Basics of Radiation Therapy

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 indirectly. The most important (severely) oxygen-deprived cells.
Perspective cellular target for radiation is DNA, Viable hypoxic cells that exist in
• X-rays were first discovered with irreparable or “misrepaired” many human tumors but that are
emanating from an energized double-stranded breaks believed to mostly absent in normal tissues may
Crooke’s tube by Wilhelm Roentgen be the lesions most responsible for be an impediment to tumor control.
in 1895.1 In 1896, Henri Becquerel cell killing. The elimination of such cells has
discovered that some naturally • Irradiation elicits diverse cellular been a long-standing clinical goal.
occurring elements emitted ionizing responses that include the sensing Hypoxia may provide avenues for
radiation.2 The radioactive elements of DNA damage, mobilization of DNA therapeutic gain through the use of
radium and polonium were isolated repair proteins, repair (or attempted hypoxia-directed therapies.
and characterized by the Curies in repair) of DNA damage, triggering of • Radiation sensitizers, particularly
1898.3 cell cycle checkpoints, and, for cytotoxic chemotherapy and, to a
• Within a year or two, ionizing irreparable or mis-rejoined damage, lesser extent, radiation protectors,
radiation was in use worldwide for cell death by one of several aim to improve the therapeutic ratio.
medical imaging and radiation mechanisms (e.g., mitotic Clinical Radiation Oncology
therapy. catastrophe, apoptosis, and • Radiation therapy is used in more
senescence).
Radiation Physics than half of all patients with cancer,
• The most commonly applied model either as an adjuvant or neoadjuvant
• Several types of ionizing radiation
of cell survival probability is the treatment in combination with
are used to treat patients; most are
linear quadratic (α/β) model, with surgery; as a definitive treatment
of the low linear energy transfer, less
the surviving fraction of irradiated alone or in combination with
biologically potent varieties.
cells described by the equation chemotherapy; as an organ-sparing
• Therapeutic x-rays (photons) and 2

electrons are produced by linear S = e –( αd+ βd ) . The α/β ratio is a therapy; or to palliate symptoms.
convenient metric for describing • Fractionation of radiation and altered
accelerators but can also be
cellular radiosensitivity and has been fractionation schedules, such as
produced by nuclear isotopes that
adapted to describe the response of accelerated hyperfractionated
undergo radioactive decay. These
irradiated tissues as a function of radiation therapy, make use of
form the basis of external beam
time, dose, and fractionation. differences in the responses of
radiotherapy and brachytherapy,
• DNA damage and repair were initially normal and malignant tissues to
respectively.
inferred by monitoring increases in irradiation to achieve higher
• Ionizing radiation interacts with
cell survival or tissue tolerance with therapeutic ratios.
matter via several processes, the
fractionation. These phenomena • Radiation produces early effects,
most important of which for clinical
were termed sublethal and such as mucositis, skin erythema, or
radiation therapy is Compton
potentially lethal damage repair or desquamation, and late effects, such
scattering.
recovery. as fibrosis and carcinogenesis.
• Megavoltage photons from linear
• Cells in different cell cycle phases
accelerators have the desirable Planning and Delivery of
possess different radiosensitivities;
property of delivering their maximum Radiation Treatment
cells are most radiosensitive in the
dose at depth within the patient, • Patient simulation uses multiple
G2 and M phases of the cell cycle,
thereby sparing the skin and, to imaging approaches to identify
and most resistant in the S phase,
some extent, other normal tissues. cancerous and healthy regions
particularly the late S phase. Cells in
The Radiobiology of the G1 phase are of intermediate within the patient and to select
Radiotherapy radiosensitivity. appropriate beams to deliver a
• Ionization of biomolecules from the • Well-oxygenated cells are as much dose to the tumor while minimizing
deposition of energy by photons or as three times more sensitive to the dose delivered to surrounding
particles can occur directly and radiation-induced cell killing than tissues.
Continued
393
394 Part I: Science of Clinical Oncology
• Three-dimensional conformal ensure that the tumor is positioned therapy combine a high dose per
treatment planning and delivery has such that the radiation beams are fraction with highly conformal
permitted escalation of doses and precisely delivered to the appropriate treatment delivery to increase the
improved sparing of normal tissues. location within the patient. therapeutic ratio while reducing
• Intensity-modulated radiation therapy Other Modalities in Radiation treatment time.
uses varying radiation beam • Brachytherapy delivers extremely • Proton therapy has dose distribution
intensities to precisely sculpt the high-dose radiation to tumor tissue advantages compared with photon
dose distribution around the tumor with a much lower dose to therapy, and it may be used to
to improve the therapeutic ratio. surrounding normal tissues. deliver high doses of radiation to
• Image-guided radiation therapy uses • Stereotactic radiosurgery and tumors in close proximity to sensitive
real-time and/or daily imaging to stereotactic body radiation normal structures.
INTRODUCTION 1400 known isotopes of the 92 naturally occurring elements, approxi-

mately 80% are unstable and spontaneously undergo a transition
Radiation therapy, one of the three established cancer treatment between energy levels, emitting energy in the process. The phenom-
modalities, is used to treat most types of solid tumors and selected enon of spontaneous energy release from a nucleus, called radioactiv-
hematologic malignancies. It is used almost entirely to treat malig- ity, can take many forms, including combinations of the emission of
nant disease, although it has a small role in preventing proliferation γ-rays, the ejection of electrons, positrons, or α-particles, and the
in benign disease. Radiation therapy is routinely combined with transmutation of one element to another.
surgery, chemotherapy, or both to improve therapeutic results. It is The term “radiation” refers to energy emitted from a source that
often used with surgery to destroy microscopic regions of tumor is transmitted through a material or space. This radiation can then
extension and with chemotherapy to more effectively destroy the deposit its energy by interacting with the matter through which it
primary tumor. An understanding of the therapeutic use of ionizing passes. Regardless of the source, most radiation used in radiation
radiation requires a basic comprehension of both the physics of radia- therapy involves electromagnetic interactions. This energy can take
tion therapy delivery and the biological effects of the interaction of the form of packets of electromagnetic waves called photons or can
radiation with matter. be carried as the kinetic energy of freely propagating particulate radia-
tion such as electrons, protons, or α-particles.
OVERVIEW OF RADIATION PHYSICS Photons are packets of oscillating electric and magnetic fields
propagating through space at the speed of light (3 × 1010 cm/second).
The toxic biological effects of ionizing radiation, although complex, Photons are characterized by their wavelength, which is the distance
varied, and incompletely understood, form the basis for the use of traversed by a wave over the course of a single oscillation. The possible
radiation therapy as a cancer treatment. These biological effects are wavelengths of photons have no real limits, but common examples
initiated when packets of energy are deposited in a volume of tissue range in wavelength from AM radio (103 m) to visible light (10−7 m)
and remove electrons from constituent atoms through a process called to gamma rays (10−12 m). Photons that have a shorter wavelength
ionization. Accordingly, the physics of radiation oncology is focused oscillate at a higher frequency (i.e., they have more oscillations per
on the details of how, where, and how much energy can be deposited unit time) and are more energetic. Energy and frequency are related
in diseased tissue in the hopes of eradicating it, while simultaneously by Planck’s constant (4.135 × 10−15 eV-sec) and are generally expressed
minimizing the energy released in healthy tissue. This process requires in units of electron volts (eVs), which are equivalent to the kinetic
an understanding of the nature of the radiation and the matter energy of a single electron accelerated over a potential of 1 volt. The
through which it passes and how that matter is changed as a result energy of a photon determines its ability to penetrate matter. Visible
of the energy deposition events. light (~1 eV) can only interact with the surface of objects. Diagnostic
(kilo eV [keV]) and therapeutic (mega eV [MeV]) photons can pen-
The Nature of Matter and Radiation etrate much more deeply, permitting therapeutic effects anywhere in
the body. Photons at therapeutic energies can pass through many
All matter, biological or otherwise, is composed of atoms. Atoms are centimeters of tissue before experiencing any interactions.
made up of groups of electrons (i.e., small negatively charged parti- Most particulate radiation consists of energetic charged particles.
cles) orbiting a nucleus consisting of protons (larger positively charged The electric fields around these particles cause them to interact with
particles) and neutrons (uncharged particles having mass similar to all the other charged particles in the surrounding medium. Charged
that of a proton). The properties of an atom are generally defined by particles are therefore much more efficient at depositing energy in
the number of protons in the nucleus. A matching number of elec- matter, because the particles will continuously lose their energy as
trons are held in orbit around the nucleus by electrostatic attraction. they attract or repel other charged particles along their path. Many
A specific, discrete set of possible electron orbits exists for each kind of these interactions will cause ionization, which correlates with the
of atom, with each electron orbit corresponding to a specific energy. amount of biological damage delivered. Heavy particles, such as
Moving an electron from one orbit to another requires adding or protons and α-particles, ionize matter very efficiently, lose energy
subtracting the energy difference between the two orbitals, and more efficiently, and have a higher linear energy transfer (LET), that
removing an electron from the atom entirely, that is, ionization, is, amount of energy loss per length of the particle’s track (discussed
requires adding the full energy of the electron orbital. later in this chapter) than do lighter particles such as electrons and
The properties of a nucleus are defined by the number of protons positrons. Although most particulate radiation is charged, uncharged
and neutrons, with the number of protons defining the type of neutrons are also capable of depositing energy in a material. Unlike
element and the number of protons and neutrons together defining charged particles, neutrons can only interact with other nuclei. Gen-
the isotope. Analogously to the arrangement of electrons in an atom, erally, this interaction takes the form of a collision with a proton. The
protons and neutrons are arranged in discrete energy levels specific proton recoils with some fraction of the neutron’s initial energy. The
to a particular nucleus, and transitioning between energy levels positively charged proton then ionizes the surrounding particles,
requires adding or removing a comparable amount of energy. Of the causing most of the biological damage.
Basics of Radiation Therapy • CHAPTER 27 395
Interactions of Radiation and Matter Compton effect
In order of roughly increasing energy, photons can interact with: e:

1. the atom as a whole; e:
2. tightly bound inner shell electrons; p;np;
3. loosely bound outer shell electrons; np; n
e: np; e:
4. the extranuclear space surrounding the nucleus; or np; n e: Fast
5. the nucleus itself. e: electron
Coherent Scatter e:
Scattered
Low-energy photons can be briefly absorbed by the bound electrons photon
of an atom. If the photon lacks the energy to remove the electron
from the atom, the photon energy will be immediately reemitted as Incident photon
another photon. The reemitted photon has the same energy as the Photoelectric effect
incident photon, and close to the same direction of travel. Because
no energy is deposited, coherent scattering does not contribute to Vacancy in k-shell
Incident photon e:
dose deposition, but the small deflections of the photons from coher- e: Fast
ent scatter can cause blurring in diagnostic images. Coherent scatter- electron
ing accounts for approximately 10% of interactions at 30 keV and is p;np;
np; n
negligible for most therapeutic energy beams. e: np; e:
np; n
Photoelectric Effect e:
Photons having sufficient energy to ionize an atomic electron can
undergo the photoelectric effect (Fig. 27-1). In this process, the e:
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 Characteristic x-rays
interaction scales with the cube of the atomic number (Z) and the Pair production
inverse cube of the photon energy (E), making the photoelectric effect
very sensitive to material type and much more prevalent for lower Incident photon e:
photon energies. The photoelectric effect is the dominant photon
e:
interaction in tissue below 30 keV. e: Positron
p;np;
np; n e; electron
Compton Scattering e: p; np; e: pair
np; n
When photon energy is significantly higher than the binding energy
e:
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 e:
electron with some fraction of the initial photon energy. The energy
of the scattered electron varies with the scattering direction. An elec- Figure 27-1 • Photons interact with atoms through three major mecha-
nisms. Low-energy photons interact through the photoelectric effect, in
tron scattered in the direction of the incident photon claims most of which photons are absorbed by an atom, which then ejects an energetic
the initial photon energy, whereas electrons scattered at greater angles electron. Higher energy photons undergo Compton scattering, in which both
have successively less energy. Compton scattering is only weakly the photon and an electron are scattered from an atom. At higher energies,
dependent on Z and is the dominant photon interaction in tissue photons can interact with the field around the nucleus and undergo pair
between 30 keV and 30 MeV. production, in which the photon spontaneously converts into an electron-
positron pair.
Pair Production
Above 1.022 MeV, photons can interact in the presence of a strong is more likely to happen during photon generation in a linear particle
nuclear field. The photon will disappear and spontaneously become accelerator (linac) than in tissue. Neutrons produced in this manner
an electron-positron pair (Fig. 27-1). The electron and positron will can contribute a significant background radiation dose to patients
divide the initial photon energy between them to create their mass receiving radiotherapy from very high energy machines. However,
and kinetic energy. These particles will lose their energy as they photodisintegration is negligible for accelerators operating below
interact with the surrounding materials. Upon losing all their energy, 10 MV.
the electrons will be absorbed into an atom. The positron, on the
other hand, will annihilate by interacting with a local electron, creat- Charged Particle Interactions
ing two 511 keV photons. (This annihilation reaction is what is Charged particles will lose and transfer their energy to a medium
detected during positron emission tomography scanning.) Pair pro- through two mechanisms: collision and radiation. Collision energy
duction is the dominant atomic interaction in tissue for photons loss by an energetic charged particle refers to the energy transfer
above 30 MeV and therefore has only a minor effect in radiation resulting in ionization, excitation, and molecular damage. In a colli-
therapy, where energies are significantly lower. sion event, energy is absorbed in the medium at or very near the site
of the interaction. Collision energy loss accounts for more than 95%
Photodisintegration of energy loss in tissue for therapeutic-energy electrons and is the
Above a threshold energy, a photon can be absorbed into an atomic major source of absorbed dose along the path of the electrons. Radia-
nucleus and cause one of the nucleons (a proton or a neutron) to be tive energy loss occurs when particles are accelerated in the electric
ejected. This process is called photodisintegration. Photodisintegra- field of a nucleus and emit a fraction of their energy as a photon.
tion is more probable in high-Z materials (such as metals), and thus This process, called bremsstrahlung, is relatively unimportant in
tissue but is fundamental to the production of therapeutic photons The dose from a photon beam is related to its intensity, defined
in a linac. as the number of photons per unit area. Two major effects serve to
Most electromagnetic interactions result from an interplay decrease the intensity of a photon beam as it passes through tissue.
between photons and electrons, because many photon interactions First, as with any photon source, the beam intensity decreases with
result in atomic ionization and release of an energetic electron, with increasing distance from the source, just as is the case for a light bulb.
some of the electron energy converted back into photons through the In addition, beam intensity decreases as photons are attenuated from
bremsstrahlung process. Thus the effects of therapeutic beams passing the beam via various scattering and absorption effects. This process
through tissue can be described as a photon-electron shower, with the leads to a characteristic decrease in intensity versus depth that varies
highly penetrating photons carrying energy deeper into tissue until based on photon energy. Although the photon intensity begins
a scattering event occurs, and the resulting scattered electrons de decreasing immediately upon entering a material, the energy released
positing most of the resulting energy locally through collisional through the photon interactions is spread over a few centimeters as
interactions. the electrons scattered by the photons gradually lose their energy as
they pass through the material. The resulting dose distribution is
The Generation of Therapeutic Radiation 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
To be useful in radiation therapy, radiation must be generated in a increases. The plot of dose versus depth is called a percent depth dose
manner in which it can be directed at the targeted tissues. Radiation curve, as shown in Figure 27-3. Because higher energy photons are
for cancer therapy is predominantly generated through two means: more penetrating, higher energy beams will attenuate more slowly,
linacs and radioactive sources. leading to a more gradual decrease in dose with depth.
Linacs designed to produce photon beams can also be configured
Linear Accelerators to produce therapeutic electron beams. Removing the photon-
The most common modality used in radiation oncology is external generating target and replacing it with a comparatively thinner elec-
beam radiation therapy. Although a small number of radiation tron scattering foil allows the transmission of the initial electron
therapy facilities generate external beams using radioactive sources beam, but not without scattering the initially narrow beam into a
such as cobalt-60, the vast majority of therapeutic electromagnetic broader distribution. Multiple filters and beam-shaping elements, as
radiation is generated in a linac. A linac is a device that accelerates shown in Figure 27-2, B, produce an even distribution of customized
charged particles (electrons) to velocities near the speed of light using shape at the surface of the patient. Electron beams lose their energy
oscillating electric fields to push the electrons through a series of through different types of interactions than photons, leading to a
accelerating cavities. A schematic of a linac is shown in Figure 27-2, different pattern of dose versus depth for electron beams. Rather than
A. Electrons are accelerated to energies typically between 4 and 18 periodically removing photons from the beam through attenuation,
MeV. Electric and magnetic fields focus and steer the high-energy electrons lose their energy gradually and at a relatively constant rate
electrons such that they strike a thin metal target that stops the elec- until the entire kinetic energy of the electron is expended and the
tron beam, with some fraction of the electron energy converted to a particles simply stop. Ideally, this phenomenon would lead to a region
spray of photons through the bremsstrahlung process. The brems- of constant dose with increasing depth until the depth of full energy
strahlung photons, called x-rays, move approximately in the same loss is reached, at which point the dose would drop abruptly to zero,
direction as the electrons and have an energy spectrum, ranging from with the depth of the dose drop-off being dependent on the initial
a few 10’s of keV up to the maximum energy of the initial electrons. electron energy. In practice, scattering and redirection of electrons
The resulting photon beam then passes through a series of filters and within the beam lead to a mildly peaked dose plateau region and a
beam-shaping elements that flatten and define the edges of the beam. somewhat more gradual dose falloff, as shown in Figure 27-3.
Electron beam Electron beam

X-ray target
X-ray target
Primary collimator Primary collimator
Forward peaked
x-ray beam Scattering foil Scattering foil Flattening filter
Carousel
Flattening filter Carousel
Ion chamber Ion chamber
Secondary Secondary
collimator collimator
Slot for wedges,
blocks, compensators Accessory
Flattened mount
x-ray beam
Electron applicator
Patient Patient
A B
Figure 27-2 • Schematic of the treatment head of a modern linear accelerator operating in photon-production mode (A) or electron-production
mode (B).
100
90
80
Depth dose (%)

70
60 100
Depth dose (%)

110 KV
50 80
6 MV
18 MV 60
40 18 MV
6 MV 40
30 20
20 60Co 0
10 6 MeV 12 MeV 20 MeV 110 KV 0 2 4 6 8 10121416 18 20
Figure 27-3 • Dose deposited versus increasing 0 Depth (mm)
depth for photon beams (110 KV, cobalt-60, 6 MV 0 5 10 15 20 25 30
and 18 MV) and electron beams (6 MeV, 12 MeV, and Depth (cm)
20 MeV).
Radioactive Sources
Table 27-1 Therapeutically Useful Radioisotopes
Unstable isotopes can spontaneously decay to lower energy states,
releasing energy in the process. This radioactive decay can result in Isotope Half-Life Average Energy (keV)
the emission of therapeutically useful photons, electrons, or other PHOTON
decay products. The degree to which a sample is radioactive is called 226
its activity and is defined as a number of decays per unit time. The Ra 1620 y 830
activity of a sample depends both on how much of the isotope is 137
Cs 30 y 662
present and how quickly the isotope decays. The historic unit of 198
Au 2.7 d 412
activity is the Curie (Ci), which is defined as 3.7 × 1010 atomic decays/ 192
Ir 73.8 d 370
second, corresponding to the decay rate of 1 g of radium-226. Activ-
125
ity is also specified in Becquerel (Bq), defined as 1 decay/second. I 60 d 28
Because the rate of disintegration is proportional to the number 103
Pd 16.97 d 21
of nuclei present, the absolute number of radioactive nuclei will decay
Isotope Half-Life Maximum Energy (keV)
exponentially. Activity is proportional to the number of nuclei, and
thus a sample’s activity, and therefore its ability to deliver dose, will BETA
decay with the same exponential behavior. The decay is described by 32
P 14.3 d 1710
A(t) = Aoe−λt, where A is the current activity, Ao is the activity at time 90
Sr/90Y 28.5 y/2.7 d 550/2280
zero, and λ is a decay constant for the isotope in question. The decay 188
rates for various isotopes are more commonly given as the time W/188Re 69.4 d/17 h 350/2120
required for half of the sample to decay away; this period is called 186
Re 3.8 d 1070
the half-life of the isotope. 62
Zn/ Cu 62
9.3 h/9.7 min 660/2930
Therapeutically useful isotopes vary in half-life and in energy of 133
emitted particles, as shown in Table 27-1. Isotopes emitting higher Xe 5.2 d 360
energy particles can deliver significant amounts of dose farther from 131
I 8.0 d 600
the radioactive source than those emitting lower energy particles. One 89
Sr 50.5 d 1495
type of radioactive source, 60Co, emits photons with an average 166
Ho 26.8 h 1850
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
From Cox JD, Ang KK, editors. Radiation oncology: rationale, technique, results.
targets deep in a patient. Most other therapeutically useful radioactive 8th ed. St Louis: Mosby; 2003.
sources emit lower energy radiation with less penetrating power and keV, Kiloelectron volt.
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 three-dimensional (3D) distribution of radioactive seeds within the
basis. The dose rate falls off very quickly with distance from a seed, volume to be treated, creating a high-dose region that decreases
both because of rapid attenuation and the rapid spread of photons as rapidly beyond the treatment volume. Both of the aforementioned
they move away from the source. treatment modalities require a 3D understanding of the patient
anatomy and require:
Delivery of Therapeutic Radiation 1. precise location of the tumor within the patient anatomy;
2. customization of a treatment plan for an individual patient; and
The cytotoxic properties of ionizing radiation provide an opportunity
3. reliable and reproducible positioning of the patient relative to the
for tumor control but also require that care be exercised to limit the
radiation sources such that the intended radiation pattern can be
exposure of healthy tissue to radiation. For external beam radiation
precisely delivered.
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 THE RADIOBIOLOGY OF RADIATION THERAPY
region of the tumor, delivering a high dose to the overlap area and a Mechanisms of Radiation Damage to Cells
comparatively low dose to other areas. For treatment based on
implanted radioactive sources, a procedure known as brachytherapy, As discussed previously, ionizing radiation (in the form of photons
proper dose delivery consists of designing and delivering a or particles) deposits energy as it traverses the absorbing medium
through which it passes, with the most salient feature of this interac- a cell macroscopically speaking but do not produce equivalent bio-
tion being the random and discrete nature of the energy deposition logical effects because it is the microscopic pattern of that energy
events. Energy is deposited in increasingly energetic packets called deposition, the spacing or density of the discrete ionization events
quanta, each of which leaves anywhere from a handful to several along the track of the photon or particle, that is key to determining
dozen ionized atoms in its wake. Assuming the absorbing medium biological effectiveness. In this example, the 1 Gy of neutrons is
is a biological system, a mammalian cell for example, any and all much more potent biologically because the average energy deposited
biological molecules contained in that cell are potential targets for locally along the length of each neutron’s track is higher than for
these highly localized energy deposition events. Secondary particles x-rays. This quantity of ionization density, typically expressed in units
set in motion by the original ionization event can themselves go of keV/µm, is termed the radiation’s LET. The concept of ionization
on to produce additional damage. This chain reaction continues density is illustrated graphically in Figure 27-5 for radiations of dif-
until all the energy deposited by the incident photon or particle is fering LET, using a strand of DNA drawn to scale as a representative
consumed. “biomolecule.” Although most radiation therapy is performed using
The total amount of energy imparted to a cell during the passage low LET x-rays, γ-rays, or electrons, a few institutions do use high
of ionizing radiation (expressed in units of dose, Gray, which in turn LET neutrons or even higher LET heavy charged particles (heavy
is expressed in units of energy deposited, joules per kilogram) is by ions), such as carbon ions, for treatment. Lower total doses of these
itself insufficient to describe its biological consequences. For example, radiations are used to achieve tumor control in keeping with their
1 Gy of x-rays and 1 Gy of neutrons deliver the same total energy to greater biological potency, and especially stringent limits are placed
on the amount of normal tissue incidentally irradiated out of justifi-
able 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 mea-
surable biological effect depends on a number of factors, including
how important the molecule is to the continued survival and function
Gantry (G) of the cell, how many copies of the molecule are normally present in
Collimator (C)
C the cell, and to what extent and how the cell responds to the loss of
G working copies. DNA is arguably the most important cellular mac-
Isocenter romolecule 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 under-
standing radiation-induced DNA damage and its repair and the
T
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
Table (T) (patient support assembly) to the DNA damage resulting from direct energy absorption by
migrating to the DNA and damaging it indirectly, as illustrated in
Figure 27-4 • Layout for gantry-based radiotherapy machines. The
linear accelerator rotates around a single point called the isocenter. Patients Figure 27-6. This mechanism is referred to as “indirect radiation
are placed on a movable table to align the area to be treated with isocenter. action” to distinguish it from “direct radiation action”4 previously
(From Bourland JD. Radiation oncology physics. In: Gunderson LL, Tepper described. Approximately 30% of the total DNA damage produced
JS, editors. Clinical radiation oncology. 3rd ed. Philadelphia: Saunders; by a given dose of x-rays is from the direct effect, and 70% is from
2012.) the indirect effect.4
Incident particle track
DNA
helix
“Spur”: 0–100 eV
10 nm
“Blob”: 100–500 eV
Short track: 500–5000 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.)
replicating or transcribing gene versus an inactive one), and, critically,

the overall repair competence of the cell in which the lesion was
created.7
Direct
For a more in-depth discussion of the molecular biology, biochem-
photon-DNA
interaction istry, 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 com-
plexes. Some of these proteins are interchangeable and participate in
different DNA repair and replication pathways, whereas others are
H2O2 unique to specific types of repair. In fact, some are not directly
involved with repair per se but rather link DNA repair to other cel-
lular functions, including damage sensing, cell cycle checkpoint
eaq H2O
control, chromatin remodeling, and apoptosis.9 Inactivation or loss
of any of these myriad proteins can lead to dysfunction of the DNA
O•
damage response, which in turn can precipitate diverse clinical syn-
dromes of varying severity including immunodeficiency, neurodegen-
Indirect erative disorders, infertility, premature aging, hypersensitivity to
interaction 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
Figure 27-6 • DNA damage that occurs after radiation exposure is a defects in other pathways, it may be that the clinical strategy of DNA
result of two types of ionization interactions. The “direct effect” occurs when
an incident photon deposits energy directly into the DNA, ionizing it. The
repair inhibition will have a greater effect on the tumor than on
“indirect effect” occurs when water molecules are ionized and the reactive normal tissues.10 The approach of combining DNA repair inhibitors
species that are created damage DNA indirectly. with radiation to produce selective tumor radiosensitization is dis-
cussed further later in this chapter.
Complex macromolecules like DNA that have been ionized and The Molecular Biology of Cellular
converted to free radicals undergo a series of chemical transmutations Radiation Responses
in an attempt to rid themselves of unpaired electrons, many of which
involve the further breakage of chemical bonds. These broken bonds Much more has been learned about the radiation response of cells at
can result in the modification or loss of a DNA base or an entire the molecular level since the molecular biology and biotechnology
nucleotide, a cross-linking of the two DNA strands, or a scission of revolutions beginning in the early 1980s. In fact, many of the radio-
the sugar phosphate backbone involving either one or both strands. biological phenomena carefully characterized decades ago but neces-
Luckily, DNA is unique in that it is the only cellular macromolecule sarily couched in operational terms (e.g., clonogenic survival, sublethal
with its own repair system, and most of this damage can be repaired damage recovery, and the cell cycle age response) now have solid
efficiently and typically with very high fidelity. Under certain circum- molecular underpinnings. Of particular interest to radiation biologists
stances, however, the cell’s attempts to repair these lesions may result is the molecular basis of radiation sensitivity, the pertinent aspects of
in large segments of DNA being lost, rearranged, exchanged, or which will be summarized here. An important ramification of our
rejoined in inappropriate ways, so-called “misrepair.” In other cases, ever-growing understanding of the molecular workings of cells is the
repair is impossible because of the complex nature of the damage promise of being able to identify and target specific genes, proteins,
itself, particularly when both DNA strands are involved (e.g., a DNA or pathways for therapeutic gain, such as to render tumors cells more
double-stranded break), or its location in the genome in time and radiosensitive or normal cells more radioresistant.
space. It is this residual DNA damage that manifests itself as chromo- A cell’s (normal or tumor) radiation response represents a complex
some aberrations the next time the cell attempts to go through mitosis interplay between intrinsic properties and extrinsic factors imposed
and that usually leads to cell death. In fact, the radiation dose response by the cell’s microenvironment. Properties intrinsic to the cell include,
for the production of asymmetrical, exchange-type chromosome for example, its capacity to recognize and repair DNA damage, its
aberrations mirrors the shape of the corresponding cell survival position in the cell cycle, and its response to being damaged, that is,
curve.5 to either adapt and grow or to die. However, extrinsic, environmental
Historically, much of what radiobiologists learned (or inferred) factors also can contribute to cellular radiosensitivity. Examples
about DNA damage and repair, its time course, and its implications include the availability of nutrients and oxygen, the ability to elimi-
for cell survival and radiotherapeutic response came at least two nate waste, and the presence or absence of cytokines, growth factors,
decades before the complex molecular underpinnings and processes or other signaling molecules that instruct the cell how to respond to
involved in the different types of mammalian DNA repair were its radiation injury.
elucidated. Normal mammalian cells have in common key molecular signal-
We now know that several different DNA repair pathways exist ing pathways that regulate growth, death, and differentiation, many
in mammalian cells, including single-step reactions that directly of which are activated in response to radiation exposure. Many of
reverse certain simple types of damage, single and multistep base these pathways also exist in tumor cells but are typically dysregulated—
excision and resynthesis processes, and multistep pathways to “clean that is to say, hyperactive or hypoactive—secondary to the activation
up,” resynthesize, and ligate single or double-stranded breaks in the of oncogenes and/or the inactivation of tumor suppressor genes. Not
DNA backbone.6 Which one (or more) of these repair pathways is surprisingly, the activity (or lack thereof ) of these pathways can influ-
activated depends on a number of factors, including the type of lesion ence both cellular radiosensitivity and other radiation responses of
produced, the physical location of the lesion in the genome (e.g., in intact tissues.
the coding region of a gene versus in apparently noncoding DNA), The first activated oncogene identified to confer radiation resis-
the functional/temporal location of the lesion (i.e., in an actively tance was NRAS (see references 11 and 12). Ras proteins, products
of RAS family member genes, are small guanosine triphosphatases Death as a permanent, irreversible cessation of vital functions is
activated by upstream receptor tyrosine kinases. They transduce not the same as what constitutes “death” to the radiation biologist or
signals to a complex downstream cascade of protein kinases that have oncologist. For proliferating cells, including those maintained in vitro
the net effect of promoting cell survival (for example, by the suppres- and the stem cells of both normal tissues and tumors in vivo, cell
sion of apoptotic cell death pathways) and unlimited proliferation death in the radiobiological sense refers to a loss of reproductive
(secondary to, for example, the downregulation of antiproliferative integrity or clonogenicity, that is, an inability to sustain proliferation
proteins), two of cancer’s hallmark phenotypes. When the ras protein indefinitely. It is important to note that the term “clonogenic death,”
is mutated, however, as is the case in approximately 30% of all human as first described more than 50 years ago, is operationally defined and
cancers, these pathways become overactive and no longer responsive today serves as a catch-all term encompassing various mechanistic
to the normal regulatory mechanisms that antagonize the ras pathway ways that cells die, all of which culminate in a cell losing its ability
and reign in excessive proliferation. This situation is exacerbated in to divide indefinitely. These modes of cell death include mitotic
many tumors by the concurrent loss of function of tumor suppressor catastrophe (the most common form of cell death after radiation
proteins. exposure), apoptosis, autophagy, necrosis, senescence, and, strictly
Ras became, accordingly, a desirable target for molecular cancer speaking, differentiation as well, to the extent that differentiated cells
drug development.13 The general approach to targeting ras focused lose their ability to divide.23 Another noteworthy feature of clono-
on its need for posttranslational modification through prenylation to genic death is that it does not necessarily preclude the possibility that
become activated.14 Despite encouraging preclinical results with a a cell may remain physically intact, metabolically active, continue its
class of prenylation-inhibiting agents known as farnesyl transferase tissue-specific functions, and even divide a limited number of times
inhibitors—drugs that, when used alone or combined with radiation, after irradiation.
produced sensitization of tumor cells with constitutively active ras The first report of a quantitative measure of intrinsic radiosensitiv-
pathways—these drugs did not meet expectations in clinical trials ity for a human cell line (HeLa, derived from a cervical carcinoma)
because of alternative prenylation pathways.13 was published by Puck and Marcus in 1956.24 For different doses of
Subsequent drug development focused on inhibiting proteins x-rays, the reproductive integrity of HeLa cells was measured by their
upstream of ras, in particular, members of the human epidermal ability to form macroscopic colonies of at least 50 cells (correspond-
growth factor receptor (EGFR) family of receptor tyrosine kinases ing to approximately six successful postirradiation cell divisions) on
that transduce growth signals through ras and other signaling pro- Petri dishes. The HeLa cell survival curve, in which the log of the
teins.15,16 These transmembrane glycoproteins are activated through surviving fraction of cells was plotted as a function of the radiation
binding of ligands belonging to the EGF family of peptide growth dose, was characterized by a roughly exponential dose response at
factors. intermediate to high doses and a bending, “shoulder” region at low
Cetuximab, a human-murine chimeric immunoglobulin G1 doses where cell killing was less effective. This phenomenon is illus-
monoclonal antibody raised against the EGFR, is among the more trated graphically in the upper panel of Figure 27-7. Radiation sur-
successful molecularly targeted drugs, yielding improved outcomes in vival curves for hundreds of cell types derived from mammalian
squamous cell head and neck cancers when combined with radiation tumors and normal tissues have been generated in the years since the
therapy.17 Details of its mechanism of action and clinical use are pioneering work of Puck and Marcus,24 and most are qualitatively
discussed later in this chapter. Other classes of drugs that target similar to the original HeLa survival curve (see lower panel of
EGFR include the small molecule tyrosine kinase inhibitors gefitinib Fig. 27-7).
and erlotinib, which inhibit EGFR phosphorylation and its down- Mathematical models were developed to fit the cell survival data,
stream cascade by blocking the intracellular catalytic domain of the with survival curve theory originating in a consideration of the
receptor.18 These drugs have shown some efficacy in selected patients physics of energy deposition in matter by ionizing radiation. An
with treatment-refractory, advanced non–small cell lung cancer assumption inherent to target theory was that a biological response
(NSCLC).19 (cell killing in this case) resulted from critical “targets” receiving
A second molecular target of interest is vascular endothelial random “hits”25 in a probabilistic manner. Further, for cell survival
growth factor (VEGF) and/or its cell surface receptor. VEGF is the curves with shoulders, each target was envisioned as requiring more
most potent of the proangiogenic endothelial cell proliferation stimu- than one hit to elicit the response, that is, that “sublethal” damage
lators and chemoattractants and plays a pivotal role in promoting had to accumulate first before the cell would be killed. One mathe-
tumor survival by stimulating the growth of new blood vessels derived matical expression derived from target theory that provided a fairly
from the host vasculature. This phenotype of sustained angiogenesis good fit to survival data was:
is a hallmark property of cancer. Several isoforms of VEGF bind
S = 1 − (1 − e − D/D0 )n
to the corresponding receptors VEGFR1, VEGFR2, and VEGFR3
(encoded, respectively, by the genes FLT1, KDR, and FLT4).20 In this equation, S is the fraction of cells that survive a given
Bevacizumab, a recombinant humanized monoclonal antibody, is dose (D), D0 is the dose increment that reduces the cell surviving
the first molecularly targeted antiangiogenic drug to gain approval fraction to 37% (1/e) of some initial value on the exponential
for clinical use by the U.S. Food and Drug Administration. This portion of the curve, and n, the extrapolation number, is the back
antibody binds to VEGF, with the net effect of eliminating signaling extrapolation of the exponential portion of the survival curve to
to vascular endothelial cells to initiate angiogenesis.21,22 The clinical zero dose.
use of bevacizumab in combination with radiation therapy is dis- Over time, it became apparent that some features of this model
cussed later in this chapter. were inadequate,26 not the least of which was that its basis was the
probabilistic nature of energy deposition in matter by ionizing radia-
Cell Survival and Tissue Dose-Response tion and not anything biologically based. For example, target theory
Curves was not concerned per se with which biomolecules in the cell were
the purported “targets” of radiation damage, what the nature of the
Tumor control is achieved only when essentially all clonogenic cells damage was in a molecular sense, or how the cell responded to it.
(the putative “tumor stem cells”) are killed or otherwise rendered (Of course, it was not lost on radiation biologists of the day that at
unable to sustain tumor growth indefinitely. To estimate the likeli- least one cellular target was likely to be the DNA contained in
hood of cure, it is necessary to know, at least to a first approximation, chromosomes.24)
how radiosensitive or resistant these cells are—that is, some measure A different and more biology-based interpretation of the dose
of cell killing efficiency per unit radiation dose. response for radiation-induced cell killing was proposed by both
Y= αD + βD2
100
Surviving fraction
e–
10:1
e–
10:2
e–
10:3
0 200 400 600 800 1000 1200
A Exposure (R)
+
100
Surviving fraction
Figure 27-8 • Chromosome aberration production can be modeled

10:1 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
10:2 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
10:3 shown on the right. (From Wilson PF, Bedford JS. Radiobiologic principles.
0 200 400 600 800 1000 1200
In: Hoppe RT, Phillips TS, Roach M, editors. Leibel and Phillips textbook
of radiation oncology. 3rd ed. Philadelphia: Saunders; 2010.)
Dose (cGy)
Hewitt and Wilson: CBA mouse leukemia and tumors in vivo.29-31 Some of these assays used the reproductive
Puck and Marcus: human carcinoma
McCulloch and Till: mouse bone marrow integrity of cells as an end point, similar in principle to the in vitro
Mutants (e.g., A-T) survival curve assay, but in which the animal essentially served as its
B own Petri dish. One classic example of an in vivo clonogenic assay is
Figure 27-7 • X-ray or γ-ray acute-dose radiation survival curves for the spleen colony assay of Till and McCulloch,30 which originally was
mammalian cells. A, The first such survival curve (for HeLa cells, obtained developed as a model system for the study of bone marrow transplan-
from a patient with cervical adenocarcinoma) was published in 1956 by Puck tation. These authors determined that lethally irradiated mice could
and Marcus.24 (Note that the dose is expressed in Roentgens (R), which for be “rescued” by a bone marrow transplant and that the transplanted,
cells x-irradiated while adherent to glass Petri dishes, must be multiplied by viable bone marrow stem cells were noted to form discrete nodules
approximately 1.4 to obtain the dose in cGy.) B, A family of survival curves or colonies in the spleens of irradiated animals. By extension, then,
for other types of mammalian cells. The dashed lines encompass the radio- a mouse’s spleen could be used as a pseudo Petri dish, with the
sensitivity range for wild-type cells, whereas the steepest curves show the number of clonogenic bone marrow colonies countable as a function
range more typical of hypersensitive mutants, such as cells from patients with of the radiation dose that the donated bone marrow received prior
the disease ataxia-telangiectasia.
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
Kellerer and Rossi27 and Chadwick and Leenhouts.28 The linear- or as parts of a more complex tissue containing many different,
quadratic (LQ) or “alpha-beta” equation, interacting cell types in 3D contact.
2 Unfortunately, in vivo clonogenic assays necessarily involved the
S = e − ( αD + β D ) sacrifice of the animal and thus obviously are not applicable for clini-
was shown to fit cell survival data quite well, particularly in the cal use. Further, such assays are labor intensive and involve long
low-dose region of the curve where the target theory model often waiting periods before results are obtained, adding to their impracti-
failed.26 In this expression, S is again the fractional cell survival cality. A second type of in vivo radiosensitivity assay is nonclonogenic,
following a dose (D), α is the rate of cell kill by a single-hit process, using a tissue structural or functional end point as a surrogate for cell
and β is the rate of cell kill by a two-hit mechanism. Implicit in survival. Data derived from nonclonogenic assays and plotted as a
the LQ model was that (borrowing the language of target theory function of radiation dose are properly called dose-response curves
for comparative purposes only) DNA (or a chromosome) was the rather than cell-survival curves, because cell survival is not the end
target, and the hits corresponded to irreparable or misrepaired lesions point being assessed. Regardless, cell-survival curves and dose-
produced by either one or two radiation tracks traversing the cell response curves are often analyzed and interpreted similarly; for
nucleus (Fig. 27-8). example, a mathematical model is commonly used to fit the data and
A comparison of the features and parameters of the target theory survival curve parameters are calculated.
and LQ survival curve models is shown in Figure 27-9. Two examples of nonclonogenic assays, one for normal tissues and
To bridge the gap between the radiation responses of single cells one for tumors, are worth mentioning, especially because aspects of
grown in culture and tissues or tumors in a laboratory animal or both are used routinely in the clinic, if not in the exact same way as
human patient, several ingenious methods were developed to measure, the laboratory assay. One of the first nonclonogenic methods devel-
or at least estimate, the radiation sensitivity of intact normal tissues oped to assess normal tissue radioresponse was the skin reaction
n S=1– (1–e-D/D0)n
Dq
Surviving fraction
α Cell kill
Surviving fraction
β Cell kill
0.01
1/e S=e – (αD + βD2)
0.0037
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
100
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 corre-
Surviving fraction
10–1
spond 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
10–2
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
10–3
dimensions (or volume) are measured periodically as a function of
time after irradiation, with the degree of tumor shrinkage assumed 0 2 4 6 8 10 12 14
to be a reflection of the fraction of clonogenic tumor cells killed. Dose (Gy)
Dose-response curves are generated by plotting the amount of growth
delay (in days) as a function of radiation dose.
High LET (alpha particles)
Intermediate LET (15 MeV neutrons)
Modifiers of Radiation Sensitivity Low LET (250 kvp x-rays)
As discussed previously, factors both intrinsic and extrinsic to the cell
can alter its radiosensitivity. In addition to the intrinsic, genetic Figure 27-10 • Dose response curves for radiations of differing linear
determinants of radiation sensitivity, other physical and chemical energy transfer (LET). The relative biological effectiveness (RBE) of neutrons
modifiers can also play important roles. The type of radiation used or alpha particles relative to that of x-rays is defined as the ratio of doses
for treatment can be considered a physical modifier of radiosensitivity (x-rays/neutrons) to yield the same biological effect. (From Wilson PF,
to the extent that high LET types of radiation (e.g., neutrons and Bedford JS. Radiobiologic principles. In: Hoppe RT, Phillips TS, Roach M,
heavy ions) are more biologically effective for a given unit of dose editors. Leibel and Phillips textbook of radiation oncology, 3rd ed. Philadel-
phia: Elsevier-Saunders; 2010.)
than low LET types (e.g., x-rays and electrons). Representative dose-
response curves for radiations with different LETs are shown in Figure
27-10. In light of these differences in biological potency, the term including the type of radiation, total dose, dose rate, dose fraction-
relative biological effectiveness (RBE) has been coined to compare and ation pattern, and the biological effect being assessed. An example of
contrast two radiation beams of different LET. RBE is defined as the how RBE values are obtained from cell survival curves is shown in
ratio of doses of a known type of low LET radiation (historically, Figure 27-11.
250 kVp x-rays were the standard, but others can also be used) to Chemical modifiers of radiation response are also important, and
that of a higher LET radiation to yield the same biological end point. perhaps the “chemical” of greatest significance in this regard is molec-
RBE is highly variable and depends on several irradiation parameters, ular oxygen, a potent radiosensitizer. Mechanistically speaking, the
1.0
OER=2 at
100
RBE0.5~5.6 doses below 2 Gy
10–1
RBE0.05~3.6
Surviving fraction
Surviving fraction
10–2
Neutrons X-rays
0.1
10–3
RBE0.0005~2.8
10–4
OER=3 at
10–5 large doses
0 2 4 6 8 10 12 14
0.01
Dose (Gy)
0 2 4 6 8 10 12 14 16 18 20 22 24
Figure 27-11 • Representative cell survival curves for x-rays and neu- Dose (Gy)
trons, illustrating the increase in relative biological effectiveness (RBE) with
decreasing dose. This phenomenon occurs because higher linear energy trans- Figure 27-12 • For x-rays, cells irradiated in the presence of oxygen are
fer (LET) radiations preferentially decrease or eliminate the shoulder on cell more radiosensitive than cells that are maintained under hypoxic conditions
survival curves. (From Zeman EM. Biologic basis of radiation oncology. (where the partial pressure of oxygen is greater than zero but less than about
In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology. 3rd ed. 10 mm Hg). The ratio of doses that produce the same level of biological
Philadelphia: Saunders; 2012.) 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
reason that well-oxygenated cells are more sensitive to radiation than fraction) below about 2 Gy.
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 carcinomas of the head and neck), and multiple readings of partial
to cellular macromolecules. Poorly oxygenated cells experience less pressure of O2 were taken at different depths along the probe’s track;
enhancement of radiation injury and are therefore more radiation the arithmetic mean pO2 value for each tumor positively correlated
resistant. This phenomenon is termed the oxygen effect. The relative with local control rate, as did the tumor volume–weighted pO2 value.
resistance of poorly oxygenated cells compared with well-oxygenated A high tumor oxygen tension was associated with a high complete
ones can be expressed in terms of an oxygen enhancement ratio response rate and vice versa. Several years later, comparable oxygen
(OER). The OER is the ratio of doses to produce the same biological electrode results for uterine cervix cancers were obtained by Höckel
effect under low versus normal conditions of oxygenation. The OER et al.38 They made the important discovery that tumor hypoxia was
typically ranges between 2.5 and 3.0 for large single doses of x-rays a negative prognostic indicator in general, regardless of whether the
or γ-rays and 1.5 to 2.0 when multiple small dose fractions are used.34 patient had received radiation therapy, suggesting that radiation resis-
Further, the oxygen effect is reduced or eliminated as the LET of the tance was only one aspect of the hypoxia problem. A large meta-
type of radiation increases; OERs of 1.5 to 2.0 are obtained for radia- analysis of the relationship between tumor oxygenation status
tions of intermediate LET, and an OER of 1.0 (i.e., no oxygen effect) measured with oxygen electrodes and clinical outcome was published
is obtained for high LET radiations. Representative radiation survival more recently for advanced head and neck tumors,39 with comparable
curves generated in the presence or relative absence of oxygen are findings of improved overall survival in patients whose tumors were
shown in Figure 27-12. less hypoxic.
Hypoxic cell radiosensitizers, exogenous chemicals that mimic the Another method of directly identifying and quantifying hypoxic
radiation damage–enhancing effects of oxygen, have been used clini- cells in tumors is through the use of “hypoxia markers.” Both exog-
cally in an attempt to combat the relative radiation resistance of enous and endogenous markers for tumor hypoxia are available and
tumors that contain a clonogenic fraction of poorly oxygenated, can be studied in relation to each other, the tumor vasculature, or
hypoxic cells. A second approach to the problem posed by tumor other “markable” features of the tumor microenvironment (e.g., the
hypoxia is to combine radiotherapy with a drug that, rather than proliferation status of tumor cells). Exogenous markers consist
sensitizing hypoxic cells, kills them outright. These drugs are called of injectable drugs or chemicals that are bioreducible only under
“bioreductive” because their toxic effects only occur secondary to the hypoxic conditions, causing them to bind to cellular proteins. These
reductive metabolism common in cells relatively lacking in oxygen.35,36 bound metabolites can be marked radioactively or with antibodies
These drugs are discussed further later in this chapter. and can be visualized using several different techniques, such as
With few exceptions, clinical trials over several decades involving autoradiography40 or fluorescence immunohistochemistry.41 Two
such hypoxia-directed therapies have been unsuccessful, in no small exogenous markers studied extensively in both preclinical cell and
part because there was no way to preselect patients whose tumors animal systems, as well as in human patients, are pimonidazole hydro-
contained sizeable hypoxic fractions and therefore might be expected chloride42,43 and EF-5.44 Both are of the chemical class known as
to reap the most benefit from the use of a hypoxic cell radiosensitizer. nitroimidazoles that were originally studied as possible radiosensitiz-
In fact, there was no way to directly measure hypoxia in human ers of hypoxic cells (e.g., see references 45 and 46, as well as the
tumors at all until the late 1980s. discussion later in this chapter) but were serendipitously found
One of the first studies demonstrating an association between to also have the property of bioreduction and binding to cellular
directly measured oxygen tension in tumors and clinical outcome macromolecules under hypoxic conditions. This facilitated their
was published in 1988 by Gatenby et al.37 An oxygen-sensing elec- use as hypoxia markers. Endogenous markers, on the other hand,
trode was inserted into patients’ tumors (advanced squamous cell consist of genes and proteins that are upregulated as part of the
cellular stress/adaptive response to hypoxic conditions and whose

expression levels can, with caveats, be used as surrogates for tissue CLINICAL RADIATION ONCOLOGY
oxygenation status.47,48 Commonly studied endogenous hypoxia Therapeutic Ratio
markers include the hypoxia-inducible factor 1–alpha (HIF-1α, a
transcription factor),48 the enzyme carbonic anhydrase IX (CA-9 or The use of radiation therapy is heavily dependent on the concept of
CAIX),49 glucose transporter–1 (GLUT1),50-52 and osteopontin.53 the therapeutic ratio. Given a high enough dose, virtually any cancer
Figure 27-13 illustrates the potential of deriving “geographic” will be destroyed with radiation therapy. Increasing the dose of radia-
information about the extent and location of hypoxia in six different tion increases the likelihood of tumor control within the radiation
human tumors, using the exogenous marker pimonidazole hydro- therapy field. However, if an excessive dose of radiation therapy is
chloride. Simultaneously marking other tumor features, the location delivered, it will produce an unacceptably high rate of normal tissue
of blood vessels and proliferating cells in these examples, provides complications. The likelihood of a complication increases as the
additional information about the tumor microenvironment. radiation dose increases and as the volume of normal tissue irradiated
A B
C D
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 condi-
tions in human head and neck squamous cell carcinomas. Oral Oncol 2004;44:335–44.)
100 The Biology of Fractionation

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
Response (%)
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.
Tumor Because of the low activity sources available, radium applications
Normal tissue involved longer overall treatment times to reach comparable total
0 doses as used in x-ray therapy. Although extended treatment times
Radiation dose (Gy) were less convenient, clinical results were frequently superior. Perceiv-
ing that the lengthening of the overall time was the critical factor and
armed with animal experiments convincingly demonstrating the
Figure 27-14 • Graphical illustration of the concept of therapeutic
ratio, which describes the relationship between the normal tissue tolerance superiority of longer treatment times,55 French physicians began to
and tumor control dose-response curves. In this example, very good tumor experiment with the use of multiple, smaller x-ray doses delivered
control can be achieved for total dose D (corresponding to the vertical dotted over extended periods in human patients.56 Clinical outcomes were
line); however, that same dose produces an unacceptably high normal tissue improved to such an extent that fractionated radiation therapy using
complication rate. Optimizing this therapeutic ratio as much as possible many small dose increments spread over several weeks’ time became
through manipulation of the radiation physics and/or radiobiology for each the standard of care and has largely remained so to the present day.
patient being treated with curative intent is the major goal of radiation Therapy using radioactive sources (such as the aforementioned
therapy. (From Horsman MR, Lindegaard JC, Grau C, et al. Dose-response radium therapy pioneered by the French) also has continued to the
modifiers in radiation therapy. In: Gunderson LL, Tepper JS, editors. Clinical present day, evolving into today’s practice of brachytherapy using
radiation oncology, 3rd ed. Philadelphia: Saunders; 2012.)
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,
increases. The technical aspects of radiation therapy are designed to and arguably for decades thereafter, was a biological basis for dose-
deliver the radiation therapy so as to avoid or minimize the amount rate/dose-fractionation effects. Radiobiologists studied dose-rate
of radiation delivered to selected normal tissues while maximizing the effects extensively in the laboratory in an attempt to better elucidate
dose of radiation to the tumor. The biological discussion is all directed the biological factors involved in radiotherapy response; however, the
to developing means to produce a differential effect between the cell clinical community was often unaware of these laboratory studies.
killing in the tumor and that in the normal tissues. This lack of cross talk between biologists and clinicians began to
The concept of therapeutic ratio reflects the ability to estimate the change with the publication in 1975 of a seminal book chapter
likelihood of complication and tumor control in a given situation. entitled The Four R’s of Radiotherapy.57 The chapter was an attempt
At a given dose, these probabilities can be estimated (although usually to explain the biological basis of fractionation by describing in simple
not very accurately in clinical practice). Advances in radiation oncol- terms the key radiobiological phenomena thought to affect the
ogy can be made by moving the normal tissue complication curve to outcome of fractionated radiotherapy: Repair, Repopulation, Reoxy-
the right (as illustrated in Figure 27-14) so as to produce fewer com- genation, and Redistribution.
plications 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 Repair
tumor (while also producing fewer complications). The tenets of target theory suggested that the shoulder region of the
Historically we have made much progress in moving the normal radiation survival curve indicated that “hits” had to accumulate prior
tissue complication curve to the right by improving radiation delivery to cell killing. Elkind and Sutton58 sought to better characterize how
techniques and taking advantage of the biology associated with dose this damage accumulated and how the cell processed it. Even in the
fractionation. The use of modern radiation therapy techniques absence of detailed information about DNA damage and repair at
(described later in this chapter), along with improved imaging to that time—the structure of DNA had only been elucidated a few
enhance tumor localization, has made a major difference in decreas- years earlier—a few facts could be gleaned. First, the hits that were
ing the morbidity of therapy while improving tumor control. The part of the damage accumulation process, yet did not in and of
ability to move the tumor control curve to the left can be accom- themselves produce cell killing, were, by definition, sublethal. Further,
plished primarily by the use of radiation-sensitizing compounds that this sublethal damage (SLD) only became lethal if and when it inter-
are given concurrently with radiation therapy or by altering fraction- acted with additional SLD. Elkind and Sutton conducted experi-
ation. Although a huge amount of effort has been expended in this ments that deliberately interfered with the damage accumulation
area, the major sensitizers that have been effective are chemothera- process by delivering part of the intended radiation dose, inserting a
peutic drugs that have both a radiation-sensitizing ability and an radiation-free interval, and then delivering the remainder of the dose
independent cytotoxic effect on the tumor. Examples include drugs in what was called a “split-dose” experiment.
such as 5-fluorouracil, cisplatinum, and mitomycin C that are used The overall surviving fraction of cells after a moderate to high
to treat, among others, head and neck squamous cell carcinomas, radiation dose was higher if that dose was split into two fractions
uterine cervix cancers, and multiple gastrointestinal (GI) tumors. with a time interval in between than if it was delivered as a single
Although great interest has been expressed in using biological agents dose. This phenomenon is illustrated graphically in the right panel
as radiation sensitizers, with the exception of the EGFR inhibitor of Figure 27-15. This finding suggested that the cells that survived
cetuximab (discussed earlier), these approaches have not made their the initial dose fraction had “repaired” some of the damage during
way into standard clinical practice. the radiation-free interval. Therefore this damage was no longer
D/2 D
Surviving fraction Proliferation

0.1
D/2-+-D/2
Reassortment
in fast-
cycling cells
0.01
Single dose
Split dose Repair SLD
Dose 0 2 4 6 8 10 12 Cell
A B Time between split doses 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 frac-
tion. 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 results in a large amount of cell killing. Stem cells (known or sus-
fraction, and thus a higher cell-surviving fraction resulted. Had the pected) of normal tissues and tumors can begin to proliferate during
total dose been delivered as a single fraction, more damage in total and after a course of radiation therapy,61 although the mechanism(s)
would have accumulated, some SLD would have been converted to the tissue uses to affect this process and the time it takes to commence
lethal damage, and the cell-surviving fraction would have been lower. varies with the tissue. Some tissues, however, do not seem to be able
The results of split-dose experiments turned out to be crucial to the to mount a repopulation response, or at least, not a prompt or robust
understanding of why and how fractionated radiation therapy works one, presumably because they only possess very small numbers of
the way it does, that is, that fractionation/protraction of a total radiation stem cells, if any.
dose reduces its toxicity, in large part because of SLD repair. This Repopulation is desirable in normal tissues because it facilitates
phenomenon is termed the dose-fractionation or dose-rate effect, and the healing of common radiotherapy complications that can develop
it occurs after low LET radiation exposure in an undiminished during or soon after treatment (e.g., oral mucositis in patients receiv-
manner regardless of the number of dose fractions. ing radiotherapy for head and neck cancer). Repopulation of tumor
When considering complete cell survival curves, SLD repair cells, on the other hand, is quite undesirable because it has the net
manifests itself as a return of the low-dose, shoulder region of the effect of counteracting the toxicity of ongoing radiation therapy. After
radiation survival curve. After an initial radiation dose and an ade- radiation therapy is complete, repopulation also can lead to tumor
quate time interval for repair to occur, the response of surviving cells recurrence.
to graded additional doses is nearly identical to that obtained from In intact tissues, it can sometimes be difficult to tease apart the
cells without previous radiation exposure (illustrated in the left panel relative contributions of repair and repopulation to the overall dose
of Fig. 27-15). rate effect, although generally speaking, repair-related effects occur
Bedford and Hall59,60 generated in vitro survival curves for HeLa over a time scale of hours to a day, whereas proliferative effects usually
cells irradiated at various dose rates and found that the killing effec- do not come into play for days or weeks (or more) after the start of
tiveness per unit dose decreased as the dose rate decreased, to a point. radiotherapy. In normal tissues capable of mounting a proliferative
A limit to this dose rate effect was reached; that is, further lowering response, molecular signals associated with the radiation injury seem-
of the dose rate did not produce a further decrease in toxicity. This ingly need to reach a certain threshold before the repopulation begins
finding is consistent with the idea that survival curves have negative in earnest, and for most tissues, this process takes a minimum of
initial slopes, as described by the “αD” component of the LQ survival a week, and more commonly, several weeks. Tissues that exhibit a
curve equation. A further implication is that small differences in prompt and robust response to radiation injury (during or within a
initial slopes of survival or dose-response curves for different tissues couple of months of treatment) and begin to repopulate are called
could be magnified into large differences when many small dose frac- “early responding,” and those that show a delayed proliferative
tions or continuous low dose rates were used. response (more than 6 to 9 months after irradiation), if any, are
referred to as “late responding.”
Repopulation For tumors, especially carcinomas, the prevailing view (although
The sparing effects of fractionated external beam and brachytherapy it is not without its detractors) is that compensatory repopulation
are largely attributed to the repair of SLD; however, other factors can does not begin until approximately a month into the course of treat-
be involved as well. Repopulation is defined as a compensatory ment.62 One clinical implication of this view is that overall treatment
increase in cell proliferation in tissues in response to an injury that times should be kept as short as practically possible, because
treatment time much longer than a month would allow for more type and extent of hypoxia present in the tumor. Slower reoxygen-
tumor cell repopulation and therefore less treatment effectiveness. ation might be expected to occur in cases in which the type of hypoxia
Some clinical data (mostly culled from fractionation studies involving is chronic, such as might occur in cells that are multiple cell diameters
treatment of head and neck cancers) suggest that up to a third away from vasculature and near or beyond the diffusion distance of
of a typical 1.8 to 2.0 Gy daily dose fraction is wasted as a result oxygen (approximately 70 µm34,44). Physiologically speaking, the
of repopulation62 and that for each day of treatment beyond the main ways that reoxygenation could occur under these circumstances
time that repopulation begins, as much as 1% of local tumor control is for aerobic cells closer to vasculature to decrease their oxygen con-
is lost. sumption, 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,
Reoxygenation which would have the net effect of bringing the chronically hypoxic
Tumor blood vessels tend to be abnormal both structurally, function- cells closer in to the existing vasculature. Some, although not all,
ally, and physiologically as a consequence of the dysregulated angio- human tumors shrink at least somewhat during the course of radio-
genesis characteristic of tumors63,64 (see also Chapter 8). One therapy. Conversely, in cases in which hypoxia is intermittent or
consequence is that tumors can develop microregions relatively cyclic, reoxygenation could occur on the order of minutes to hours,
lacking in nutrients and oxygen. And although prolonged oxygen as has been noted for many experimental rodent tumors.69,70
deprivation, that is, anoxia, will eventually kill even the hardiest of
tumor cells, hypoxia—a state of very low tissue oxygenation on the Redistribution
order of 0.5% oxygen or less (corresponding to a partial pressure of Tumors that contain a sizeable fraction of actively proliferating cells
oxygen of about 10 mm Hg)65—is potentially survivable, particularly will necessarily contain subsets of cells in different phases of their cell
when it is intermittent or cyclic in nature. In contrast, the structure cycle, much more so than for some normal tissues in which cells are
and function of the vasculature of normal tissues is such that it differentiated, no longer able to proliferate, and reside in G0 phase.
specifically avoids (in nearly all cases) the development of such Furthermore, even for the normal tissues that do contain stem cell
gradients of oxygen and nutrients. Thus hypoxia has a built-in speci- compartments consisting of undifferentiated, proliferating cells, these
ficity for tumors, which, ironically, is an attractive feature clinically, tend to be few in number compared with the tissue as a whole, nor
where differences between normal tissues and tumors might be do they necessarily proliferate rapidly. Thus tumors are much more
exploitable. heterogeneous than normal tissues with respect to cell cycle phase
Unfortunately, as previously discussed, maintenance under distribution.
hypoxic conditions renders cells more radiation resistant by upward It was the pioneering work of Terasima and Tolmach71 during the
of a factor of three (i.e., three times the total dose would be required 1960s that led first to the development of a relatively simple method
to achieve the same biological end point). Thus a tumor containing of obtaining populations of cells synchronized with respect to cell
even the smallest fraction of clonogenic, hypoxic cells could easily cycle phase, followed by the generation of radiation survival curves
make or break the success of radiation therapy that is necessarily for each phase.
limited by the response of the aerobic, and therefore more radiosensi- After a single dose of approximately 7 Gy of x-rays, Chinese
tive, normal tissues.66 Many types of experimental solid tumors in hamster V79 cells in culture were noted to be most radioresistant in
laboratory rodents and spontaneous tumors in veterinary patients and (late) S phase. Cells in G1 phase were of intermediate radiosensitivity
humans studied to date show an average pretreatment hypoxic frac- (i.e., more resistant at the beginning of the phase but somewhat more
tion of approximately 15% to 20%, although the range of values is sensitive toward the end of the phase), and G2 cells were increasingly
quite broad,45,67 as might be expected given intra- and intertumor sensitive as they moved toward the most radiosensitive M phase. This
heterogeneity. phenomenon was termed the cell cycle “age response” for ionizing
Of course, tumor hypoxia would not constitute a barrier to clinical radiation71 and is a general feature of mammalian cell radiation
success if, during the course of fractionated radiotherapy, the fraction response.72 (The original work by Terasima and Tolmach71,73 also
of hypoxic cells decreased, ideally to zero. This process is called reoxy- showed this feature to be true for human HeLa cells.) Differences in
genation, and it has been studied extensively in experimental rodent radiosensitivity for cells in each phase were largely attributable to
tumors (e.g., see reference 68), and to a limited extent in human changes in the shoulder regions of their respective survival curves,
tumors as well (e.g., see reference 64). with late S-phase cells characterized by broad survival curve shoul-
The reoxygenation process can be either slow (days to weeks) or ders, and mitotic cells showing strictly exponential cell killing with
fast (hours), and it can be complete or incomplete, depending on the no survival curve shoulders (Fig. 27-16). It should also be noted that
1.0
7.1 Gy
0.2
0.1 0.1
Surviving fraction
0.05
0.02
0.01 0.01
Figure 27-16 • The age response through 0.005
the cell cycle. A, Cell survival curves for synchro- Late S
nized populations of Chinese hamster cells irradi- 0.001 Early S M G1 S G2
G1
ated in different phases of the cell cycle. B, An G2/M
illustration of how these radiosensitivity differ- Cell cycle phase
ences translate into age response patterns. Cells in
the S phase (especially the late S phase) are the 5.0 10.0 15.0
most radiation resistant, and cells in the G2 and A Dose (Gy) B
M phases are the most radiosensitive.
when high LET radiations such as neutrons are used in place of their DNA remains somewhat unclear. However, it is likely that both
x-rays, the age response variation through the cell cycle is significantly the formation of more complex radiation-induced lesions caused by
reduced or eliminated. the presence of the halogen atoms and an interference in DNA repair
Because of the age response through the cell cycle for low LET are involved.77
radiations, an initially asynchronous population of cells surviving a The clinical use of halogenated pyrimidines began in the late
dose of radiation becomes enriched with more resistant cells (S-phase, 1960s, with a major clinical trial in persons with head and neck
and to a lesser extent, G1-phase cells). This partial synchrony decays cancer.78 Although BrdUdR did improve the tumor response to radio-
rapidly, however, in part because of radiation-induced perturbations therapy, it also produced severe oral mucositis as, in retrospect, might
in cell cycle progression and also because of natural variations in cell have been expected given that the mucosa also contains rapidly pro-
cycle phase durations. Such cells are said to have “redistributed,”74 liferating cells that would have been radiosensitized. As a result, the
with the net effect of sensitizing the population as a whole to subse- therapeutic ratio did not improve. Subsequently, these drugs were
quent dose fractions compared with what would have been expected evaluated in more appropriate disease sites such as brain tumors and
had the cells remained in their resistant phases. The redistribution sarcomas, which consist of rapidly growing tumor cells against a
process can be demonstrated in rapidly growing cells in vitro but background of slowly proliferating or nonproliferating cells of the
tends to be dampened in vivo because of the longer (and dispersed) surrounding normal tissues.79,80 Unfortunately, these drugs did not
cell cycle times and lower fractions of actively proliferating cells in improve outcomes sufficiently to warrant their adoption for routine
tumors. Attempts to take advantage of redistribution clinically, clinical use.
however, such as by carefully timing each dose fraction to correspond
to times when tumor cells would be expected to be most radiosensi- Sensitizers of Hypoxic Cells
tive, have been unsuccessful.75 In fact, it has been difficult to dem- The increased radiosensitivity of cells in the presence of oxygen is due
onstrate that redistribution has occurred in tumors (or normal tissues, to oxygen’s affinity for the electrons produced by the ionization of
for that matter) at all, other than by indirect inference, that is, that biomolecules. Molecules other than oxygen also have this chemical
increasing resistance to each subsequent dose fraction during radio- property, known as “electron affinity,”81 some of which are not con-
therapy does not occur. sumed by the cell for other purposes, as is oxygen. Assuming that
such an oxygen-mimetic compound is not otherwise used by the cell,
Radiosensitizers and Radioprotectors it should diffuse further from capillaries and reach hypoxic regions
of a tumor, sensitizing the hypoxic cells to radiation.
The use of radiosensitizing or radioprotective compounds in combi- One class of compounds that represented a reasonable trade-off
nation with radiation therapy is predicated on the idea that tumors between efficiency as a radiosensitizer (i.e., compared with oxygen)
contain one or more radioresistant (or effectively so) subpopulations and diffusion effectiveness was the nitroimidazoles, which include the
of cells that threaten the success of treatment. Historically, three such drugs misonidazole, etanidazole, and nimorazole, all of which were
subpopulations in tumors that fit this description are inherently the subjects of intensive preclinical and clinical studies over several
radioresistant cells, hypoxic cells, and rapidly proliferating cells. decades. Unfortunately, the nitroimidazoles were found to cause
The latter may not be radioresistant per se, but rather have the net adverse effects in normal tissues (in particular, peripheral neurop
effect of making the tumor seem less responsive to treatment because athy), which curtailed their clinical utility.82,83 In fact, the only one
the production of new cells outpaces the cytotoxic action of of this class of compounds currently approved for clinical use is
radiotherapy. nimorazole, which is used in Europe for subgroups of patients with
Radiosensitizers and radioprotectors can be defined generically as advanced head and neck cancer.84
any chemical or pharmacologic agent that increases or decreases, Another class of hypoxic cell radiosensitizers does not sensitize
respectively, the cytotoxicity of ionizing radiation. “True” radiosensi- cells per se but rather kills them outright. This action produces the
tizers and protectors meet the stricter criterion of being relatively net effect of (apparent) sensitization of the tumor because of the
nontoxic in and of themselves, acting only to potentiate or ameliorate elimination of an otherwise radioresistant subpopulation of cells.
radiation toxicity. “Apparent” radiosensitizers and protectors still Agents selectively toxic to hypoxic cells are termed “bioreductive
produce the net effect of making tumors more sensitive or normal drugs,” with the organic nitroxide tirapazamine (formerly SR
tissues less so, yet their mechanisms of action are not necessarily 4233)34,85 being the lead compound.
synergistic, nor are the agents necessarily nontoxic when given alone. In preclinical models, tirapazamine has been shown to outperform
Finally, it is important to realize that the use of any chemical the nitroimidazole radiosensitizers using clinically relevant fraction-
modifier of radiation response is only as good as it is selective, or at ated radiotherapy86 and with some chemotherapy drugs either alone
minimum, partially selective, for either tumors or normal tissues; or in chemoradiotherapy regimens.87 In humans, more than 20 clini-
agents that show little or no differential effect between tumors and cal trials are ongoing or complete, including randomized phase 2 and
normal tissues do not improve the therapeutic ratio, and therefore 3 trials with tirapazamine combined with radiotherapy and/or che-
may not be of much clinical utility. motherapy (particularly, cisplatinum) for advanced head and neck,
cervix, and lung cancers. Although tirapazamine has improved out-
Traditional Radiosensitizers comes for some standard regimens, results overall have been mixed
(e.g., see references 88 and 89). Thus although the drug has in no
Sensitizers of Proliferating Cells way become a staple of clinical practice, its activity against some
Halogenated analogs of the DNA precursor thymidine, such as bro- tumors warrants further investigation, as does the search for more
modeoxyuridine (BrdUdR) and iododeoxyuridine (IdUdR), can be effective agents from the same or similar chemical classes.
incorporated into the DNA of actively proliferating S-phase cells in
place of thymidine because of close structural similarities between the Traditional Radioprotectors
compounds. Cells that contain DNA substituted with these com-
pounds are more radiosensitive than their unsubstituted counterparts, In theory, if normal tissues could be made to tolerate higher total
with the amount of sensitization directly proportional to the fraction doses of radiation through the use of radioprotectors, then the relative
of thymidine replaced.76 In general, the radiosensitization takes the radioresistance of hypoxic tumor cells would no longer limit treat-
form of a decrease in or elimination of the shoulder region of the ment. One such agent, amifostine, is a compound containing thiol
radiation survival curve. The molecular basis of the ability of BrdUdR moiety that was developed by the U.S. Army for use as a radiation
and IdUdR to radiosensitize the cells that incorporate the drugs into protector for soldiers on a nuclear battlefield. It subsequently was
repurposed for clinical use. Chemically, amifostine is an analog of been generated for quite a few of these agents, with even newer
naturally occurring radioprotective sulfhydryl compounds found in compounds constantly being developed, the only two that have gone
cells, such as cysteine, cysteamine, and glutathione.90 Like those anti- through substantial clinical testing and entered the treatment main-
oxidant compounds, amifostine’s mechanism of action involves either stream are anti-EGFR inhibitors used to treat squamous cell carcino-
the scavenging of free radicals produced by ionizing radiation, radi- mas of the head and neck17 and anti-VEGF therapies in the treatment
cals that otherwise could go on to damage other cellular macromol- of GI tract tumors.101
ecules, or reacting with oxygen, thereby preventing “fixation” of The use of cetuximab, a monoclonal antibody raised against the
damage that has already been registered. Amifostine can also detoxify EGFR, has been shown to improve outcomes in head and neck
other reactive species, and because of this mechanism, the drug can cancers when combined with radiation therapy17 and is being explored
also be used as a chemoprotective agent.91 in a variety of other clinical situations. Cetuximab competitively
Amifostine is approved for use in patients receiving radiotherapy binds to the extracellular domain of EGFR, preventing activation of
for head and neck cancer to reduce xerostomia as a result of exposure the receptor by endogenous ligands, which abrogates its near-constant
of the parotid glands.92 It is also indicated for the reduction of renal signaling to cancer cells to proliferate. The antibody-receptor complex
toxicity associated with cisplatin chemotherapy in patients with is then internalized and degraded, resulting in a downregulation of
advanced ovarian and NSCLC.93 EGFR expression relative to the overexpression often displayed by
diseases such as squamous cell cancers of the head and neck.
Chemotherapy Drugs as Radiosensitizers Bevacizumab exploits a different cancer hallmark, namely the
One of the major changes that has occurred in the clinical practice ability of tumors to continuously recruit new blood vessels from sur-
of radiation therapy during the past two decades is the large percent- rounding normal tissues. This recruitment is accomplished through
age of patients who are treated with concurrent radiation therapy and the production and release into their microenvironment by tumor
chemotherapy. This combination is used in two ways: chemotherapy cells of large quantities of (among other proangiogenic factors) VEGF,
used independently for its cytotoxic effect on the tumor, and chemo- the principal stimulant of endothelial cells of the host vasculature to
therapy used to enhance the effect of the radiation therapy through reproduce and migrate into the tumor mass, forming new—if imma-
a drug sensitization effect. It is this second approach that will be ture and aberrant—blood vessels. The observation that tumors
discussed here. As mentioned earlier in this chapter, the value of cannot grow beyond a size of approximately 2 mm3 without the
radiation sensitization is dependent on producing a differential sen- support of neovascularization102 has led to accelerated development
sitization of the tumor compared with the adjacent normal tissue of angiogenesis-inhibiting agents, many of which target either VEGF
(therapeutic ratio). A drug has little value if its only effect is to or its endothelial cell surface receptor.103,104
decrease the amount of time the radiation therapy machine is Bevacizumab is a humanized monoclonal antibody raised against
turned on. VEGF.105 The binding of the antibody to VEGF prevents it from
It has been known for decades that certain pharmaceutical agents binding to its receptor on the surface of vascular endothelial cells,
can increase the tumor cell kill produced by radiation therapy.94 One which has the net effect of inhibiting the downstream signaling events
of the earlier approaches used in this manner, and one that is still that cause these cells to begin proliferating and forming vessel
very commonly used, is the combination of a fluoropyrimidine (typi- “sprouts” that migrate toward the tumor mass. At first blush, therapy
cally 5-fluorouracil or, more recently, capecitabine) with radiation that blocks new blood vessel formation might be expected to create
therapy for a variety of tumors, but especially those of the GI tract.95 more tumor hypoxia, and therefore more radiation resistance.
The underlying mechanism(s) of action of these fluorinated pyrimi- However, findings of both preclinical and clinical studies with beva-
dines as radiation sensitizers is still not completely clear, but it most cizumab and related inhibitors of angiogenesis show that they most
likely involves some combination of the drug’s selective toxicity to often promote radiation (and chemotherapy) sensitivity, not resis-
otherwise radioresistant S-phase cells, interference with DNA synthe- tance. One hypothesis to explain this observation is that antiangio-
sis and repair, and ability to dysregulate the cell cycle.94 At present a genic therapy actually “normalizes” tumor vasculature106 by selectively
fluoropyrimidine is used routinely in the therapy of most tumors of pruning away small, immature, abnormal tumor blood vessels,
the GI tract, including esophageal, gastric, pancreatic, rectal, and anal leaving the larger, most “normal-like” vessels behind. This process
cancers. In the past, the combination had been used in head and neck would lead to improved tumor oxygenation and better access of
and uterine cervix squamous cell carcinomas, although that practice chemotherapy agents.
is much less common at present. The details of these combinations Bevacizumab had been shown to prolong both overall survival and
are described more fully in the individual disease site chapters in this progression-free survival in patients with advanced colorectal cancer
book. However, it should be noted that local control has been con- when added to a standard chemotherapy regime consisting of irino-
sistently improved by this approach and has had a beneficial effect tecan, 5-fluorouracil, and leucovorin.107,108 In persons with rectal
on survival in some of these diseases. cancer,109 bevacizumab has been evaluated in combination with radia-
Another drug commonly used with concurrent therapy is cisplati- tion therapy, and although initial reports were encouraging, with
num, an inorganic compound consisting of a coplanar complex excellent early responses, it remains unclear whether the combination
capable of producing both inter- and intrastrand DNA and protein will improve clinical efficacy. Also, despite prolonged progression-free
cross-links.94 The cross-linking produced by cisplatinum most likely survival, no clear overall survival benefit of bevacizumab was seen in
interferes with cellular repair of radiation damage, particularly DNA large clinical trials for NSCLC,110 renal cell carcinoma,111 and meta-
double-stranded breaks, resulting in radiation sensitization,96 although static breast cancer.112 In response to the disappointing results in
as in the case of the fluoropyrimidines, additional mechanisms of persons with metastatic breast cancer, the U.S. Food and Drug
action have also been proposed.94 This combination is routinely used Administration has recently withdrawn its approval of bevacizumab
for head and neck and uterine cervix cancers (e.g., as described in as a first-line therapy, concluding that the drug’s benefit did not
references 97 and 98), with a major impact on long-term outcome. outweigh its adverse effects, which can include hypertension, protein-
Mitomycin C is routinely used in the therapy of anal cancer,99 temo- uria, bleeding episodes, and thrombotic events.113 Continued interest
zolomide is in standard use in the therapy of high-grade gliomas,100 exists in trying to explore the vascular normalization hypothesis in a
and various other combination therapies have also been explored. variety of tumor types.
Because many newer biological agents have been shown to have
Molecularly Targeted Drugs and Biologics radiation-sensitizing properties in vitro and in animal systems, inves-
Investigators have a great interest in the use of biological therapies in tigators have a great interest in translating this information to the
combination with radiation therapy. Although preclinical data have clinic. For example, one class of drugs currently in clinical trials is
the poly(adenosine diphosphate–ribose) polymerase or “PARP” Second, although it is generally true that tissues known to be
inhibitors. The PARP family of proteins participate in a number of composed of radiosensitive cells have lower tolerance doses (e.g.,
cellular functions, including detecting the presence of DNA strand the tolerance dose for a 5% risk of radiation-induced bone marrow
breaks and activating signaling pathways that recruit and mobilize aplasia within 5 years of treatment, the “TD5/5,” is ≈2.5 Gy) com-
DNA repair proteins to the site of the damage.114 PARP1 is by far pared with the tolerance doses for tissues containing more radiore-
the most abundant member of this family and has been the most sistant cells (e.g., the TD5/5 for rectal stenosis or fistula formation
frequently targeted for inhibition. PARP inhibitors have been evalu- is ≈60 Gy),45 this situation is not universally the case because radio-
ated in preclinical models as potential radiation sensitizers, given that sensitivity is not the sole determinant of radiation response. Early
unrepaired or mis-rejoined DNA double-strand breaks are considered and late effects in irradiated normal tissues do result from the killing
the lethal lesions with respect to the cytotoxic effects of radiation and of critical target cells either directly or indirectly; however, the
that PARP inhibition might be expected to enhance this damage and “process” that culminates in the complication is both complex and
increase toxicity. dynamic, involving radiation-inducible gene expression (including
DNA repair inhibition will only be clinically useful insofar as it production of cytokines and growth factors), cellular signaling cas-
is selective for tumors, because inhibiting repair in irradiated normal cades, different modes of cell death, and compensatory proliferative
tissues could have adverse results. Fortuitously, PARP inhibition was responses.
found to be selective for tumors, in particular the tumors whose cells Tolerance dose data for representative early- and late-responding
were already defective in at least one DNA repair pathway, as is the normal tissues are shown in Table 27-2. Data are included for select
case for cells that carry mutations in the BRCA1 or BRCA2 genes, normal tissues from three seminal publications (each about 20 years
for example.115,116 Because cells from normal tissues have intact alter- apart) that compiled such information based on exhaustive reviews
nate or “salvage” pathways for DNA repair, the PARP inhibitors of the literature and updated to reflect new knowledge about the
should be less toxic. Phases 1 and 2 clinical trials of PARP inhibitors etiology of normal tissue complications and changes in treatment
are currently under way for brain tumors. technique over the years.
Radiation Carcinogenesis
Normal Tissue Toxicity
With increasing numbers of long-term cancer survivors, one late
In the delivery of radiation therapy, an understanding of the biology normal tissue complication of radiotherapy that is of particular
of normal tissue response to injury is critical. Normal tissue complica- concern is the production of second malignancies. Leukemia accounts
tions that arise during or after radiotherapy are the result of the killing for about 20% of these second cancers, with the remainder presenting
of critical target cells crucial to the tissue’s continued functional and/ as solid tumors that develop in and around the previously irradiated
or structural integrity. The loss of these target cells can occur either site.117,118 Large epidemiological studies have assessed the breast and
as a direct consequence of the cytotoxic action of the radiation, or lung cancer risk in Hodgkin lymphoma survivors119 and leukemia
indirectly because of the loss of other cells that support them. Further, and sarcomas in cervical cancer survivors.120 Certain subpopulations
especially in the case of late-responding tissues, the response to the of previously irradiated patients are at an even higher risk than the
depletion of the tissue’s target cells involves a long, complex, and majority, including children and young adults (who would be
somewhat cyclic process that can actually exacerbate the injury. For expected to live long enough for such second cancers to develop, and,
example, the hyperproliferation of fibroblasts and deposition of col- in the case of children, who are more radiosensitive than adults to
lagen after a tissue injury can culminate over time in the replacement begin with), immunocompromised individuals, and persons with a
of a large proportion of that tissue’s parenchymal cells, resulting in known genetic predisposition to cancer. Large studies of previously
fibrosis, a common complication of radiation therapy. irradiated patients demonstrate that the risk of late cancer developing
in an incidentally irradiated organ will very roughly double the base-
Tolerance Doses line risk.121 Fortunately, the baseline risk in an individual organ is
Several important considerations in determining tolerance doses for quite low, and thus the absolute impact of a radiation-induced cancer
different tissues include the radiosensitivity of the tissue’s component is also low, assuming there is clinical benefit in the original therapy.
cells, the proliferative organization of the tissue (which determines However, the impact of a second cancer occurring many years after
the earliness or lateness of the tissue response to radiation), the a prior cancer developed can be severe.
volume of the tissue irradiated, and the tissue’s fractionation sensitiv-
ity. As such, it follows that tolerance doses for particular complica- Volume Effects
tions in particular tissues are necessarily average values that take all By convention, normal organs have been divided into what are called
of these factors into consideration. That tolerance doses are average “serial” and “parallel” organs, by analogy with electrical circuits.122 A
values is reinforced by the fact that these doses have been determined serial organ is one in which a severe injury at any anatomic point in
by pooling clinical outcomes data on thousands of patients over long the normal structure will produce a severe functional loss. The classic
periods (decades, generally). Bearing this in mind, several general example of a serial organ is the spinal cord. If there is major damage
findings about normal tissue tolerance are worth mentioning. to the cord at any level, from a small dosimetric hot spot, for example,
First, because tissues and organs contain, by definition, more than all function can be lost below that level. Examples of parallel organs
one cell type (each with its own inherent radiosensitivity), it follows are the kidneys and the liver. Radiation injury to a portion of one of
that one tissue could manifest more than one complication after these organs will generally just decrease its function by an amount
radiation therapy, with the severity of each determined by the radio- approximately equal to the percent of the organ that is destroyed but
sensitivity of the particular target cell whose death precipitates the often will not produce a major functional deficit unless the irradiated
complication and by the time-dose-fractionation schedule used. In volume is large.
addition, the severity of one complication does not necessarily predict Some organs behave as if they have both a serial and a parallel
for the severity of another complication, even within the same tissue. component. The liver can be viewed in this manner because the
Using skin as an example, an early effect of treatment might consist hepatic parenchyma functions as a parallel structure, but the biliary
of dry or moist desquamation (killing of basal cells of the epidermis), system near the hilum functions as a serial structure; obstruction of
whereas late effects might include fibrosis (loss of tissue parenchymal the common bile duct is a major complication affecting the entire
cells and some dermal fibroblasts, resulting in overproliferation of organ. Thus the radiation oncologist can design radiation therapy
survivors) or telangiectasia (damage to small blood vessels in the fields that totally destroy portions of the parenchyma of the liver
dermis, resulting in abnormal regrowth). without a clinical problem to the patient, whereas damage to any
Table 27-2 Radiation Tolerance Dose and Complication Frequency Data for Select Normal Tissues
Irradiation and Volume Tolerance Dose or Complication
Tissue Early/Late End Point Details Frequency Author
Lung Early Pneumonitis Conventional fractionation; TD5/5 ≈20 Gy Rubin and
>½ of organ irradiated Casarett (1968)
Conventional fractionation; TD5/5 (1/3) ≈45 Gy Emami (1991)
1/3 or whole organ irradiated
TD5/5 (whole) ≈17.5 Gy
Conventional fractionation; 7 Gy ≈5% complication frequency QUANTEC (2010)
3D-CRT; whole organ 20 Gy ≈20% complication frequency
irradiated 27 Gy ≈40% complication frequency
Rectum Late Ulcer/perforation/ Conventional fractionation TD5/5 ≈65 Gy Rubin and
fistula/stricture Casarett (1968)
Conventional fractionation; TD5/5 ≈60 Gy Emami (1991)
100 cm3 field
Conventional fractionation; V50 <50%: <15% complication frequency QUANTEC (2010)
3D-CRT V65 <25%: <15% complication frequency
V75 <15%: <15% complication frequency
Spinal Cord Late Myelopathy Conventional fractionation; TD5/5 ≈50 Gy Rubin and
5- to 10-cm field Casarett (1968)
Conventional fractionation; TD5/5 (5 cm) ≈50 Gy Emami (1991)
5- or 20-cm field TD5/5 (20 cm) ≈47 Gy
Conventional fractionation; Dmax = 50 Gy: <1% complication frequency QUANTEC (2010)
3D-CRT; partial organ Dmax = 60 Gy: 6% complication frequency
irradiation, including full Dmax = 69 Gy: 50% complication frequency
cord cross section
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 Representative dose-response curve shapes for tissues characterized
consequences. 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
Fractionation Sensitivity downward rather abruptly as the dose increases. Conversely, the curve
During the 1960s and 1970s, research interest among radiobiologists with the high α/β ratio has a steeper initial slope and bends more
focused on the shape of the shoulder region of cell survival curves, gradually as the dose increases.
the nature of dose-rate and dose-fractionation effects, and their rel- In parallel with the fractionation experiments used to determine
evance to the practice of radiation therapy. This research was timely tissue α/β ratios, other investigators124 quantified the fractionation
given the growing appreciation clinically that tissue tolerances varied, sensitivity of experimental tumors and normal tissues using a plot of
sometimes widely, depending on the exact time, dose, and fraction- the log of the total dose to achieve a particular tissue end point versus
ation pattern used for treatment. This research ultimately led to the dose per fraction; this is called an isoeffect curve, and this method of
replacement of the target theory model of cell survival with the LQ plotting tolerance dose data had been in common practice in radia-
model, as well as the use of the LQ model for a new, biologically tion oncology since the 1940s.125 Plotted in this way, the curves for
based approach to clinical isoeffect modeling. slowly proliferating or nonproliferating normal tissues such as the
In multifraction experiments assessing skin reactions in mice, kidney and spinal cord, for example, were found to be steeper than
Douglas and Fowler123 analyzed their data using what was then a those for more rapidly proliferating, early-responding tissues, such as
novel method that allowed the derivation of values for the ratio α/β, skin and gut epithelium, and most tumors.124,125 Taken together, the
parameters of the LQ formula. This new approach to isoeffect analy- low α/β ratio and steep isoeffect curve suggest that late-responding
sis focused on the shape of dose-response curves, particularly in the tissues are more sensitive to changes in dose per fraction, thus expe-
low-dose region, and by extension, that the critical parameter in riencing greater sparing with decreasing fraction size than their early
radiotherapy planning was the size of the dose per fraction. More effects counterparts. This phenomenon is illustrated graphically in
widespread use of this technique in subsequent years revealed that in Figure 27-18. It was immediately evident that this phenomenon
most cases, a systematic difference was found between early- and could be exploited for clinical benefit.
late-responding normal tissues and tumors in their responses to dif-
ferent fractionation patterns. The α/β ratios tended to be low for Clinical Application of the LQ Isoeffect Model
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 The shapes of tissue and tumor isoeffect curves and their calculated
tissue and tumor end points (usually 7 to 20 Gy, with an average of α/β ratios have a number of clinical applications. One is to use α/β
about 10 Gy). Table 27-3 shows α/β ratios determined for a variety ratios to generate alternate treatment schedules using different-sized
of human normal tissues and tumors; worth noting are the few tumor doses per fraction in order to match the probability of causing a
types (melanoma and prostate cancer for example) that are exceptions tissue injury. Making such a calculation assumes the overall treat-
to the general trend and are characterized by low α/β ratios. ment times are similar in both schedules or that the tissue at risk
of a complication is relatively insensitive to treatment duration.126

Table 27-3 Representative α/β Ratios for Human The equation,
Normal Tissues and Tumors
D2/D1 = (α /β + d1)/(α /β + d 2 )
α/β Ratio can be used for this purpose, where D1 and d1 are, respectively, the
Tissue Type (and End Point) (±95% Confidence Interval) total dose and dose per fraction of one radiotherapy treatment plan
EARLY-RESPONDING NORMAL TISSUES and D2 and d2 are, respectively, the total dose and dose per fraction
Skin: Erythema 10.6 (1.8; 22.8) Gy for an alternate treatment plan intended to be biologically equivalent
Desquamation 11.2 (8.5; 17.6) Gy for a particular tissue effect, and with the fractionation sensitivity of
Lung: pneumonitis ≤90 d after >8.8 Gy
that tissue defined by its α/β ratio. One example of the utility of this
radiotherapy
approach is to express particular time-dose-fractionation schedules in
terms of “equivalent total dose if the treatment had been given in
Oral mucosa: mucositis 8-15 Gy 2 Gy fractions” or EQD2,
LATE-RESPONDING NORMAL TISSUES  ( d + α/β ) 
EQD2 = D  
Skin: Telangiectasia ~2.7 (−0.1; 8.1) Gy  ( 2 + α/β ) 
Fibrosis 1.7 (0.6; 3.0) Gy
where D is the total dose actually delivered and d is the dose per
Breast: poor cosmesis 3.4 (2.3; 4.5) Gy fraction actually used. When comparing clinical trial data from mul-
Fibrosis 3.1 (1.8; 4.4) Gy tiple institutions, one can specify treatment parameters using EQD2
Lung: pneumonitis >90 days 4.0 (2.2; 5.8) Gy doses rather than the actual doses used, which makes the pooling of
after radiotherapy data with varying fractionation schedules more manageable, with the
Bowel: perforation/stricture 3.9 (2.5; 5.3) Gy caveat that the results will only apply to the tissue of interest.
Another important implication of the steeper isoeffect curves for
Spinal cord: myelopathy <3.3 Gy late-responding tissues compared with those for tumors is that it
TUMORS might be possible to increase the therapeutic ratio by using larger
Head and neck: nasopharynx 16 (−11; 43) Gy
numbers of smaller fractions to a somewhat higher total dose than
Vocal cord ~13 Gy traditionally used.127 Although such treatments would be expected to
Tonsil 7.2 (3.6; ∞) Gy exacerbate acute effects in some normal tissues (undesirable, but
Larynx 14.5 (4.9; 24) Gy usually manageable) and in the tumor (desirable), late effects would
be spared preferentially (also desirable). The use of multiple fractions
Lung: squamous cell carcinoma ~50-90 Gy per day of smaller than conventional size (less than about 1.8 Gy)
Cervix: squamous cell carcinoma >13.9 Gy but to a somewhat higher total dose, with little or no change in overall
Skin: Squamous cell carcinoma 8.5 (4.5; 11.3) Gy treatment time, has been termed hyperfractionation.
Melanoma 0.6 (−1.1; 2.5) Gy Hypofractionation, that is, the use of one or a few large dose frac-
tions delivered over short periods (as would be the case for stereotactic
Prostate 1.1 (−3.3; 5.6) Gy
radiosurgery or intraoperative radiation therapy), is also an option.
Breast (early-stage invasive 4.6 (1.1; 8.1) Gy Indications for the use of hypofractionation would include cases in
ductal, lobular, and mixed) which the complete ablation of small tumors is the goal, or in the
relatively unusual circumstance in which the tumor is suspected of
Data from Joiner M, van der Kogel A, editors. Basic clinical radiobiology. 4th ed. having a low, rather than high, α/β ratio. Prostate cancer and mela-
London: Hodder Arnold; 2009.
Table excerpted from Zeman EM. Biologic basis of radiation oncology.
noma appear to be tumor types that meet this criterion, although this
In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology. 3rd ed. topic remains controversial, as does the use of hypofractionation in
Philadelphia: Saunders; 2012. general.128-130
With particularly aggressive tumors that proliferate rapidly,
another clinical strategy has been suggested, although it is not explic-
itly derived from the LQ model. Multiple treatments per day might
Tumor and early- also be useful to decrease the overall treatment time, thereby allowing
responding tissue less time for repopulation of clonogenic tumor cells.131 Treatment
Late-responding tissue
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,
Surviving fraction
a combination of accelerated and hyperfractionated treatment is most

often used.132
Of course, determining the best treatment schedule for a particu-
lar patient is not simply a matter of avoiding a normal tissue com-
plication 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
Dose
number of infinitely small dose fractions. BEDs would be quite large
for tissues characterized by low α/β ratios and steep isoeffect curves
Figure 27-17 • Underlying dose response curves for tissues character- (like many late-responding normal tissues) and appreciably smaller
ized by low (yellow line) or high ( purple line) α/β ratios. The α/β ratio for for tissues characterized by high α/β ratios and shallower isoeffect
most late-responding normal tissues averages about 3 Gy, and for most early- curves (like most tumors and early-responding normal tissues). BEDs
responding normal tissues and tumors, it is about 10 Gy. are not real doses but extrapolations based on the shapes of
80 Skin necrosis
Skin
70 desquamation
60 Skin
contraction Lung
50 sis) (LD50’ pneumonitis)
r aly
pa
Total dose for various isoeffects (Gy) 40 rd( cells
co crypt
in al colon
Sp s of Kidney (LD50)
30 Los
)
onia
atog
erm
of sp Loss of jejunal crypt cells
is (loss
20 Test
Loss control of fibrosarcoma
Vertebral growth inhibition

10
Bone marrow abalation (LD50)
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 chemotherapy. However, substantial changes have occurred over the
reason, the units used to describe these theoretical, extrapolated doses years in the conceptual use of radiation therapy.
are, for example, “Gy3’s” or “Gy10’s” rather than “Gy’s,” with the Although it is still used for the reasons previously described, at
subscripts 3 and 10 referring to the α/β ratios for the tissues at risk. the present time, radiation therapy is routinely combined with con-
Although two radiotherapy treatment schedules can be compared current chemotherapy (either cytotoxic or “targeted”). It is commonly
qualitatively on the basis of their respective Gy3 or Gy10 “doses,” Gy3’s used in combination with surgery as either a preoperative or a post-
and Gy10’s cannot be intercompared. operative approach, and the timing of radiation therapy with surgery
Even with the BED concept being only semiquantitative at best, and chemotherapy can vary.
its use for treatment planning purposes during the past two decades Radiation therapy has the substantial benefit of being able to
has changed the radiotherapy standards of care for several tumor types provide organ preservation in many clinical situations and to be able
and provided a wealth of clinical data that has allowed a better defini- to sterilize microscopic disease when used in conjunction with
tion of what is or isn’t tolerable for particular normal tissues, in terms surgery. Thus we can categorize the use of radiation therapy as
of Gy3’s or Gy10’s. Using head and neck cancer as an example, follows:
Fowler133 has suggested that for acute mucosal reactions, the maxi-
mally tolerated BED is in the range of 59 to 61 Gy10, and for brain 1. Radiation therapy alone. Radiation therapy alone is often used
necrosis, it is approximately 110 to 115 Gy3. for small tumors for which surgery would be excessive therapy
either because of the precise location of the tumor or because of
Radiation Therapy Delivery Approaches the limitations of surgical resection. Radiation therapy can also be
used in this manner when a patient is too frail for a surgical pro-
Historically, radiation therapy was used as a single treatment modal- cedure or when a patient refuses surgical intervention. Radiation
ity, either for very early stage disease for which radical surgery would therapy alone is used much less commonly for locally advanced
be overtreatment (such as a total laryngectomy for early-stage glottic disease, because it is now often combined with concurrent che-
cancer) or for advanced disease in which surgery would be insufficient motherapy, and surgical procedures can often be performed even
for control of the disease extent (e.g., lung cancer with mediastinal for extensive local-regional disease. Examples of this category
disease or stage III cervical cancer). Treatments also focused heavily include treatment of early stage cancers of the head and neck,
on the use of radiation therapy for organ preservation. In these prostate cancer of all stages, early-stage cervical cancer, and selected
situations, radiation therapy would rarely be combined with basal cell carcinomas of the skin.
2. Preoperative or postoperative radiation therapy. For some pattern. Radiation treatments are usually given daily, 5 days a week,
tumors, surgical therapy is required, but surgery alone is likely to and can extend in duration from 1 week (or less) for certain types of
leave residual disease either in the tumor bed or in regional lym- palliative therapy to courses extending for 7 to 8 weeks of daily
phatics that are not completely resected. Radiation therapy in this therapy. Total doses can range from close to 8000 Gy in 8 to 9 weeks
situation will often be given with concurrent chemotherapy for at the high end to 2000 Gy in 1 week (or 800 Gy in a single fraction)
the radiation-sensitizing effects of the chemotherapy. Examples for palliation.
include soft tissue sarcomas, certain cancers of the head and
neck, intermediate and high-grade gliomas, and early-stage breast
Simulation, Treatment Planning, and Delivery
cancers. of External Beam Radiotherapy
3. Primary radiation therapy with concurrent chemotherapy. For After diagnosis, the first step in designing and delivering radiation
many tumors, surgical resection is not an option because of the therapy to a patient is called “simulation.” Simulation is a process for
inability to perform a grossly complete surgical resection, and thus determining the proper selection and orientation of beams so that
radiation therapy becomes the primary local therapy. Chemo- they properly overlap a target. Simulation requires the determination
therapy can be added either concurrently as a radiation sensitizer of patient dimensions for dose calculation and the determination and/
to enhance local control or before or after radiation therapy for or creation of identifiable reference points to ensure that beams are
control of systemic disease. Examples include all anal cancers and being aimed correctly. Historically, patient dimensions were deter-
locally advanced tumors of the uterine cervix, esophagus, pan- mined by methods as simple as forming a lead wire or plaster cast
creas, and head and neck. around the patient. Target volumes and patient anatomy were identi-
4. Tri-modality therapy. Often all three primary therapeutic fied and located by examining bony structures on a series of radio-
modalities—surgery, radiation therapy, and chemotherapy—are graphs. These radiographs were generally acquired using a device
needed for control of local, regional, and systemic disease. The called a simulator. A simulator is a diagnostic x-ray source configured
timing of the therapies is dependent on the individual clinical to mimic the geometric beam delivery configuration of a radiotherapy
situation. Tri-modality therapy is perhaps the most common linac. The x-ray source is mounted on a rotating gantry, similar to a
approach at the present time. Examples include a large group of linac, with a detector rotating in the opposite position on the far side
tumors, including esophageal, glioblastoma, head and neck, of the patient. This approach allows fluoroscopic imaging from mul-
esophagus, pancreas, breast, and rectum tumors. tiple angles, which facilitates positioning the patient so that the center
of gantry rotation can be placed in the tumor area. Once this position,
RADIATION THERAPY DELIVERY TECHNIQUES called the isocenter, is selected, radiographs are taken from all desired
beam angles. These radiographs are taken as a record for comparison
The radiation oncologist has multiple tools that can be used for with future portal films (taken during treatment) and as an aid for
delivery of radiation therapy, depending on the specific circum- the physician in refining each beam shape. Finally, room-mounted
stances. Often combinations of techniques are used to optimize thera- lasers indicate the location of isocenter on the patient’s skin, allowing
peutic delivery. Because many possible combinations exist, only the these points to be marked by a small tattoo or similar marking. These
general framework will be described. The technical issues have been markings can later be aligned with identically placed lasers in the
described earlier in the chapter. linac treatment room to position the patient on each treatment day.
Poor soft tissue contrast from fluoroscopic imaging means that,
External Beam Fractionated Radiation Therapy on a conventional simulator, treatment parameters such as isocenter
and beam boundaries can only be defined relative to visible landmarks,
External beam fractionated radiotherapy is by far the most common such as bony anatomy. More recently, techniques have been developed
technique used clinically. Radiation beams usually are delivered to use dedicated computed tomography (CT) scanners for “virtual”
through multiple angles of approach to the lesion, with each of the simulation, replacing conventional simulators in many radiation
beams shaped and altered in intensity to maximize the delivery of oncology departments. Virtual simulation is simulation that is based
dose to the tumor while minimizing the dose to normal tissues. solely on the CT scan of a patient, and it is made possible by the
External beam therapy can be delivered with conformal radiation ability to reproduce any arbitrary radiograph from a CT data set. In
therapy techniques (i.e., shaping the beams based on 3D reconstruc- virtual simulation, the patient is placed in the orientation and position
tions of the tumor size and shape and the location of nearby normal to be used for treatment delivery. A CT scan is acquired, and, with
tissues). Intensity-modulated radiation therapy changes the intensity the patient still positioned on the scanning table, the physician uses
of each small segment (“beamlet”) of an individual beam to obtain the superior soft tissue contrast of the CT scan to select a location
even more precise dose localization and avoidance of normal tissue for isocenter within the target area (Fig. 27-19). An integrated laser
irradiation. system then moves to indicate the position of the physician-selected
Generally these treatments are given using either low (6 MV) or isocenter on the patient surface, allowing the external markers or
high (≈10 to 15 MV) energy x-rays, but they can also be delivered tattoos to be placed for future alignment with the linear accelerator
with electrons of various energies, with the higher energies having a vault laser systems. The superior soft tissue contrast on CT images
greater depth of penetration into tissue. The radiation oncologist allows improved tumor localization and improved beam selection
decides the proper treatment based on both personal experience and compared with fluoroscopy-based conventional simulators.
literature estimates of tolerance doses for normal tissue complications After simulation is completed, the CT scan and other images can
and curative doses for tumors for different fractionation schedules. be sent to a computer-based planning workstation, where the team
This decision is a balancing effort, in an attempt to give the highest of physicians, dosimetrists, and physicists can begin the treatment
probability of tumor control with the lowest reasonable level of clini- planning process. Treatment planning includes the identification of
cally significant normal tissue injury. Often, depending on the indi- target volumes and normal structures requiring dose tracking and the
vidual anatomy and tumor extent, radiation doses will need to be selection and modification of beams to achieve specified dosimetric
modified. goals. The contouring process of identifying the boundaries of all
The radiation fields used with external beam radiation therapy treatment and avoidance structures takes place on the CT scan
often target areas of presumed subclinical disease (such as nodal acquired at the time of simulation, but it may be supplemented by
drainage regions), as well as the clinically apparent tumor. As a result, other imaging modalities, such as magnetic resonance imaging, posi-
it is critical for the radiation oncologist to have an excellent under- tron emission tomography, or ultrasound. Normal structures are typi-
standing of the natural history of each disease and its specific spread cally defined at their anatomic boundaries. The volume to be treated,
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 A
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.
Source
defined as the target volume inInternational Commission on Radia-

tion 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 pos-
sible 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 Multileaf collimator
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 clini-
cal 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 Projected field
beam energy, orientation, and shape. Beams are typically shaped to
match the cross section of the PTV plus some small margin to maxi- B
mize overlap with the tumor while limiting the amount of normal
tissue directly exposed to the radiation beam. This goal can be accom- Figure 27-20 • A, A multileaf collimator device on a linear accelerator.
plished by designing a customized block made from an easily cast B, The individual collimator leaves can be adjusted to form arbitrarily shaped
metal alloy such as Cerrobend, but on modern machines it is typically fields. (From Bourland JD. Radiation oncology physics. In: Gunderson LL,
performed with use of automated beam-shaping devices such as a Tepper JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saun-
multileaf collimator (Fig. 27-20). Use of multiple beams overlapping ders; 2012.)
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 representation of dose levels superimposed on the patient image and
location and the proximity of normal structures, as well as clinical indicate regions of high and low dose on any user-selected plane. As
factors, such as prior or planned surgery, overall patient health, shown in Figure 27-21, isodose lines correlate dose with anatomic
history of prior irradiation, likelihood of future irradiation, and the location and can indicate regions of insufficient or excessive dose and
effects of concurrent chemotherapy. suggest beam arrangements and weightings that can better meet the
The dosimetry of a sample treatment plan must be evaluated for dosimetric goals for the plan. Aggregate dose to contoured structures
likely treatment efficacy of the tumor and the possibility of toxicity are expressed as dose-volume histograms, which display the percent-
to normal structures. Dosimetry can be evaluated by examining age or absolute volume of the structure receiving a specified dose or
isodose lines and dose-volume histograms. Isodose lines are a 3D lower (Fig. 27-22). Most dose constraints applied to treatment
Figure 27-21 • Four-field treatment plan for a thoracic lesion. A com-

bination 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 Figure 27-23 • Wedges in the opposing lateral beams for treatment of
of the lung. the larynx. The thick ends of the wedges provide extra beam attenuation
where the patient is thinnest.
100
Tumor
80 Liver
Spinal cord
Volume (%)
60
40
20
0
0 20 40 60 80 100
Dose (%)
Figure 27-22 • A dose-volume histogram expressed in terms of what Figure 27-24 • Sample intensity-modulated radiation therapy beams
percentage of the structure volume receives at least what percentage of the for treatment of a patient with head and neck cancer. Each of the seven beams
total dose. In this example, only 10% of the spinal cord receives 15 Gy or has a computer-optimized intensity distribution that combines with the other
greater, whereas almost 100% of the tumor receives 100% of the target dose. beams in such a way as to produce highly conformal dose distributions.
planning are expressed in terms of dose-volume histograms. For obliquity or irregular patient surfaces commonly lead to uneven dose
example, a typical constraint imposed on treating lung lesions is to distributions across a given beam depth. In other cases, the presence
limit the total volume of lung receiving 20 Gy or more to 30%.135 of a sensitive normal structure in the vicinity of the target region may
Determining appropriate dose constraints for normal structures from make it desirable that the photon intensity be lessened across all or
clinical data is critical; compilations of so-called “tolerance doses” for part of a given beam. Varying the intensity of multiple radiation
different normal tissue effects are generated periodically as clinical beams in a manner that improves the overall homogeneity of the dose
data accrues and have most recently been aggregated in the Quantita- to the target and helps to decrease the dose to normal tissue is referred
tive Analyses of Normal Tissue Effects in the Clinic (QUANTEC) to as intensity-modulated radiation therapy (IMRT).137
publications.136 The simplest form of intensity modulation, wedge filters, has been
in use in radiotherapy since the 1960s. A wedge is an angled piece
Intensity-Modulated Radiation Therapy of high-density material that preferentially attenuates a photon beam
In conventional radiotherapy, treatment plans are designed to deliver on its thick end, resulting in a dose gradient across the beam. Wedges
a roughly homogeneous dose distribution to the tumor region. This are often used to flatten the dose distribution for beams striking
goal is most easily accomplished by covering the target with overlap- sloped surfaces, as illustrated in Figure 27-23. More recently, complex
ping homogeneous beams. For this reason, most modern linacs are intensity distributions have been created by combining multiple
designed to deliver just such flat dose distributions. Attaining a beamlets of varying intensity into a single beam having an intensity
homogeneous dose distribution across a target can be complicated by profile customized to meet the needs of a specific patient (Fig. 27-24).
a variety of factors. For example, geometric concerns such as beam The delivery of multiple beamlets for IMRT is made practical by the
development of the multileaf collimator, which allows each beamlet pelvic primary tumor and draining lymphatics. Then an implant is
to be formed and delivered in sequence without requiring the inter- used to give an even higher dose of radiation to the primary tumor
vention of a radiation technologist. The widespread implementation through the use of tubes that are placed in the uterus and the vagina
of multileaf collimators has allowed IMRT to grow from an experi- and subsequently loaded with radioactive sources. Although in the
mental procedure practiced at a small number of academic centers in past it was very common to use “low dose rate” sources for the
the 1990s to a standard technique applied in clinics all around the brachytherapy, delivering the prescribed radiation dose continuously
world. (in an inpatient setting) over 2 to 4 days, it is now more common to
Calculating the proper intensity distributions for multiple inter- use high dose rate sources for which the applicators are inserted daily
secting beams is too complex a task for human hand calculations. or weekly and treatment is delivered over 10 to 15 minutes each week
Rather than having the physician and physicist create a treatment for approximately five sessions.
plan by manually selecting beam orientations and field shapes, IMRT Temporary implants are also used for treatment of selected head
fields are designed by computer algorithms called optimizers. The and neck squamous cell carcinomas, melanomas of the choroid in the
treatment planners specify the hoped-for dose distribution, expressed eye, and occasionally for tumors of other anatomic sites where it is
as dose goals and toxicity limits, and the optimizer uses mathematical difficult to otherwise deliver the desired radiation dose.
techniques to alter the intensity profile of each beam until the dose Prostate brachytherapy is delivered by the placement of perma-
goals are met to the greatest extent possible. The first optimizers only nent radioactive seeds into the prostate. Depending on the radioiso-
considered purely dosimetric goals, but recent efforts have been made tope, the treatment will be delivered over the course of months, with
to include biological end point models in optimization functions, the implanted radiation sources continuously delivering therapy until
such as effective uniform dose, tumor control probability, and normal the sources have decayed to the point that they are barely radioactive.
tissue complication probability. IMRT optimization has been used in Fortunately, the energy of the radiation deposited by these isotopes
a variety of clinical circumstances and has been shown to have clinical is low, and thus there is minimal public health risk or risk to family
benefits for treatments in many anatomic sites, such as treatments for members. This approach is probably the most cost-effective way to
prostate,138 lung,139 and head and neck cancers.140 definitively treat early-stage prostate cancer and is very effective
Once a treatment plan has been completed, approved, peer because of the high dose of radiation therapy delivered to the
reviewed, and passed through a rigorous quality assurance program, prostate.
the patient is ready to begin treatment. On each treatment day the
Simulation, Treatment Planning,
patient must be positioned in an orientation identical to that used
during simulation, and thus the position within the patient desig- and Delivery of Brachytherapy
nated as the isocenter must be placed in the room position matching The short range of radiation from most brachytherapy sources con-
the center of rotation of the linear accelerator. Rough alignment can fines the majority of the dose to the immediate vicinity of the sources
be accomplished by aligning the tattoos from the simulation step with themselves, allowing highly conformal dose distributions through the
in-room lasers in the accelerator vault. For more precise alignment of careful placement of sources within or near the target volume. This
the patient, image-guided radiation therapy (IGRT) techniques can arrangement allows a degree of sparing of nearby normal structures
be used. Global patient positioning can be refined using video that may be superior to that achievable with use of external beam
imaging of the patient surface141 or two-dimensional imaging of bony radiation therapy. Because of the high degree of conformity involved,
anatomy (MV portal films or kV radiographs). Techniques to image brachytherapy is most effective for relatively small, well-localized
soft tissue structures to improve patient alignment include the use of tumors. Most radionuclides used for radiation therapy use γ-ray
in-room CT scanners, linac-mounted cone-beam CT scans,142 photon emission as the primary source of therapeutic energy. Early
implantable fiducial markers detectable by radiograph, radiofre- brachytherapy procedures used radium or radon sources, but these
quency signal,143 or ultrasound.144 Adjustments to patient position sources have been almost completely replaced by safer, artificially
based on these techniques can be made prior to radiation delivery. produced radionuclides such as cesium-137, iridium-192, iodine-
To ensure that the patient moves as little as possible between position- 125, and palladium-103 (Table 27-1). Brachytherapy sources are
ing and the delivery of radiation, several forms of patient immobiliza- generally enclosed in multiple layers of inert material. The inert layers
tion may be used. prevent leakage of the radioactive material and, for photon sources,
During the delivery of radiation, the patient lies as motionless as absorb unwanted decay products such as α-particles and electrons.
possible while the linac rotates around the patient from position to Brachytherapy doses can either be delivered over a short period (tem-
position, delivering the beams specified during the treatment plan- porary implants) or gradually over the lifetime of the seeds (perma-
ning. Treatments are delivered and supervised by radiation therapists, nent implants).
who operate the linac and monitor the patient and linac position to Brachytherapy treatments are generally delivered using either
ensure that both are in the proper location. A typical treatment interstitial or intracavitary techniques. In interstitial brachytherapy,
session lasts 10 to 15 minutes, although some cases involving extra radioactive seeds are surgically placed within the tumor volume. The
imaging or delivery of high doses can last 1 hour or longer. The seed placement can be permanent or temporary. Permanent seeds are
delivery of the radiation itself is undetectable by the patient, because deposited in the tumor volume using needles. Temporary seeds are
the actual energy deposited in tissue for a typical 2-Gy fraction, placed and removed from the tumor volume through implanted
although sufficient to cause irreparable cellular damage, will only raise catheters. A common permanent interstitial procedure is treatment
the temperature of the tissue by approximately one one-thousandth for early-stage prostate cancer, in which approximately 100 125I seeds,
of 1°F. each the size of a grain of rice, are placed in the prostate. Temporary
interstitial procedures typically use fewer seeds, with MammoSite
Brachytherapy therapy for partial breast irradiation using a single 192Ir seed applied
through a catheter.145
Although it is not used as commonly at present as in the past, the Intracavity treatments are the most common technique in current
use of radioactive implants is still a standard part of the tool kit that use for brachytherapy. In this form of brachytherapy, seeds are placed
the radiation oncologist has at his or her disposal to be able to put in existing body cavities in the vicinity of the tumor volume. Radioac-
the radiation dose precisely where the tumor is located. This tech- tive seeds are deployed in catheters arranged in specially designed
nique is most commonly used in gynecologic tumors and in the applicators that are inserted into the appropriate cavity. Intracavitary
treatment of prostate cancer. For gynecologic malignancies such as treatment is most commonly used for treatment of gynecologic
cervical cancer, external radiation therapy is initially used to treat the cancers but may also be used in other sites, such as the nasopharynx,
the biliary tree, or the esophagus. Intracavitary brachytherapy treat- still delivering a clinically useful dose to the malignant tissue.
ments are always temporary, ranging in duration from a few minutes Although this approach helps minimize normal tissue toxicity, the
to several days. goal of greater tumor control could be increased further by using large
Two additional brachytherapy techniques include surface applica- doses in fewer fractions (e.g., one to five fractions of 5 to 20 Gy each).
tion and intravascular brachytherapy. Surface application of brachy- The large doses used in hypofractionated treatments are highly toxic
therapy sources is conceptually similar to intracavitary treatment, in to normal tissues as well as tumors, and thus hypofractionated treat-
that the radioactive sources are placed in an applicator and positioned ments can only be delivered safely and with acceptable normal tissue
adjacent to the treatment area, although in this case the sources are morbidity under the following conditions:
placed on an exterior surface. Surface application is common for
1. well-circumscribed tumors (minimal or no CTV expansion);
treatments on the eye, including cancerous (choroidal melanoma)
2. minimal treatment margin around the lesion (minimal PTV
and noncancerous (pterygium) conditions. Intravascular brachyther-
expansion);
apy deploys radioactive seed(s) through a catheter placed in a blood
3. rapid dose falloff away from the target area; and
vessel. This technique has been used to treat tumors in the liver via
4. very precise (1 to 5 mm) targeting and localization of the tumor.
the hepatic artery, where the radioactive particle is placed on special
beads that are then embolized in the hepatic vasculature, effectively Stereotactic radiosurgery (SRS) refers to a single-fraction delivery
limiting the dose to the tumor area in the liver. of a high dose to an intracranial target. The term “radiosurgery” was
coined in 1951 by a neurosurgeon named Lars Leskel,146 who devel-
Stereotactic Radiosurgery oped the original techniques for SRS in the 1940s using orthovoltage
x-rays. Since that time, patients undergoing SRS have been treated
Although attempts at stereotactic delivery of radiation therapy have with heavy charged particles, megavoltage x-rays, and γ-rays from
been considered for decades, only during the past few years has there radioactive sources. During the following decades, the use of SRS has
been a marked increase in interest and use of this approach. Whereas been documented in more than 4000 publications,147 demonstrating
conventional external beam radiation therapy is designed to preserve the effectiveness of the technique in treating primary and metastatic
the normal tissue that is being irradiated, the intent with radiosurgical brain lesions, as well as nonmalignant functional disorders such as
approaches is that a small amount of tissue that includes the tumor arteriovenous malformations and trigeminal neuralgias. The single-
will be ablated by this therapy. Depending on the precise location, if fraction doses in SRS are sufficient to kill any tissue, cancerous or
the volume irradiated to high dose is small, the likelihood of clinically otherwise, and thus great care must be taken to produce a high-dose
significant injury is low, similar to what would be the case with surgi- region that is tightly conformal to the target area and to ensure that
cal excision. This technique is entirely dependent on very precise dose the dose is delivered to the correct location in the patient. Highly
localization and the use of many radiation beams so that only the conformal dose distributions can be created using 100 to 200 overlap-
tumor and immediately adjacent tissues receive a high dose. ping beams (Fig. 27-25, A) or by delivering dose continuously as
The reason this approach has an advantage over surgery is that a a linear accelerator moves around the patient in one or more arcs
surgical procedure is not required to implement it, and it can often (Fig. 27-25, B). Positioning the patient correctly relative to the beams
ablate tumors that are not easily accessible by other approaches. Treat- requires much stricter immobilization than is typically used for stan-
ment is usually given in one to five sessions, although more can be dard radiotherapy. Traditionally, patients would be placed in a rigid
used in special situations. Very large doses (20 Gy) are typically used stereotactic head frame, which would then be positioned relative to
for single fraction therapy, doses that otherwise would not be con- the radiation beams by affixing the frame to either the treatment table
sidered for standard external beam therapy because of the high risk or a room-mounted pedestal. The frame, which is affixed to the
of normal tissue complications. For multifraction therapy, common patient’s skull prior to patient imaging, provides a known offset
fractionation schemes include three fractions of 7 to 15 Gy each, or between radiation isocenter and the tumor location, allowing dose
four to five fractions of 5 to 12 Gy or higher. delivery with an accuracy of approximately 1 mm. Newer SRS immo-
The first radiosurgical approaches were designed for treatment of bilization techniques have been able to approach the accuracy of
intracranial lesions, but the same technique is now used for multiple stereotactic frames without requiring fixation to the patient’s skull,
anatomic sites. The ability to deliver radiation in this manner is having the advantages of being less invasive and more reproducible
heavily dependent on the development of radiation therapy hardware if fractionation is warranted. Examples of these techniques include
and computer software to design a large number of radiation beams vacuum-based frame fixation to the hard palate and IGRT-intensive
that intersect at the tumor. The Gamma Knife approach was the frameless radiosurgery. SRS can be delivered to multiple tumor sites
first widely used technique, using a large number of 60Co radiation in the brain during a single treatment and is generally limited to
sources for the treatment of intracranial lesions. A number of differ- well-defined lesions 2 cm or smaller.
ent approaches now exist that use linac techniques for delivering Stereotactic body radiotherapy (SBRT) is hypofractionated treat-
x-rays stereotactically. ment applied to extracranial targets, such as in the abdominal, pelvic,
Radiosurgery is used for many clinical situations, including treat- and spinal regions. SBRT has a much shorter history than SRS, with
ment of brain metastases and other intracranial tumors, but treatment the first clinical outcomes for SBRT reported in 1995.148 Early SBRT
of isolated lesions in the lung, liver, kidney, prostate, and vertebral studies focused on the treatment of lung and liver lesions, but more
bodies are all increasing in use as the technology and our understand- recent efforts have included studies of spine, prostate, kidney, pan-
ing of the biology both improve. An area of great interest is in the creas, and gynecologic cancers. The delayed development of SBRT
therapy of oligometastatic disease (i.e., with a small number of meta- relative to SRS is largely due to increased difficulties in target localiza-
static sites), either in the liver, lung, brain, or elsewhere. It is now tion. For example, whereas intracranial lesions can be expected to
clear that substantial numbers of patients can be cured by eradicating maintain a constant position relative to the patient’s skull, soft tissue
a solitary focus of metastatic disease (or a few foci of tumor). Stereo- lesions in the body can move relative to bony anatomy or any external
tactic approaches are ideal for this type of therapy. markers used for patient setup. Minimizing this uncertainty requires
the use of in-room imaging devices to ensure accurate beam delivery.
Stereotactic Radiosurgery and Stereotactic Body
Soft-tissue imaging may be facilitated by implanting radiographically
Radiotherapy Physics visible fiducial markers in the region of the tumor. The extensive use
As previously discussed, the long fractionation schemes used in exter- of in-room imaging (IGRT) has largely replaced the use of stereotac-
nal beam radiotherapy (e.g., 2-Gy doses delivered in 30 to 40 daily tic body frames in SBRT. Lesions in the thoracic or abdominal cavi-
fractions) are designed to give normal tissue a chance to recover while ties may also move during beam delivery as a result of respiratory
Source
Helmet positions
(collimator)
Upper
door
Treatment ON
Focus (isocenter) helmet position
Patient support Source

shield
Lower
door
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
Rotational axis:
Support
collimator, headframe,
stand
and turntable
Floor 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 overlap-
ping beams. (From Bourland JD. Radiation oncology physics. In: Gunderson LL, Tepper JS, editors. Clinical radiation oncology, 3rd ed. Philadelphia: Saunders;
2012.)
motion. Techniques for minimizing the effects of respiratory motion surgeon opens the patient and removes as much of the suspected
include: cancerous tissue as possible. The electron linac is then maneuvered
into position directly over the surgical site, and the tumor bed and
1. gating, in which dose is only delivered during a small portion of
other high-risk tissues are irradiated. The appropriate electron beam
the breathing cycle;
energy is selected based on the desired depth of treatment, and an
2. tracking, in which the beam delivery device moves with the target;
applicator cone is attached to confine the beam to the intended area.
and
The patient is then moved into position under the linac and the
3. immobilization, in which patient breathing is regulated or limited
tumor bed and other high-risk tissues are aligned with the radiation
to reduce the degree of tumor motion during treatment.
beam. A dose of 10 to 20 Gy is then delivered to the treatment area,
All of these techniques increase the uncertainty of beam delivery, the patient is moved away from the accelerator, and the surgical team
requiring larger margins around the GTV and consequently larger completes the surgery.
volumes of irradiated normal tissue. Partially because of this situation,
SBRT treatments are typically delivered in three to five fractions. Specialized Radiotherapy Techniques and
Facilities
Intraoperative Radiation Therapy
Investigators have great interest in the use of specialized radiation
In oncologic surgery, it is not always possible to remove all cancerous modalities that require different machines that produce either
tissue during the procedure. Presumed microscopic infiltration of protons, neutrons, or other high-energy particles. Although treat-
cancer cells into the tumor bed and/or portions of the tumor left ment with photon beams is the most common form of radiotherapy,
unresected because of the excessive risk of morbidity can be treated particle beam therapy also has many clinically useful properties. As
in the operating room using short-range radiation. Intraoperative discussed elsewhere in this chapter, light charged particles such as
radiation therapy (IORT) was attempted as early as 1909149 but did electrons lose their energy gradually, depositing dose approximately
not become a mature treatment modality until the 1980s. In IORT, evenly as the beam passes through tissue. This process continues until
a large single dose of radiation is delivered to an exposed tumor or all energy is expended, at which point the dose delivery stops abruptly,
tumor bed with the intention of improving the probability of local as illustrated in Figure 27-3. Thus particle beams can be used to treat
control. Performing the irradiation during the surgical procedure a target while delivering almost no dose to anatomic structures
allows sensitive normal structures to be surgically moved out of the beyond the target region. Therapeutic electrons in clinical use are
beam path, minimizing the dose received by healthy tissue. limited to treatment depths of 5 to 6 cm, limiting their applicability
Although radiation oncologists have been delivering radiation to shallow lesions. These high-energy electrons can scatter at large
therapy in conjunction with surgeons for many years, techniques to angles, causing the electron beam to spread as it passes through tissue.
best accomplish IORT continue to evolve. The intraoperative deliv- This effect blurs the edges of the dose distribution, making precision
ery of electrons (or sometimes orthovoltage x-rays) when a tumor or dosimetry difficult.
tumor bed is exposed provides the potential advantage of direct These limitations can be overcome through the use of heavier
visualization of the tissues that need to be treated combined with an charged particles, such as protons, neutrons, or heavy ions. The use
ability to control the depth of penetration of the radiation beam by of heavier particles has several advantages:
using variable energies of electrons.
1. heavier particles scatter at smaller angles, allowing less blurring
The technique usually requires a dedicated irradiator in the oper-
and more precise dose delivery;
ating room, and thus it is available only at specialized centers. IORT
2. heavier particles typically have a higher LET, leading to greater
provides the greatest advantage in treating deep-seated tumors for
biological effectiveness than an equivalent energy deposition from
which surgery will be performed, but for which the ability of the
standard photon or electron therapy; and
surgeon to completely excise all the tissues at high risk of tumor is
3. for particles such as protons, the distal end of the dose distribution
severely limited. Radiation is given in a single session using a high
is quite sharp, allowing much more accuracy in avoiding irradia-
single dose of radiation on the order of 10 to 15 Gy. This treatment
tion of normal tissues deep to the tumor.
is often preceded or followed by a course of standard external beam
radiation therapy, with the intraoperative component viewed as a
radiation boost. Protons
The technique has been used most commonly for intraabdominal Protons are charged particles that can be accelerated and directed into
tumors, and especially for recurrent tumors in the pelvis, for example, tissue, where they deposit their dose. Protons deliver a lower dose to
recurrent rectal cancer. It may have a role in the treatment of retro- superficial tissues, then a higher radiation dose at depth where the
peritoneal sarcomas and has been evaluated for the treatment of tumor is, and then virtually no dose to normal tissues beyond the
pancreatic and breast cancers. IORT has also been delivered with low tumor, which provides an advantage compared with conventional
energy (orthovoltage), low penetrability x-rays to the tumor bed of x-rays, which deliver the highest doses (from a single beam) to more
small or superficial cancers and with approaches that use a combina- superficial tissues. Thus protons can allow for more precise delivery
tion of brachytherapy implant and IORT techniques. 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
Physics Considerations for Intraoperative
slightly more biologically effective than x-rays or electrons. The prin-
Radiation Therapy cipal advantage of proton therapy, therefore, is improved dose
IORT treatment modalities require short-range radiation to minimize distributions.
the dose to tissue behind the irradiated area, and include high dose Proton therapy is the most common type of heavy particle therapy.
rate brachytherapy sources (typically 192Ir), low-energy photon beams, Proton beams are produced by accelerating ionized hydrogen in a
or electrons from linear accelerators. Early efforts in IORT required cyclotron or synchrotron to energies in excess of 100 MeV. These
either a dedicated operating suite with permanent irradiation equip- devices are considerably larger and more expensive than conventional
ment or that the patient be transferred from the operating room to clinical accelerators, and thus they tend to be built as stand-alone
a shielded accelerator room. Most modern IORT in the United States facilities, although research into smaller scale proton devices is
is performed using mobile electron linacs. The advantages of electron ongoing. Unlike electrons that lose energy roughly evenly across the
linear accelerators include greater dose homogeneity over the targeted range of therapeutic energies, protons lose their energy at an increas-
region, similar dose absorption in tissue and bone, and relatively ing rate as the beams loses energy with depth. This effect culminates
modest shielding requirements. In a typical IORT treatment, the in a region of rapid dose deposition near the depth of maximum
is incumbent upon persons using protons for radiotherapy to dem-

onstrate that the extra expense translates into better tumor control
Modulated
proton beam rates and/or fewer normal tissue complications. The lack of such level
SOBP
100 I evidence to date has made many persons concerned about the rapid
proliferation of proton facilities.
Neutrons
80
Relative dose (%)
Neutrons are heavy particles that are not charged, and they too are
10 MV X rays produced by specialized machines. Neutrons interact with matter
60 through different mechanisms than the photons and particles previ-
ously discussed; these interactions can cause low-energy protons and
heavier ions to be ejected during collisions between neutrons and
40 target nuclei. These ejected particles cause biological damage in accor-
dance with their LET. Neutron beams therefore have an energy-
dependent, average RBE that can vary between 5 and 20.
20 Unmodulated
proton beam 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
0
the potential to destroy more effectively certain tumors that are rela-
0 4 8 12 16 tively radioresistant, including melanomas, sarcomas, and salivary
Depth in tissue (cm) gland tumors. Many clinical studies involving neutron therapy have
been conducted, but it has been difficult to find a clear advantage to
Figure 27-26 • Depth-dose comparison between 10 MV x-rays, this approach over conventional treatment methods.
unmodulated, and modulated proton beams. Monoenergetic (unmodulated)
proton beams produce narrow regions of high dose, often requiring beam Heavy Ions
modulation to spread the dose distribution over a wider range. Both unmodu- Investigators have had a long-standing interest in using other heavy
lated and modulated proton beams compare favorably with photon beams charged particles, such as accelerated carbon or neon ions, for thera-
for minimizing dose both upstream and downstream of the target area. (From peutic purposes, and that interest continues to the present day. These
Verhey LJ, Petti PL. Principles of radiation physics. In: Hoppe RT, Phillips particles have the potential to combine both the biological advantages
TS, Roach M, editors. Leibel and Phillips textbook of radiation oncology.
3rd ed. Philadelphia: Saunders; 2010.) 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 develop-
penetration, called the Bragg peak (Fig. 27-26). The depth of the ment and use to only a handful of facilities worldwide.152,153
Bragg peak increases with beam energy, allowing careful energy selec-
tion to ensure that the highest dose is delivered to the tumor volume, FUTURE DIRECTIONS
with lower doses upstream of the target and negligible dose down-
stream of the target. The width of the Bragg peak is virtually always Enormous advances in radiation therapy have been made in the past
narrower than the region to be targeted, requiring a range of proton two decades. Such therapy has the ability to localize tumors more
energies to “paint” high, uniform doses across the target. This widened accurately than other modalities and then to deliver radiation much
dose distribution, known as a spread out Bragg peak, can be created more precisely to the volume of interest while minimizing the dose
either by varying the proton beam energy in a synchrotron or by delivered to normal tissue. Most of these advances have been techno-
using a spinning modulator of varying thickness to selectively vary logical, and it is highly likely that further advances will be produced.
the beam energy, shown in Figure 27-26. Interest is now increasing in melding biology with therapy in terms
The largest clinical experience with the use of proton radiotherapy of improved biological definition of the tumor location with func-
has been for the treatment of prostate cancer. However, although their tional imaging. In addition, better elucidation of tumor subtypes will
use in this site has a theoretical advantage, that advantage has never allow us to define better which patients are at high risk of local recur-
been demonstrated in clinical trials.150 Protons are very appealing for rence and therefore require additional local therapy, or which patients
the treatment of certain pediatric tumors, because the effects of will benefit from various combination treatments. It is also likely that
unwanted irradiation of normal tissues can be severe. In this context, combinations of radiation therapy and biologics (as well as new
protons have been used extensively in the treatment of pediatric cytotoxics) will have a substantially greater role in clinical practice in
central nervous system tumors.151 Studies exploring the use of protons the future by enhancing the selective killing of tumor cells.
for therapy of lung cancer and tumors at other anatomic sites are
ongoing. Because the cost of a proton irradiator (and its specialized The complete reference list is available online at
facility) is far greater than for traditional x-ray and electron linacs, it www.expertconsult.com.
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Basics of Radiation Therapy

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27 Basics of Radiation Therapy

Elaine M. Zeman, Eric C. Schreiber, and Joel E. Tepper

INTRODUCTION 1400 known isotopes of the 92 naturally occurring elements, approxi-

Interactions of Radiation and Matter Compton effect

In order of roughly increasing energy, photons can interact with: e:

Electron beam Electron beam

Primary collimator Primary collimator

Depth dose (%)

Depth dose (%)

Incident particle track

replicating or transcribing gene versus an inactive one), and, critically,

Figure 27-8 • Chromosome aberration production can be modeled

A Dose (Gy) B Dose (Gy)

cellular stress/adaptive response to hypoxic conditions and whose

100 The Biology of Fractionation

Surviving fraction Proliferation

of a complication is relatively insensitive to treatment duration.126

a combination of accelerated and hyperfractionated treatment is most

Loss control of fibrosarcoma

Vertebral growth inhibition

Figure 27-19 • Isocenter selection in the center of a lung tumor allows

defined as the target volume inInternational Commission on Radia-

Figure 27-21 • Four-field treatment plan for a thoracic lesion. A com-

Patient support Source

Electron beam path

Head frame Small radiation beam

Gantry rotation axis

is incumbent upon persons using protons for radiotherapy to dem-

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