Gy: 6% complication frequency
Dmax = 69 Gy: 50% complication frequency
QUANTEC (2010)
Data from Rubin P, Casarett GW. Clinical radiation pathology, vol. 1. Philadelphia: Saunders; 1968; Emami B, Lyman J, Broun A, et al. Tolerance of normal tissue to therapeutic
irradiation. Int J Radiat Oncol Biol Phys 1991;21:109–22; and Marks LB, Yorke ED, Jackson A, et al. Use of normal tissue complication probability models in the clinic. Int J Radiat
Oncol Biol Phys 2010;76(3 Suppl.):S10–9.
Conventional fractionation = 1.8 to 2.0 Gy per fraction, one fraction per day, 5 days per week; Dmax = maximum radiation dose (Gy) to the irradiated volume; QUANTEC,
Quantitative Analyses of Normal Tissue Effects in the Clinic; TD5/5 = the total radiation dose that results in approximately a 5% risk of a complication within 5 years of treatment;
3D-CRT, three-dimensional, conformal radiotherapy; V50, V65, V75 = volume (%) of irradiated organ receiving ≥50, 65, or 75 Gy.
tubular structure (the esophagus, for example) can produce severe
consequences.
Fractionation Sensitivity
During the 1960s and 1970s, research interest among radiobiologists
focused on the shape of the shoulder region of cell survival curves,
the nature of dose-rate and dose-fractionation effects, and their relevance to the practice of radiation therapy. This research was timely
given the growing appreciation clinically that tissue tolerances varied,
sometimes widely, depending on the exact time, dose, and fractionation pattern used for treatment. This research ultimately led to the
replacement of the target theory model of cell survival with the LQ
model, as well as the use of the LQ model for a new, biologically
based approach to clinical isoeffect modeling.
In multifraction experiments assessing skin reactions in mice,
Douglas and Fowler123 analyzed their data using what was then a
novel method that allowed the derivation of values for the ratio α/β,
parameters of the LQ formula. This new approach to isoeffect analysis focused on the shape of dose-response curves, particularly in the
low-dose region, and by extension, that the critical parameter in
radiotherapy planning was the size of the dose per fraction. More
widespread use of this technique in subsequent years revealed that in
most cases, a systematic difference was found between early- and
late-responding normal tissues and tumors in their responses to different fractionation patterns. The α/β ratios tended to be low for
late-responding normal tissue end points (on the order of 1 to 6 Gy,
with an average of about 3 Gy), and high for early-responding normal
tissue and tumor end points (usually 7 to 20 Gy, with an average of
about 10 Gy). Table 27-3 shows α/β ratios determined for a variety
of human normal tissues and tumors; worth noting are the few tumor
types (melanoma and prostate cancer for example) that are exceptions
to the general trend and are characterized by low α/β ratios.
Representative dose-response curve shapes for tissues characterized
by low or high α/β ratios are shown in Figure 27-17. The curve with
the low α/β ratio has a shallow initial slope at low doses but curves
downward rather abruptly as the dose increases. Conversely, the curve
with the high α/β ratio has a steeper initial slope and bends more
gradually as the dose increases.
In parallel with the fractionation experiments used to determine
tissue α/β ratios, other investigators124 quantified the fractionation
sensitivity of experimental tumors and normal tissues using a plot of
the log of the total dose to achieve a particular tissue end point versus
dose per fraction; this is called an isoeffect curve, and this method of
plotting tolerance dose data had been in common practice in radiation oncology since the 1940s.125 Plotted in this way, the curves for
slowly proliferating or nonproliferating normal tissues such as the
kidney and spinal cord, for example, were found to be steeper than
those for more rapidly proliferating, early-responding tissues, such as
skin and gut epithelium, and most tumors.124,125 Taken together, the
low α/β ratio and steep isoeffect curve suggest that late-responding
tissues are more sensitive to changes in dose per fraction, thus experiencing greater sparing with decreasing fraction size than their early
effects counterparts. This phenomenon is illustrated graphically in
Figure 27-18. It was immediately evident that this phenomenon
could be exploited for clinical benefit.
Clinical Application of the LQ Isoeffect Model
The shapes of tissue and tumor isoeffect curves and their calculated
α/β ratios have a number of clinical applications. One is to use α/β
ratios to generate alternate treatment schedules using different-sized
doses per fraction in order to match the probability of causing a
tissue injury. Making such a calculation assumes the overall treatment times are similar in both schedules or that the tissue at risk
Part I: Science of Clinical Oncology
Table 27-3 Representative α/β Ratios for Human
Normal Tissues and Tumors
α/β Ratio
Tissue Type (and End Point)
(±95% Confidence Interval)
EARLY-RESPONDING NORMAL TISSUES
Skin: Erythema
Desquamation
10.6 (1.8; 22.8) Gy
11.2 (8.5; 17.6) Gy
Lung: pneumonitis ≤90 d after
radiotherapy
>8.8 Gy
Oral mucosa: mucositis
8-15 Gy
LATE-RESPONDING NORMAL TISSUES
Skin: Telangiectasia
Fibrosis
~2.7 (−0.1; 8.1) Gy
1.7 (0.6; 3.0) Gy
Breast: poor cosmesis
Fibrosis
3.4 (2.3; 4.5) Gy
3.1 (1.8; 4.4) Gy
Lung: pneumonitis >90 days
after radiotherapy
4.0 (2.2; 5.8) Gy
Bowel: perforation/stricture
3.9 (2.5; 5.3) Gy
Spinal cord: myelopathy
<3.3 Gy
TUMORS
Head and neck: nasopharynx
Vocal cord
Tonsil
Larynx
16 (−11; 43) Gy
~13 Gy
7.2 (3.6; ∞) Gy
14.5 (4.9; 24) Gy
Lung: squamous cell carcinoma
~50-90 Gy
Cervix: squamous cell carcinoma
>13.9 Gy
Skin: Squamous cell carcinoma
Melanoma
8.5 (4.5; 11.3) Gy
0.6 (−1.1; 2.5) Gy
Prostate
1.1 (−3.3; 5.6) Gy
Breast (early-stage invasive
ductal, lobular, and mixed)
4.6 (1.1; 8.1) Gy
Data from Joiner M, van der Kogel A, editors. Basic clinical radiobiology. 4th ed.
London: Hodder Arnold; 2009.
Table excerpted from Zeman EM. Biologic basis of radiation oncology.
In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology. 3rd ed.
Philadelphia: Saunders; 2012.
Tumor and earlyresponding tissue
Late-responding tissue
Surviving fraction
412
Dose
Figure 27-17 • Underlying dose response curves for tissues characterized by low (yellow line) or high ( purple line) α/β ratios. The α/β ratio for
most late-responding normal tissues averages about 3 Gy, and for most earlyresponding normal tissues and tumors, it is about 10 Gy.
of a complication is relatively insensitive to treatment duration.126
The equation,
D2/D1 = (α /β + d1)/(α /β + d 2 )
can be used for this purpose, where D1 and d1 are, respectively, the
total dose and dose per fraction of one radiotherapy treatment plan
and D2 and d2 are, respectively, the total dose and dose per fraction
for an alternate treatment plan intended to be biologically equivalent
for a particular tissue effect, and with the fractionation sensitivity of
that tissue defined by its α/β ratio. One example of the utility of this
approach is to express particular time-dose-fractionation schedules in
terms of “equivalent total dose if the treatment had been given in
2 Gy fractions” or EQD2,
 ( d + α/β ) 
EQD2 = D 

 ( 2 + α/β ) 
where D is the total dose actually delivered and d is the dose per
fraction actually used. When comparing clinical trial data from multiple institutions, one can specify treatment parameters using EQD2
doses rather than the actual doses used, which makes the pooling of
data with varying fractionation schedules more manageable, with the
caveat that the results will only apply to the tissue of interest.
Another important implication of the steeper isoeffect curves for
late-responding tissues compared with those for tumors is that it
might be possible to increase the therapeutic ratio by using larger
numbers of smaller fractions to a somewhat higher total dose than
traditionally used.127 Although such treatments would be expected to
exacerbate acute effects in some normal tissues (undesirable, but
usually manageable) and in the tumor (desirable), late effects would
be spared preferentially (also desirable). The use of multiple fractions
per day of smaller than conventional size (less than about 1.8 Gy)
but to a somewhat higher total dose, with little or no change in overall
treatment time, has been termed hyperfractionation.
Hypofractionation, that is, the use of one or a few large dose fractions delivered over short periods (as would be the case for stereotactic
radiosurgery or intraoperative radiation therapy), is also an option.
Indications for the use of hypofractionation would include cases in
which the complete ablation of small tumors is the goal, or in the
relatively unusual circumstance in which the tumor is suspected of
having a low, rather than high, α/β ratio. Prostate cancer and melanoma appear to be tumor types that meet this criterion, although this
topic remains controversial, as does the use of hypofractionation in
general.128-130
With particularly aggressive tumors that proliferate rapidly,
another clinical strategy has been suggested, although it is not explicitly derived from the LQ model. Multiple treatments per day might
also be useful to decrease the overall treatment time, thereby allowing
less time for repopulation of clonogenic tumor cells.131 Treatment
with multiple daily fractions of approximately standard size and
number (and to about the same total dose), but in shorter overall
times, has been called accelerated fractionation. In practice, however,
a combination of accelerated and hyperfractionated treatment is most
often used.132
Of course, determining the best treatment schedule for a particular patient is not simply a matter of avoiding a normal tissue complication or delivering a curative dose to the tumor, but rather, how
the probabilities of both change when comparing different treatment
possibilities. The “biologically effective dose” or BED method,133
another derivative of the LQ model, attempts to address this issue.
BEDs are theoretical doses to achieve a particular tissue effect under
conditions in which the fractionation pattern consists of an infinite
number of infinitely small dose fractions. BEDs would be quite large
for tissues characterized by low α/β ratios and steep isoeffect curves
(like many late-responding normal tissues) and appreciably smaller
for tissues characterized by high α/β ratios and shallower isoeffect
curves (like most tumors and early-responding normal tissues). BEDs
are not real doses but extrapolations based on the shapes of
Basics of Radiation Therapy • CHAPTER 27 413
Skin necrosis
80
Skin
desquamation
70
60
50
Total dose for various isoeffects (Gy)
Skin
contraction
is)
40
al
in
Sp
30
r
pa
d(
r
co
s
aly
ypt
cr
olon
is
Test
20
(loss
Kidney (LD50)
)
onia
atog
erm
of sp
cells
c
s of
Los
Lung
(LD50’ pneumonitis)
Loss of jejunal crypt cells
Loss control of fibrosarcoma
Vertebral growth inhibition
10
Bone marrow abalation (LD50)
8
6
10
8
6
4
2
1
0.8
0.6
Dose per fraction (Gy)
Figure 27-18 • Isoeffect curves in which the total dose necessary to produce a certain normal tissue or tumor end point (indicated on the graph) is
plotted as a function of the dose per fraction. Isoeffect curves for late-responding normal tissues (solid lines) tend to be steeper than those for early-responding
normal tissues and tumors (dashed lines). This phenomenon suggests that by using smaller than conventionally sized dose fractions, a somewhat higher total
dose could be given for the same probability of a late complication but with a higher tumor control probability. (From Zeman EM. Biologic basis of radiation
oncology. In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saunders; 2012.)
dose-response curves characterized by particular α/β ratios. For this
reason, the units used to describe these theoretical, extrapolated doses
are, for example, “Gy3’s” or “Gy10’s” rather than “Gy’s,” with the
subscripts 3 and 10 referring to the α/β ratios for the tissues at risk.
Although two radiotherapy treatment schedules can be compared
qualitatively on the basis of their respective Gy3 or Gy10 “doses,” Gy3’s
and Gy10’s cannot be intercompared.
Even with the BED concept being only semiquantitative at best,
its use for treatment planning purposes during the past two decades
has changed the radiotherapy standards of care for several tumor types
and provided a wealth of clinical data that has allowed a better definition of what is or isn’t tolerable for particular normal tissues, in terms
of Gy3’s or Gy10’s. Using head and neck cancer as an example,
Fowler133 has suggested that for acute mucosal reactions, the maximally tolerated BED is in the range of 59 to 61 Gy10, and for brain
necrosis, it is approximately 110 to 115 Gy3.
Radiation Therapy Delivery Approaches
Historically, radiation therapy was used as a single treatment modality, either for very early stage disease for which radical surgery would
be overtreatment (such as a total laryngectomy for early-stage glottic
cancer) or for advanced disease in which surgery would be insufficient
for control of the disease extent (e.g., lung cancer with mediastinal
disease or stage III cervical cancer). Treatments also focused heavily
on the use of radiation therapy for organ preservation. In these
situations, radiation therapy would rarely be combined with
chemotherapy. However, substantial changes have occurred over the
years in the conceptual use of radiation therapy.
Although it is still used for the reasons previously described, at
the present time, radiation therapy is routinely combined with concurrent chemotherapy (either cytotoxic or “targeted”). It is commonly
used in combination with surgery as either a preoperative or a postoperative approach, and the timing of radiation therapy with surgery
and chemotherapy can vary.
Radiation therapy has the substantial benefit of being able to
provide organ preservation in many clinical situations and to be able
to sterilize microscopic disease when used in conjunction with
surgery. Thus we can categorize the use of radiation therapy as
follows:
1. Radiation therapy alone. Radiation therapy alone is often used
for small tumors for which surgery would be excessive therapy
either because of the precise location of the tumor or because of
the limitations of surgical resection. Radiation therapy can also be
used in this manner when a patient is too frail for a surgical procedure or when a patient refuses surgical intervention. Radiation
therapy alone is used much less commonly for locally advanced
disease, because it is now often combined with concurrent chemotherapy, and surgical procedures can often be performed even
for extensive local-regional disease. Examples of this category
include treatment of early stage cancers of the head and neck,
prostate cancer of all stages, early-stage cervical cancer, and selected
basal cell carcinomas of the skin.
414
Part I: Science of Clinical Oncology
2. Preoperative or postoperative radiation therapy. For some
tumors, surgical therapy is required, but surgery alone is likely to
leave residual disease either in the tumor bed or in regional lymphatics that are not completely resected. Radiation therapy in this
situation will often be given with concurrent chemotherapy for
the radiation-sensitizing effects of the chemotherapy. Examples
include soft tissue sarcomas, certain cancers of the head and
neck, intermediate and high-grade gliomas, and early-stage breast
cancers.
3. Primary radiation therapy with concurrent chemotherapy. For
many tumors, surgical resection is not an option because of the
inability to perform a grossly complete surgical resection, and thus
radiation therapy becomes the primary local therapy. Chemotherapy can be added either concurrently as a radiation sensitizer
to enhance local control or before or after radiation therapy for
control of systemic disease. Examples include all anal cancers and
locally advanced tumors of the uterine cervix, esophagus, pancreas, and head and neck.
4. Tri-modality therapy. Often all three primary therapeutic
modalities—surgery, radiation therapy, and chemotherapy—are
needed for control of local, regional, and systemic disease. The
timing of the therapies is dependent on the individual clinical
situation. Tri-modality therapy is perhaps the most common
approach at the present time. Examples include a large group of
tumors, including esophageal, glioblastoma, head and neck,
esophagus, pancreas, breast, and rectum tumors.
RADIATION THERAPY DELIVERY TECHNIQUES
The radiation oncologist has multiple tools that can be used for
delivery of radiation therapy, depending on the specific circumstances. Often combinations of techniques are used to optimize therapeutic delivery. Because many possible combinations exist, only the
general framework will be described. The technical issues have been
described earlier in the chapter.
External Beam Fractionated Radiation Therapy
External beam fractionated radiotherapy is by far the most common
technique used clinically. Radiation beams usually are delivered
through multiple angles of approach to the lesion, with each of the
beams shaped and altered in intensity to maximize the delivery of
dose to the tumor while minimizing the dose to normal tissues.
External beam therapy can be delivered with conformal radiation
therapy techniques (i.e., shaping the beams based on 3D reconstructions of the tumor size and shape and the location of nearby normal
tissues). Intensity-modulated radiation therapy changes the intensity
of each small segment (“beamlet”) of an individual beam to obtain
even more precise dose localization and avoidance of normal tissue
irradiation.
Generally these treatments are given using either low (6 MV) or
high (≈10 to 15 MV) energy x-rays, but they can also be delivered
with electrons of various energies, with the higher energies having a
greater depth of penetration into tissue. The radiation oncologist
decides the proper treatment based on both personal experience and
literature estimates of tolerance doses for normal tissue complications
and curative doses for tumors for different fractionation schedules.
This decision is a balancing effort, in an attempt to give the highest
probability of tumor control with the lowest reasonable level of clinically significant normal tissue injury. Often, depending on the individual anatomy and tumor extent, radiation doses will need to be
modified.
The radiation fields used with external beam radiation therapy
often target areas of presumed subclinical disease (such as nodal
drainage regions), as well as the clinically apparent tumor. As a result,
it is critical for the radiation oncologist to have an excellent understanding of the natural history of each disease and its specific spread
pattern. Radiation treatments are usually given daily, 5 days a week,
and can extend in duration from 1 week (or less) for certain types of
palliative therapy to courses extending for 7 to 8 weeks of daily
therapy. Total doses can range from close to 8000 Gy in 8 to 9 weeks
at the high end to 2000 Gy in 1 week (or 800 Gy in a single fraction)
for palliation.
Simulation, Treatment Planning, and Delivery
of External Beam Radiotherapy
After diagnosis, the first step in designing and delivering radiation
therapy to a patient is called “simulation.” Simulation is a process for
determining the proper selection and orientation of beams so that
they properly overlap a target. Simulation requires the determination
of patient dimensions for dose calculation and the determination and/
or creation of identifiable reference points to ensure that beams are
being aimed correctly. Historically, patient dimensions were determined by methods as simple as forming a lead wire or plaster cast
around the patient. Target volumes and patient anatomy were identified and located by examining bony structures on a series of radiographs. These radiographs were generally acquired using a device
called a simulator. A simulator is a diagnostic x-ray source configured
to mimic the geometric beam delivery configuration of a radiotherapy
linac. The x-ray source is mounted on a rotating gantry, similar to a
linac, with a detector rotating in the opposite position on the far side
of the patient. This approach allows fluoroscopic imaging from multiple angles, which facilitates positioning the patient so that the center
of gantry rotation can be placed in the tumor area. Once this position,
called the isocenter, is selected, radiographs are taken from all desired
beam angles. These radiographs are taken as a record for comparison
with future portal films (taken during treatment) and as an aid for
the physician in refining each beam shape. Finally, room-mounted
lasers indicate the location of isocenter on the patient’s skin, allowing
these points to be marked by a small tattoo or similar marking. These
markings can later be aligned with identically placed lasers in the
linac treatment room to position the patient on each treatment day.
Poor soft tissue contrast from fluoroscopic imaging means that,
on a conventional simulator, treatment parameters such as isocenter
and beam boundaries can only be defined relative to visible landmarks,
such as bony anatomy. More recently, techniques have been developed
to use dedicated computed tomography (CT) scanners for “virtual”
simulation, replacing conventional simulators in many radiation
oncology departments. Virtual simulation is simulation that is based
solely on the CT scan of a patient, and it is made possible by the
ability to reproduce any arbitrary radiograph from a CT data set. In
virtual simulation, the patient is placed in the orientation and position
to be used for treatment delivery. A CT scan is acquired, and, with
the patient still positioned on the scanning table, the physician uses
the superior soft tissue contrast of the CT scan to select a location
for isocenter within the target area (Fig. 27-19). An integrated laser
system then moves to indicate the position of the physician-selected
isocenter on the patient surface, allowing the external markers or
tattoos to be placed for future alignment with the linear accelerator
vault laser systems. The superior soft tissue contrast on CT images
allows improved tumor localization and improved beam selection
compared with fluoroscopy-based conventional simulators.
After simulation is completed, the CT scan and other images can
be sent to a computer-based planning workstation, where the team
of physicians, dosimetrists, and physicists can begin the treatment
planning process. Treatment planning includes the identification of
target volumes and normal structures requiring dose tracking and the
selection and modification of beams to achieve specified dosimetric
goals. The contouring process of identifying the boundaries of all
treatment and avoidance structures takes place on the CT scan
acquired at the time of simulation, but it may be supplemented by
other imaging modalities, such as magnetic resonance imaging, positron emission tomography, or ultrasound. Normal structures are typically defined at their anatomic boundaries. The volume to be treated,
Basics of Radiation Therapy • CHAPTER 27 415
Figure 27-19 • Isocenter selection in the center of a lung tumor allows
beams from any gantry angle to be centered on the lesion. Skin markers
placed at centroid of the anterior and lateral beams shown above can be
aligned with treatment room lasers to assist in placing the patient in the
proper treatment position.
defined as the target volume inInternational Commission on Radiation Units & Measurements Report 60 (ICRU 60),134 is created by
combining three structures: the gross tumor volume (GTV), the
clinical tumor volume (CTV), and the planning target volume
(PTV). The GTV includes all disease detectable on each imaging
modality, including visible primary tumor and involved lymph nodes.
The CTV is an expansion of the GTV that includes regions of possible or probable microscopic disease, including both adjacent tissue
and draining lymph nodes. The PTV is a further expansion of the
CTV to account for anatomic motion and expected variations of
patient daily setup. Expansions from GTV to CTV to PTV vary with
disease, technique, and patient history, but typical expansion numbers
from CTV to PTV are usually on the order of 1 cm or less. Expansion
from GTV to CTV is entirely dependent on the biology of the clinical situation. At times, no GTV is present (such as treatment in the
postoperative setting), in which case the CTV is based entirely on
the assumed high-risk areas for residual disease.
Once target and avoidance structures are identified and defined
on the patient images, a specific strategy for dose delivery can be
developed by the physicians, physicists, and dosimetrists involved.
The essential task of treatment planning is to select, arrange, and
characterize a group of radiation beams to deliver a high dose to the
tumor while keeping the dose delivered to normal structures under
acceptable limits. The treatment plan must be specified in terms of
the total dose and the number of fractions in which the dose will be
delivered. Individual beams can be customized by specifying the
beam energy, orientation, and shape. Beams are typically shaped to
match the cross section of the PTV plus some small margin to maximize overlap with the tumor while limiting the amount of normal
tissue directly exposed to the radiation beam. This goal can be accomplished by designing a customized block made from an easily cast
metal alloy such as Cerrobend, but on modern machines it is typically
performed with use of automated beam-shaping devices such as a
multileaf collimator (Fig. 27-20). Use of multiple beams overlapping
on the tumor site can maximize the dose received by the tumor. The
appropriate number, orientation, and relative weighting of beams in
a treatment plan will depend on geometric factors, such as tumor
location and the proximity of normal structures, as well as clinical
factors, such as prior or planned surgery, overall patient health,
history of prior irradiation, likelihood of future irradiation, and the
effects of concurrent chemotherapy.
The dosimetry of a sample treatment plan must be evaluated for
likely treatment efficacy of the tumor and the possibility of toxicity
to normal structures. Dosimetry can be evaluated by examining
isodose lines and dose-volume histograms. Isodose lines are a 3D
A
Source
Multileaf collimator
Projected field
B
Figure 27-20 • A, A multileaf collimator device on a linear accelerator.
B, The individual collimator leaves can be adjusted to form arbitrarily shaped
fields. (From Bourland JD. Radiation oncology physics. In: Gunderson LL,
Tepper JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saunders; 2012.)
representation of dose levels superimposed on the patient image and
indicate regions of high and low dose on any user-selected plane. As
shown in Figure 27-21, isodose lines correlate dose with anatomic
location and can indicate regions of insufficient or excessive dose and
suggest beam arrangements and weightings that can better meet the
dosimetric goals for the plan. Aggregate dose to contoured structures
are expressed as dose-volume histograms, which display the percentage or absolute volume of the structure receiving a specified dose or
lower (Fig. 27-22). Most dose constraints applied to treatment
Part I: Science of Clinical Oncology
Figure 27-21 • Four-field treatment plan for a thoracic lesion. A combination of anterior-posterior and oblique fields produce isodose lines that
keep the 90% dose region (indicated by the yellow isodose line) away from the
spinal cord and the 50% dose region (indicated by the blue isodose line) out
of the lung.
Figure 27-23 • Wedges in the opposing lateral beams for treatment of
the larynx. The thick ends of the wedges provide extra beam attenuation
where the patient is thinnest.
100
Tumor
Liver
Spinal cord
80
Volume (%)
416
60
40
20
0
0
20
40
60
Dose (%)
80
100
Figure 27-22 • A dose-volume histogram expressed in terms of what
percentage of the structure volume receives at least what percentage of the
total dose. In this example, only 10% of the spinal cord receives 15 Gy or
greater, whereas almost 100% of the tumor receives 100% of the target dose.
Figure 27-24 • Sample intensity-modulated radiation therapy beams
planning are expressed in terms of dose-volume histograms. For
example, a typical constraint imposed on treating lung lesions is to
limit the total volume of lung receiving 20 Gy or more to 30%.135
Determining appropriate dose constraints for normal structures from
clinical data is critical; compilations of so-called “tolerance doses” for
different normal tissue effects are generated periodically as clinical
data accrues and have most recently been aggregated in the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC)
publications.136
obliquity or irregular patient surfaces commonly lead to uneven dose
distributions across a given beam depth. In other cases, the presence
of a sensitive normal structure in the vicinity of the target region may
make it desirable that the photon intensity be lessened across all or
part of a given beam. Varying the intensity of multiple radiation
beams in a manner that improves the overall homogeneity of the dose
to the target and helps to decrease the dose to normal tissue is referred
to as intensity-modulated radiation therapy (IMRT).137
The simplest form of intensity modulation, wedge filters, has been
in use in radiotherapy since the 1960s. A wedge is an angled piece
of high-density material that preferentially attenuates a photon beam
on its thick end, resulting in a dose gradient across the beam. Wedges
are often used to flatten the dose distribution for beams striking
sloped surfaces, as illustrated in Figure 27-23. More recently, complex
intensity distributions have been created by combining multiple
beamlets of varying intensity into a single beam having an intensity
profile customized to meet the needs of a specific patient (Fig. 27-24).
The delivery of multiple beamlets for IMRT is made practical by the
Intensity-Modulated Radiation Therapy
In conventional radiotherapy, treatment plans are designed to deliver
a roughly homogeneous dose distribution to the tumor region. This
goal is most easily accomplished by covering the target with overlapping homogeneous beams. For this reason, most modern linacs are
designed to deliver just such flat dose distributions. Attaining a
homogeneous dose distribution across a target can be complicated by
a variety of factors. For example, geometric concerns such as beam
for treatment of a patient with head and neck cancer. Each of the seven beams
has a computer-optimized intensity distribution that combines with the other
beams in such a way as to produce highly conformal dose distributions.
Basics of Radiation Therapy • CHAPTER 27 417
development of the multileaf collimator, which allows each beamlet
to be formed and delivered in sequence without requiring the intervention of a radiation technologist. The widespread implementation
of multileaf collimators has allowed IMRT to grow from an experimental procedure practiced at a small number of academic centers in
the 1990s to a standard technique applied in clinics all around the
world.
Calculating the proper intensity distributions for multiple intersecting beams is too complex a task for human hand calculations.
Rather than having the physician and physicist create a treatment
plan by manually selecting beam orientations and field shapes, IMRT
fields are designed by computer algorithms called optimizers. The
treatment planners specify the hoped-for dose distribution, expressed
as dose goals and toxicity limits, and the optimizer uses mathematical
techniques to alter the intensity profile of each beam until the dose
goals are met to the greatest extent possible. The first optimizers only
considered purely dosimetric goals, but recent efforts have been made
to include biological end point models in optimization functions,
such as effective uniform dose, tumor control probability, and normal
tissue complication probability. IMRT optimization has been used in
a variety of clinical circumstances and has been shown to have clinical
benefits for treatments in many anatomic sites, such as treatments for
prostate,138 lung,139 and head and neck cancers.140
Once a treatment plan has been completed, approved, peer
reviewed, and passed through a rigorous quality assurance program,
the patient is ready to begin treatment. On each treatment day the
patient must be positioned in an orientation identical to that used
during simulation, and thus the position within the patient designated as the isocenter must be placed in the room position matching
the center of rotation of the linear accelerator. Rough alignment can
be accomplished by aligning the tattoos from the simulation step with
in-room lasers in the accelerator vault. For more precise alignment of
the patient, image-guided radiation therapy (IGRT) techniques can
be used. Global patient positioning can be refined using video
imaging of the patient surface141 or two-dimensional imaging of bony
anatomy (MV portal films or kV radiographs). Techniques to image
soft tissue structures to improve patient alignment include the use of
in-room CT scanners, linac-mounted cone-beam CT scans,142
implantable fiducial markers detectable by radiograph, radiofrequency signal,143 or ultrasound.144 Adjustments to patient position
based on these techniques can be made prior to radiation delivery.
To ensure that the patient moves as little as possible between positioning and the delivery of radiation, several forms of patient immobilization may be used.
During the delivery of radiation, the patient lies as motionless as
possible while the linac rotates around the patient from position to
position, delivering the beams specified during the treatment planning. Treatments are delivered and supervised by radiation therapists,
who operate the linac and monitor the patient and linac position to
ensure that both are in the proper location. A typical treatment
session lasts 10 to 15 minutes, although some cases involving extra
imaging or delivery of high doses can last 1 hour or longer. The
delivery of the radiation itself is undetectable by the patient, because
the actual energy deposited in tissue for a typical 2-Gy fraction,
although sufficient to cause irreparable cellular damage, will only raise
the temperature of the tissue by approximately one one-thousandth
of 1°F.
Brachytherapy
Although it is not used as commonly at present as in the past, the
use of radioactive implants is still a standard part of the tool kit that
the radiation oncologist has at his or her disposal to be able to put
the radiation dose precisely where the tumor is located. This technique is most commonly used in gynecologic tumors and in the
treatment of prostate cancer. For gynecologic malignancies such as
cervical cancer, external radiation therapy is initially used to treat the
pelvic primary tumor and draining lymphatics. Then an implant is
used to give an even higher dose of radiation to the primary tumor
through the use of tubes that are placed in the uterus and the vagina
and subsequently loaded with radioactive sources. Although in the
past it was very common to use “low dose rate” sources for the
brachytherapy, delivering the prescribed radiation dose continuously
(in an inpatient setting) over 2 to 4 days, it is now more common to
use high dose rate sources for which the applicators are inserted daily
or weekly and treatment is delivered over 10 to 15 minutes each week
for approximately five sessions.
Temporary implants are also used for treatment of selected head
and neck squamous cell carcinomas, melanomas of the choroid in the
eye, and occasionally for tumors of other anatomic sites where it is
difficult to otherwise deliver the desired radiation dose.
Prostate brachytherapy is delivered by the placement of permanent radioactive seeds into the prostate. Depending on the radioisotope, the treatment will be delivered over the course of months, with
the implanted radiation sources continuously delivering therapy until
the sources have decayed to the point that they are barely radioactive.
Fortunately, the energy of the radiation deposited by these isotopes
is low, and thus there is minimal public health risk or risk to family
members. This approach is probably the most cost-effective way to
definitively treat early-stage prostate cancer and is very effective
because of the high dose of radiation therapy delivered to the
prostate.
Simulation, Treatment Planning,
and Delivery of Brachytherapy
The short range of radiation from most brachytherapy sources confines the majority of the dose to the immediate vicinity of the sources
themselves, allowing highly conformal dose distributions through the
careful placement of sources within or near the target volume. This
arrangement allows a degree of sparing of nearby normal structures
that may be superior to that achievable with use of external beam
radiation therapy. Because of the high degree of conformity involved,
brachytherapy is most effective for relatively small, well-localized
tumors. Most radionuclides used for radiation therapy use γ-ray
photon emission as the primary source of therapeutic energy. Early
brachytherapy procedures used radium or radon sources, but these
sources have been almost completely replaced by safer, artificially
produced radionuclides such as cesium-137, iridium-192, iodine125, and palladium-103 (Table 27-1). Brachytherapy sources are
generally enclosed in multiple layers of inert material. The inert layers
prevent leakage of the radioactive material and, for photon sources,
absorb unwanted decay products such as α-particles and electrons.
Brachytherapy doses can either be delivered over a short period (temporary implants) or gradually over the lifetime of the seeds (permanent implants).
Brachytherapy treatments are generally delivered using either
interstitial or intracavitary techniques. In interstitial brachytherapy,
radioactive seeds are surgically placed within the tumor volume. The
seed placement can be permanent or temporary. Permanent seeds are
deposited in the tumor volume using needles. Temporary seeds are
placed and removed from the tumor volume through implanted
catheters. A common permanent interstitial procedure is treatment
for early-stage prostate cancer, in which approximately 100 125I seeds,
each the size of a grain of rice, are placed in the prostate. Temporary
interstitial procedures typically use fewer seeds, with MammoSite
therapy for partial breast irradiation using a single 192Ir seed applied
through a catheter.145
Intracavity treatments are the most common technique in current
use for brachytherapy. In this form of brachytherapy, seeds are placed
in existing body cavities in the vicinity of the tumor volume. Radioactive seeds are deployed in catheters arranged in specially designed
applicators that are inserted into the appropriate cavity. Intracavitary
treatment is most commonly used for treatment of gynecologic
cancers but may also be used in other sites, such as the nasopharynx,
418
Part I: Science of Clinical Oncology
the biliary tree, or the esophagus. Intracavitary brachytherapy treatments are always temporary, ranging in duration from a few minutes
to several days.
Two additional brachytherapy techniques include surface application and intravascular brachytherapy. Surface application of brachytherapy sources is conceptually similar to intracavitary treatment, in
that the radioactive sources are placed in an applicator and positioned
adjacent to the treatment area, although in this case the sources are
placed on an exterior surface. Surface application is common for
treatments on the eye, including cancerous (choroidal melanoma)
and noncancerous (pterygium) conditions. Intravascular brachytherapy deploys radioactive seed(s) through a catheter placed in a blood
vessel. This technique has been used to treat tumors in the liver via
the hepatic artery, where the radioactive particle is placed on special
beads that are then embolized in the hepatic vasculature, effectively
limiting the dose to the tumor area in the liver.
Stereotactic Radiosurgery
Although attempts at stereotactic delivery of radiation therapy have
been considered for decades, only during the past few years has there
been a marked increase in interest and use of this approach. Whereas
conventional external beam radiation therapy is designed to preserve
the normal tissue that is being irradiated, the intent with radiosurgical
approaches is that a small amount of tissue that includes the tumor
will be ablated by this therapy. Depending on the precise location, if
the volume irradiated to high dose is small, the likelihood of clinically
significant injury is low, similar to what would be the case with surgical excision. This technique is entirely dependent on very precise dose
localization and the use of many radiation beams so that only the
tumor and immediately adjacent tissues receive a high dose.
The reason this approach has an advantage over surgery is that a
surgical procedure is not required to implement it, and it can often
ablate tumors that are not easily accessible by other approaches. Treatment is usually given in one to five sessions, although more can be
used in special situations. Very large doses (20 Gy) are typically used
for single fraction therapy, doses that otherwise would not be considered for standard external beam therapy because of the high risk
of normal tissue complications. For multifraction therapy, common
fractionation schemes include three fractions of 7 to 15 Gy each, or
four to five fractions of 5 to 12 Gy or higher.
The first radiosurgical approaches were designed for treatment of
intracranial lesions, but the same technique is now used for multiple
anatomic sites. The ability to deliver radiation in this manner is
heavily dependent on the development of radiation therapy hardware
and computer software to design a large number of radiation beams
that intersect at the tumor. The Gamma Knife approach was the
first widely used technique, using a large number of 60Co radiation
sources for the treatment of intracranial lesions. A number of different approaches now exist that use linac techniques for delivering
x-rays stereotactically.
Radiosurgery is used for many clinical situations, including treatment of brain metastases and other intracranial tumors, but treatment
of isolated lesions in the lung, liver, kidney, prostate, and vertebral
bodies are all increasing in use as the technology and our understanding of the biology both improve. An area of great interest is in the
therapy of oligometastatic disease (i.e., with a small number of metastatic sites), either in the liver, lung, brain, or elsewhere. It is now
clear that substantial numbers of patients can be cured by eradicating
a solitary focus of metastatic disease (or a few foci of tumor). Stereotactic approaches are ideal for this type of therapy.
Stereotactic Radiosurgery and Stereotactic Body
Radiotherapy Physics
As previously discussed, the long fractionation schemes used in external beam radiotherapy (e.g., 2-Gy doses delivered in 30 to 40 daily
fractions) are designed to give normal tissue a chance to recover while
still delivering a clinically useful dose to the malignant tissue.
Although this approach helps minimize normal tissue toxicity, the
goal of greater tumor control could be increased further by using large
doses in fewer fractions (e.g., one to five fractions of 5 to 20 Gy each).
The large doses used in hypofractionated treatments are highly toxic
to normal tissues as well as tumors, and thus hypofractionated treatments can only be delivered safely and with acceptable normal tissue
morbidity under the following conditions:
1. well-circumscribed tumors (minimal or no CTV expansion);
2. minimal treatment margin around the lesion (minimal PTV
expansion);
3. rapid dose falloff away from the target area; and
4. very precise (1 to 5 mm) targeting and localization of the tumor.
Stereotactic radiosurgery (SRS) refers to a single-fraction delivery
of a high dose to an intracranial target. The term “radiosurgery” was
coined in 1951 by a neurosurgeon named Lars Leskel,146 who developed the original techniques for SRS in the 1940s using orthovoltage
x-rays. Since that time, patients undergoing SRS have been treated
with heavy charged particles, megavoltage x-rays, and γ-rays from
radioactive sources. During the following decades, the use of SRS has
been documented in more than 4000 publications,147 demonstrating
the effectiveness of the technique in treating primary and metastatic
brain lesions, as well as nonmalignant functional disorders such as
arteriovenous malformations and trigeminal neuralgias. The singlefraction doses in SRS are sufficient to kill any tissue, cancerous or
otherwise, and thus great care must be taken to produce a high-dose
region that is tightly conformal to the target area and to ensure that
the dose is delivered to the correct location in the patient. Highly
conformal dose distributions can be created using 100 to 200 overlapping beams (Fig. 27-25, A) or by delivering dose continuously as
a linear accelerator moves around the patient in one or more arcs
(Fig. 27-25, B). Positioning the patient correctly relative to the beams
requires much stricter immobilization than is typically used for standard radiotherapy. Traditionally, patients would be placed in a rigid
stereotactic head frame, which would then be positioned relative to
the radiation beams by affixing the frame to either the treatment table
or a room-mounted pedestal. The frame, which is affixed to the
patient’s skull prior to patient imaging, provides a known offset
between radiation isocenter and the tumor location, allowing dose
delivery with an accuracy of approximately 1 mm. Newer SRS immobilization techniques have been able to approach the accuracy of
stereotactic frames without requiring fixation to the patient’s skull,
having the advantages of being less invasive and more reproducible
if fractionation is warranted. Examples of these techniques include
vacuum-based frame fixation to the hard palate and IGRT-intensive
frameless radiosurgery. SRS can be delivered to multiple tumor sites
in the brain during a single treatment and is generally limited to
well-defined lesions 2 cm or smaller.
Stereotactic body radiotherapy (SBRT) is hypofractionated treatment applied to extracranial targets, such as in the abdominal, pelvic,
and spinal regions. SBRT has a much shorter history than SRS, with
the first clinical outcomes for SBRT reported in 1995.148 Early SBRT
studies focused on the treatment of lung and liver lesions, but more
recent efforts have included studies of spine, prostate, kidney, pancreas, and gynecologic cancers. The delayed development of SBRT
relative to SRS is largely due to increased difficulties in target localization. For example, whereas intracranial lesions can be expected to
maintain a constant position relative to the patient’s skull, soft tissue
lesions in the body can move relative to bony anatomy or any external
markers used for patient setup. Minimizing this uncertainty requires
the use of in-room imaging devices to ensure accurate beam delivery.
Soft-tissue imaging may be facilitated by implanting radiographically
visible fiducial markers in the region of the tumor. The extensive use
of in-room imaging (IGRT) has largely replaced the use of stereotactic body frames in SBRT. Lesions in the thoracic or abdominal cavities may also move during beam delivery as a result of respiratory
Basics of Radiation Therapy • CHAPTER 27 419
Source
positions
Helmet
(collimator)
Upper
door
Focus (isocenter)
Patient support
Lower
door
Treatment ON
helmet position
Source
shield
A
Linear accelerator
Electron beam path
Flattening filter
Collimator jaws
Tertiary
collimator
assembly
Head frame
Small radiation beam
Gantry rotation axis
Patient
Isocenter
Treatment table
XYZ slides
Support
stand
Floor
Rotational axis:
collimator, headframe,
and turntable
Turntable
B
Figure 27-25 • Techniques and devices to deliver the highly conformal dose distributions required for stereotactic radiosurgery include the Gamma Knife
and linear particle accelerator (linac)-based arc therapy. A, Gamma Knife consists of more than 200 cobalt-60 sources arranged and collimated to overlap at
a single point. B, Linac-based radiosurgery uses a head frame or other device to immobilize the patient’s skull such that the target is located as close as possible
to isocenter. The linac delivers beam continuously as the gantry rotates in an arc around the patient, producing an effect similar to a large number of overlapping beams. (From Bourland JD. Radiation oncology physics. In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saunders;
2012.)
420
Part I: Science of Clinical Oncology
motion. Techniques for minimizing the effects of respiratory motion
include:
1. gating, in which dose is only delivered during a small portion of
the breathing cycle;
2. tracking, in which the beam delivery device moves with the target;
and
3. immobilization, in which patient breathing is regulated or limited
to reduce the degree of tumor motion during treatment.
All of these techniques increase the uncertainty of beam delivery,
requiring larger margins around the GTV and consequently larger
volumes of irradiated normal tissue. Partially because of this situation,
SBRT treatments are typically delivered in three to five fractions.
Intraoperative Radiation Therapy
In oncologic surgery, it is not always possible to remove all cancerous
tissue during the procedure. Presumed microscopic infiltration of
cancer cells into the tumor bed and/or portions of the tumor left
unresected because of the excessive risk of morbidity can be treated
in the operating room using short-range radiation. Intraoperative
radiation therapy (IORT) was attempted as early as 1909149 but did
not become a mature treatment modality until the 1980s. In IORT,
a large single dose of radiation is delivered to an exposed tumor or
tumor bed with the intention of improving the probability of local
control. Performing the irradiation during the surgical procedure
allows sensitive normal structures to be surgically moved out of the
beam path, minimizing the dose received by healthy tissue.
Although radiation oncologists have been delivering radiation
therapy in conjunction with surgeons for many years, techniques to
best accomplish IORT continue to evolve. The intraoperative delivery of electrons (or sometimes orthovoltage x-rays) when a tumor or
tumor bed is exposed provides the potential advantage of direct
visualization of the tissues that need to be treated combined with an
ability to control the depth of penetration of the radiation beam by
using variable energies of electrons.
The technique usually requires a dedicated irradiator in the operating room, and thus it is available only at specialized centers. IORT
provides the greatest advantage in treating deep-seated tumors for
which surgery will be performed, but for which the ability of the
surgeon to completely excise all the tissues at high risk of tumor is
severely limited. Radiation is given in a single session using a high
single dose of radiation on the order of 10 to 15 Gy. This treatment
is often preceded or followed by a course of standard external beam
radiation therapy, with the intraoperative component viewed as a
radiation boost.
The technique has been used most commonly for intraabdominal
tumors, and especially for recurrent tumors in the pelvis, for example,
recurrent rectal cancer. It may have a role in the treatment of retroperitoneal sarcomas and has been evaluated for the treatment of
pancreatic and breast cancers. IORT has also been delivered with low
energy (orthovoltage), low penetrability x-rays to the tumor bed of
small or superficial cancers and with approaches that use a combination of brachytherapy implant and IORT techniques.
Physics Considerations for Intraoperative
Radiation Therapy
IORT treatment modalities require short-range radiation to minimize
the dose to tissue behind the irradiated area, and include high dose
rate brachytherapy sources (typically 192Ir), low-energy photon beams,
or electrons from linear accelerators. Early efforts in IORT required
either a dedicated operating suite with permanent irradiation equipment or that the patient be transferred from the operating room to
a shielded accelerator room. Most modern IORT in the United States
is performed using mobile electron linacs. The advantages of electron
linear accelerators include greater dose homogeneity over the targeted
region, similar dose absorption in tissue and bone, and relatively
modest shielding requirements. In a typical IORT treatment, the
surgeon opens the patient and removes as much of the suspected
cancerous tissue as possible. The electron linac is then maneuvered
into position directly over the surgical site, and the tumor bed and
other high-risk tissues are irradiated. The appropriate electron beam
energy is selected based on the desired depth of treatment, and an
applicator cone is attached to confine the beam to the intended area.
The patient is then moved into position under the linac and the
tumor bed and other high-risk tissues are aligned with the radiation
beam. A dose of 10 to 20 Gy is then delivered to the treatment area,
the patient is moved away from the accelerator, and the surgical team
completes the surgery.
Specialized Radiotherapy Techniques and
Facilities
Investigators have great interest in the use of specialized radiation
modalities that require different machines that produce either
protons, neutrons, or other high-energy particles. Although treatment with photon beams is the most common form of radiotherapy,
particle beam therapy also has many clinically useful properties. As
discussed elsewhere in this chapter, light charged particles such as
electrons lose their energy gradually, depositing dose approximately
evenly as the beam passes through tissue. This process continues until
all energy is expended, at which point the dose delivery stops abruptly,
as illustrated in Figure 27-3. Thus particle beams can be used to treat
a target while delivering almost no dose to anatomic structures
beyond the target region. Therapeutic electrons in clinical use are
limited to treatment depths of 5 to 6 cm, limiting their applicability
to shallow lesions. These high-energy electrons can scatter at large
angles, causing the electron beam to spread as it passes through tissue.
This effect blurs the edges of the dose distribution, making precision
dosimetry difficult.
These limitations can be overcome through the use of heavier
charged particles, such as protons, neutrons, or heavy ions. The use
of heavier particles has several advantages:
1. heavier particles scatter at smaller angles, allowing less blurring
and more precise dose delivery;
2. heavier particles typically have a higher LET, leading to greater
biological effectiveness than an equivalent energy deposition from
standard photon or electron therapy; and
3. for particles such as protons, the distal end of the dose distribution
is quite sharp, allowing much more accuracy in avoiding irradiation of normal tissues deep to the tumor.
Protons
Protons are charged particles that can be accelerated and directed into
tissue, where they deposit their dose. Protons deliver a lower dose to
superficial tissues, then a higher radiation dose at depth where the
tumor is, and then virtually no dose to normal tissues beyond the
tumor, which provides an advantage compared with conventional
x-rays, which deliver the highest doses (from a single beam) to more
superficial tissues. Thus protons can allow for more precise delivery
of the radiation dose to the tumor in comparison with normal tissues.
The RBE for protons is approximately 1.1, and thus they are only
slightly more biologically effective than x-rays or electrons. The principal advantage of proton therapy, therefore, is improved dose
distributions.
Proton therapy is the most common type of heavy particle therapy.
Proton beams are produced by accelerating ionized hydrogen in a
cyclotron or synchrotron to energies in excess of 100 MeV. These
devices are considerably larger and more expensive than conventional
clinical accelerators, and thus they tend to be built as stand-alone
facilities, although research into smaller scale proton devices is
ongoing. Unlike electrons that lose energy roughly evenly across the
range of therapeutic energies, protons lose their energy at an increasing rate as the beams loses energy with depth. This effect culminates
in a region of rapid dose deposition near the depth of maximum
Basics of Radiation Therapy • CHAPTER 27 421
Modulated
proton beam
SOBP
100
Relative dose (%)
is incumbent upon persons using protons for radiotherapy to demonstrate that the extra expense translates into better tumor control
rates and/or fewer normal tissue complications. The lack of such level
I evidence to date has made many persons concerned about the rapid
proliferation of proton facilities.
Neutrons
80
10 MV X rays
60
40
Unmodulated
proton beam
20
0
0
4
8
12
16
Depth in tissue (cm)
Figure 27-26 • Depth-dose comparison between 10 MV x-rays,
unmodulated, and modulated proton beams. Monoenergetic (unmodulated)
proton beams produce narrow regions of high dose, often requiring beam
modulation to spread the dose distribution over a wider range. Both unmodulated and modulated proton beams compare favorably with photon beams
for minimizing dose both upstream and downstream of the target area. (From
Verhey LJ, Petti PL. Principles of radiation physics. In: Hoppe RT, Phillips
TS, Roach M, editors. Leibel and Phillips textbook of radiation oncology.
3rd ed. Philadelphia: Saunders; 2010.)
penetration, called the Bragg peak (Fig. 27-26). The depth of the
Bragg peak increases with beam energy, allowing careful energy selection to ensure that the highest dose is delivered to the tumor volume,
with lower doses upstream of the target and negligible dose downstream of the target. The width of the Bragg peak is virtually always
narrower than the region to be targeted, requiring a range of proton
energies to “paint” high, uniform doses across the target. This widened
dose distribution, known as a spread out Bragg peak, can be created
either by varying the proton beam energy in a synchrotron or by
using a spinning modulator of varying thickness to selectively vary
the beam energy, shown in Figure 27-26.
The largest clinical experience with the use of proton radiotherapy
has been for the treatment of prostate cancer. However, although their
use in this site has a theoretical advantage, that advantage has never
been demonstrated in clinical trials.150 Protons are very appealing for
the treatment of certain pediatric tumors, because the effects of
unwanted irradiation of normal tissues can be severe. In this context,
protons have been used extensively in the treatment of pediatric
central nervous system tumors.151 Studies exploring the use of protons
for therapy of lung cancer and tumors at other anatomic sites are
ongoing. Because the cost of a proton irradiator (and its specialized
facility) is far greater than for traditional x-ray and electron linacs, it
Neutrons are heavy particles that are not charged, and they too are
produced by specialized machines. Neutrons interact with matter
through different mechanisms than the photons and particles previously discussed; these interactions can cause low-energy protons and
heavier ions to be ejected during collisions between neutrons and
target nuclei. These ejected particles cause biological damage in accordance with their LET. Neutron beams therefore have an energydependent, average RBE that can vary between 5 and 20.
Neutrons have no dose distribution advantage over x-rays and in
fact have a disadvantage in dose delivery. However, they are more
potent biologically because of their higher RBE and therefore have
the potential to destroy more effectively certain tumors that are relatively radioresistant, including melanomas, sarcomas, and salivary
gland tumors. Many clinical studies involving neutron therapy have
been conducted, but it has been difficult to find a clear advantage to
this approach over conventional treatment methods.
Heavy Ions
Investigators have had a long-standing interest in using other heavy
charged particles, such as accelerated carbon or neon ions, for therapeutic purposes, and that interest continues to the present day. These
particles have the potential to combine both the biological advantages
of neutrons and the dose distribution advantage of protons. Machines
to produce these particles and the associated operating costs are very
expensive, however, which has substantially limited their development and use to only a handful of facilities worldwide.152,153
FUTURE DIRECTIONS
Enormous advances in radiation therapy have been made in the past
two decades. Such therapy has the ability to localize tumors more
accurately than other modalities and then to deliver radiation much
more precisely to the volume of interest while minimizing the dose
delivered to normal tissue. Most of these advances have been technological, and it is highly likely that further advances will be produced.
Interest is now increasing in melding biology with therapy in terms
of improved biological definition of the tumor location with functional imaging. In addition, better elucidation of tumor subtypes will
allow us to define better which patients are at high risk of local recurrence and therefore require additional local therapy, or which patients
will benefit from various combination treatments. It is also likely that
combinations of radiation therapy and biologics (as well as new
cytotoxics) will have a substantially greater role in clinical practice in
the future by enhancing the selective killing of tumor cells.
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