Basics of Radiation Therapy 27 

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

S UMMARY OF K EY P OI NT S
Introduction and Historical cellular target for radiation is DNA, impediment to tumor control. The
Perspective with irreparable or “misrepaired” elimination of such cells has been a
• X-rays were discovered emanating double-stranded breaks believed to long-standing clinical goal; however,
from an energized Crookes tube by be the lesions most responsible for hypoxia also may provide avenues
Wilhelm Roentgen in 1895.1 That cell killing. for therapeutic gain through the use
some naturally occurring elements • Radiation elicits diverse cellular of hypoxia-directed therapies.
emitted ionizing radiation was responses that include the sensing • Radiation sensitizers, particularly
discovered by Henri Becquerel of DNA damage, mobilization of DNA cytotoxic chemotherapy, and, to a
1896.2 The radioactive elements repair proteins, repair (or attempted lesser extent, radiation protectors
radium and polonium were isolated repair) of DNA damage, triggering of aim to improve the therapeutic ratio.
and characterized by the Curies in cell cycle checkpoints, and, for Increasingly, targeted agents and
1898.3 irreparable or misrejoined damage, immunotherapy are being combined
• Within a year or two, ionizing radiation cell death by one of several with radiation in the hopes of
was in use worldwide for medical mechanisms. therapeutic benefit.
imaging and radiation therapy. • The most commonly applied model Clinical Radiation Oncology
Radiation Physics of cell survival probability is the • Radiation therapy is used in more
• Several types of ionizing radiation linear-quadratic (alpha/beta) model, than half of all patients with cancer,
are used to treat patients; most are with the surviving fraction of either as an adjuvant or neoadjuvant
of the low linear energy transfer irradiated cells described by the treatment in combination with
2

(LET), less biologically potent equation S = e−(αD + βD ). Whereas surgery, as a definitive treatment
varieties. the α/β ratio can be used as a alone or in combination with
• Therapeutic x-rays (photons) and metric for describing cellular chemotherapy, as an organ-sparing
electrons are produced by linear radiosensitivity, it has also been therapy, or to palliate cancer-related
accelerators but can also be adapted to describe the time, dose, symptoms.
produced by nuclear isotopes that and fractionation response of • Fractionation of radiation and altered
undergo radioactive decay. These irradiated tissues. fractionation schedules, including
form the basis of, respectively, • DNA damage and repair were initially accelerated, hyperfractionated and
external beam radiation therapy and inferred by monitoring increases in hypofractionated radiation therapy,
brachytherapy. cell survival or tissue tolerance with make use of differences in the
• Ionizing radiation interacts with fractionation. These phenomena fractionation sensitivity of normal
matter via several processes, the were termed sublethal and and malignant tissues to achieve
most important of which for clinical potentially lethal damage repair or higher therapeutic ratios.
radiation therapy is Compton recovery. • Radiation produces early effects
scattering. • Cells in different cell cycle phases such as mucositis, skin erythema,
• Megavoltage photons from linear possess different radiosensitivities; or desquamation and late
accelerators have the desirable cells are most radiosensitive in the effects such as fibrosis and
property of delivering their maximum M phase of the cell cycle, and most carcinogenesis.
dose at 1 to 3 cm within the patient, resistant in S phase, particularly late
S phase. Cells in G1 phase are of Planning and Delivery of
thereby sparing the skin and, to Radiation Treatment
some extent, other normal tissues. intermediate radiosensitivity.
• Well-oxygenated cells are as much • Patient simulation uses multiple
Radiobiology of Radiation as three times more sensitive to imaging approaches to identify
Therapy radiation-induced killing than cancerous and healthy regions within
• Ionization of biomolecules from the (severely) oxygen-deprived cells. the patient and to select appropriate
deposition of energy by photons or Viable, hypoxic cells that exist in beams to deliver dose to the tumor
particles can occur directly and many human tumors but are mostly while minimizing dose to surrounding
indirectly. The most important absent in normal tissues may be an tissues.

Continued

431
432 Part I: Science and Clinical Oncology

• The use of three-dimensional ensure that the tumor is positioned • Stereotactic radiosurgery and
conformal treatment planning and such that the radiation beams stereotactic body radiation therapy
delivery has permitted escalation of are precisely delivered to the combine high dose-per-fraction
dose and improved sparing of appropriate location within the irradiation with highly conformal
normal tissues. patient. treatment delivery to increase the
• Intensity-modulated radiation therapy Other Modalities in Radiation therapeutic ratio while reducing
uses varying radiation beam • Brachytherapy, the placement of overall treatment time.
intensities to more precisely sculpt radioactive sources immediately • Proton therapy has dose distribution
the dose distribution around the adjacent to the tumor, delivers advantages over photon therapy,
tumor to improve the therapeutic extremely high-dose radiation and it may be used to deliver high
ratio. to tumor tissue with a much doses of radiation to tumors in close
• Image-guided radiation therapy uses lower dose to surrounding normal proximity to sensitive normal
real-time and/or daily imaging to tissues. structures.

Radiation therapy is one of the three established cancer treatment removing a comparable amount of energy. Of the 1400 known isotopes
modalities and is used for the therapy of most types of solid tumors of the 92 naturally occurring elements, approximately 80% are unstable
and for selected hematologic malignancies. It is used almost entirely and spontaneously undergo a transition between energy levels, emitting
for therapy of malignant disease, although it has a small role in prevent- energy in the process. The phenomenon of spontaneous energy release
ing proliferation in selected benign diseases. Radiation therapy is from a nucleus, called radioactivity, can take many forms, including
routinely combined with surgery, chemotherapy, or both to improve combinations of the emission of γ-rays, the ejection of electrons,
therapeutic results. It is often used with surgery to destroy microscopic positrons, or alpha particles, and the transmutation of one element
regions of tumor extension and with chemotherapy to destroy more to another.
effectively the primary tumor. An understanding of the therapeutic The term radiation refers to energy emitted from a source that is
use of ionizing radiation requires a basic comprehension of both the transmitted through a material or space. This radiation can then deposit
physics of radiation therapy delivery and the biologic effects of the its energy by interacting with the matter through which it passes.
interaction of radiation with matter. Regardless of source, most radiation used in radiation therapy involves
electromagnetic interactions. This energy can take the form of packets
OVERVIEW OF RADIATION PHYSICS of electromagnetic waves called photons, or it can be carried as the
kinetic energy of freely propagating particulate radiation such as
The toxic biologic effects of ionizing radiation, although complex, electrons, protons, or alpha particles.
varied, and incompletely understood, form the basis for the use of Photons are packets of oscillating electric and magnetic fields
radiation therapy as a cancer treatment. These biologic effects are propagating through space at the speed of light (3 × 1010 cm/s).
initiated when packets of energy are deposited in a volume of tissue Photons are characterized by their wavelength, which is the distance
and remove electrons from constituent atoms through a process called traversed by a wave over the course of a single oscillation. There are
ionization. Accordingly, the physics of radiation oncology is focused no real limits on the possible wavelengths of photons, but common
on the details of how, where, and how much energy can be deposited examples range in wavelength from AM radio (103 m) to visible light
in diseased tissue in the hopes of eradicating it while minimizing (10−7 m) to γ-rays (10−12 m). Photons that have a shorter wavelength
the energy released in healthy tissue. This requires an understand- oscillate at a higher frequency (more oscillations per unit time) and
ing of the nature of the radiation and the matter through which are more energetic. Energy and frequency are related by the Planck
it passes, and how that matter is changed as a result of the energy constant (4.135 × 10−15 eV-s) and are generally expressed in units of
deposition events. electron volts (eV). Each eV is equivalent to the kinetic energy required
to move one electron through a potential difference of 1 volt. The
Nature of Matter and Radiation energy of a photon determines its ability to penetrate matter. Visible
light (~1 eV) can interact with only the surface of objects. Diagnostic
All matter, biologic or otherwise, is composed of atoms. Atoms are (kilo-electron-volts [keV]) and therapeutic (mega-electron-volts [MeV])
made up of groups of electrons (small negatively charged particles) photons can penetrate much more deeply, allowing therapeutic
orbiting a nucleus consisting of protons (larger positively charged effects anywhere in the body. Photons at therapeutic energies can
particles) and neutrons (uncharged particles having mass similar to pass through many centimeters of tissue before experiencing any
that of a proton). A number of electrons that matches the number interactions.
of protons is held in orbit around the nucleus by electrostatic attraction. Most particulate radiation consists of energetic charged particles.
A specific discrete set of possible electron orbits exists for each kind The electric fields around these particles cause them to interact with
of atom, with each electron orbit corresponding to a specific energy. all the other charged particles in the surrounding medium. Charged
Moving an electron from one orbit to another requires adding or particles are therefore much more efficient at depositing energy in
subtracting the energy difference between the two orbitals, and removing matter, as the particles will continuously lose their energy as they
an electron from the atom entirely, a process called ionization, requires attract or repel other charged particles along their path. Many of these
adding the full energy of the electron orbital. interactions will cause ionization, which correlates with the amount
The properties of a nucleus are defined by the number of protons of biologic damage delivered. Heavy particles such as protons and
and neutrons, with the number of protons defining the type of element alpha particles ionize matter very efficiently, lose energy more efficiently,
and the number of protons and neutrons together defining the isotope. and have a higher linear energy transfer (LET; i.e., amount of energy
Analogously to the arrangement of electrons in an atom, protons and loss per length of the particle’s track; see also later) than lighter particles
neutrons are arranged in discrete energy levels specific to a particular such as electrons and positrons. Although most particulate radiation
nucleus, and transitioning between energy levels requires adding or is charged, uncharged neutrons are also capable of depositing energy
 Basics of Radiation Therapy  •  CHAPTER 27 433

in a material. Unlike charged particles, neutrons can interact only Compton effect
with other nuclei. In general, this interaction takes the form of a
collision with a proton. The proton recoils with some fraction of the e:
neutron’s initial energy. The positively charged proton then ionizes
the surrounding particles, causing most of the biologic damage. e:
p;np;
np; n
e: np; e:
Interactions of Radiation and Matter np; n e: Fast
e: electron
In order of roughly increasing energy, photons can interact with:

1. The atom as a whole e:

Scattered
2. Tightly bound inner shell electrons photon
3. Loosely bound outer shell electrons
4. The extranuclear space surrounding the nucleus Incident photon
5. The nucleus itself Photoelectric effect
Coherent Scatter Vacancy in k-shell
Incident photon e:
Low-energy photons can be briefly absorbed by the bound electrons e: Fast
of an atom. If the photon lacks the energy to remove the electron electron
from the atom, the photon energy will be immediately reemitted as p;np;
np; n
another photon. The reemitted photon has the same energy as the e: np; e:
incident photon, and close to the same direction of travel. Because np; n
no energy is deposited, coherent scattering does not contribute to e:
dose deposition, but the small deflections of the photons from coherent
scatter can cause blurring in diagnostic images. Coherent scattering e:
accounts for approximately 10% of interactions at 30 keV and is
negligible for most therapeutic energy beams.
Characteristic x-rays
Photoelectric Effect
Pair production
Photons having sufficient energy to ionize an atomic electron can
undergo the photoelectric effect (Fig. 27.1). In this process, the photon Incident photon e:
energy is entirely absorbed. Some energy is lost to breaking the electron
e:
binding energy, and the rest is carried away as kinetic energy of the e: Positron
p;np;
ejected electron. The probability of a photoelectric interaction scales np; n e; electron
with the cube of the atomic number (Z) and the inverse cube of the e: p; np; e: pair
np; n
photon energy (E), making the photoelectric effect very sensitive to
e:
material type and much more prevalent for lower photon energies.
The photoelectric effect is the dominant photon interaction in tissue
below 30 keV. e:

Compton Scattering Figure 27.1  •  Photons interact with atoms through three major mechanisms.
When photon energy is significantly higher than the binding energy Low-energy photons interact through the photoelectric effect, in which photons
are absorbed by an atom, which then ejects an energetic electron. Higher-energy
of an electron, the photon can scatter from the electron without being photons undergo Compton scattering, in which both a lower-energy photon
absorbed, as illustrated in Fig. 27.1. The result of this interaction is and an electron are scattered from an atom. At higher energies, photons can
a photon with reduced energy and new direction, and a recoil electron interact with the field around the nucleus and undergo pair production, in
with some fraction of the initial photon energy. The energy of the which the photon spontaneously converts into an electron-positron pair.
scattered electron varies with the scattering direction. An electron
scattered in the direction of the incident photon claims most of the
initial photon energy, whereas electrons scattered at greater angles
have successively less energy. Compton scattering is only weakly
dependent on Z and is the dominant photon interaction in tissue Photodisintegration
between 30 keV and 30 MeV. Above a threshold energy, a photon can be absorbed into an atomic
nucleus and cause one of the nucleons (a proton or a neutron) to be
Pair Production ejected. This process is called photodisintegration. Photodisintegration
Above 1.022 MeV, photons can interact in the presence of a strong is more probable in high-Z materials (such as metals) and therefore
nuclear field. The photon will disappear and spontaneously become is more likely to happen during photon generation in a linear accelerator
an electron-positron pair (see Fig. 27.1). The electron and positron than in tissue. Neutrons produced in this manner can contribute a
will divide the initial photon energy between them to create their significant background radiation dose to patients receiving radiation
mass and kinetic energy. These particles will lose their energy as they therapy from very high-energy machines. However, photodisintegration
interact with the surrounding materials. On losing all their energy, is negligible for accelerators operating below 10 MV.
the electrons will be absorbed into an atom. The positron, on the
other hand, will annihilate by interacting with a local electron, creating Charged Particle Interactions
two 511-keV photons. (This annihilation reaction is what is detected Charged particles will lose and transfer their energy to a medium
during positron emission tomography [PET] scanning.) Pair production through two mechanisms: collision and radiation. Collision energy
is the dominant atomic interaction in tissue for photons above 30 MeV, loss by an energetic charged particle refers to the energy transfer
and therefore has only a minor effect in radiation therapy in which resulting in ionization, excitation, and molecular damage. In a collision
energies are significantly lower. event, energy is absorbed in the medium at or very near the site of
434 Part I: Science and Clinical Oncology

the interaction. Collision energy loss accounts for more than 95% of being converted to a spray of photons through the bremsstrahlung
energy loss in tissue for therapeutic energy electrons, and is the major process. The bremsstrahlung photons, called x-rays, move approximately
source of absorbed dose along the path of the electrons. Radiative in the same direction as the electrons and have an energy spectrum
energy loss occurs when particles are accelerated in the electric field ranging from a few 10s of keV up to the maximum energy of the
of a nucleus and emit a fraction of their energy as a photon. This initial electrons. The resulting photon beam then passes through a
process, called bremsstrahlung, is relatively unimportant in tissue but series of filters and beam-shaping elements that flatten and define the
is fundamental to the production of therapeutic photons in a linear edges of the beam.
accelerator. The dose from a photon beam is related to its intensity, defined
Most electromagnetic interactions result from an interplay between as the number of photons per unit area. Two major effects serve to
photons and electrons because many photon interactions result in decrease the intensity of a photon beam as it passes through tissue.
atomic ionization and release of an energetic electron, with some of First, as with any photon source, the beam intensity decreases with
the electron energy being converted back into photons through the increasing distance from the source, just as is the case for a light bulb.
bremsstrahlung process. Thus the effects of therapeutic beams passing In addition, beam intensity decreases as photons are attenuated from
through tissue can be described as a photon-electron shower, with the the beam via various scattering and absorption effects. This leads to
highly penetrating photons carrying energy deeper into tissue until a a characteristic decrease in intensity versus depth in tissue that varies
scattering event occurs, and the resulting scattered electrons depositing based on photon energy. Although the photon intensity begins decreas-
most of the resulting energy locally through collisional interactions. ing immediately on entering a material, the energy released through
the photon interactions is spread over a few centimeters as the electrons
Generation of Therapeutic Radiation scattered by the photons gradually lose their energy as they pass through
the material. The resulting dose distribution is characterized by a
To be useful in radiation therapy, radiation must be generated in a region of rapid increase near the surface, a leveling off of dose at a
manner in which it can be directed at the targeted tissues. Radiation depth of 1 to 3 cm, and a gradual dose fall-off as depth increases.
for cancer therapy is predominantly generated through two means: The plot of dose versus depth is called a percentage depth dose (PDD)
linear accelerators and radioactive sources. curve, as shown in Fig. 27.3. Because higher-energy photons are more
penetrating, higher-energy beams will attenuate more slowly, leading
Linear Accelerators to a more gradual decrease in dose with depth.
The most common modality used in radiation oncology is external Linear accelerators designed to produce photon beams can also be
beam radiation therapy (EBRT). Although a small number of radiation configured to produce therapeutic electron beams. Removing the
therapy facilities generate external beams using radioactive sources photon-generating target and replacing it with a comparatively thinner
such as cobalt-60 (60Co), the vast majority of therapeutic electromagnetic electron scattering foil allows the transmission of the initial electron
radiation is generated in a linear accelerator. A linear accelerator is a beam, but not without scattering the initially narrow beam into a
device that accelerates charged particles (electrons) to velocities near broader distribution. Multiple filters and beam-shaping elements, as
the speed of light by using oscillating electric fields to push the electrons shown in Fig. 27.2B, produce an even distribution of customized
through a series of accelerating cavities. A schematic of a linear shape at the surface of the patient. Electron beams lose their energy
accelerator is shown in Fig. 27.2A. Electrons are accelerated to energies through different types of interactions than photons, leading to a
between 4 and 18 MeV. Electric and magnetic fields focus and steer different pattern of dose versus depth for electron beams. Rather than
the high-energy electrons such that they strike a thin metal target that periodically removing photons from the beam through attenuation,
stops the electron beam, with some fraction of the electron energy electrons lose their energy gradually and at a relatively constant rate

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).
 Basics of Radiation Therapy  •  CHAPTER 27 435

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
0 Depth (mm)

0 5 10 15 20 25 30
Depth (cm)

Figure 27.3  •  Percent depth-dose curves for a variety of radiation types used in clinical radiation oncology. These include photons (110 KV, cobalt-60
[60Co], 6 MV and 18 MV) and various energies of electrons (6 MeV, 12 MeV, and 20 MeV). The inset shows the pattern or absorption at shallow depths
and provides an illustration of the skin-sparing effect of photons.

until the entire kinetic energy of the electron is expended, and the
particles simply stop. Ideally, this would lead to a region of constant Table 27.1  Therapeutically Useful Radioisotopes
dose with increasing depth until the depth of full energy loss is reached, Half-Life
at which point the dose would drop abruptly to zero, with the depth Isotope Average Energy (keV)
of the dose drop-off being dependent on the initial electron energy.
PHOTON
In practice, scattering and redirection of electrons within the beam
lead to a mildly peaked dose plateau region and a somewhat more Radium-226 (226Ra) 1620 yr 830
gradual dose fall-off, as shown in Fig. 27.3. Cesium-137 (137Cs) 30 yr 662
Radioactive Sources Gold-198 (198Au) 2.7 days 412
Iridium-192 (192Ir) 73.8 days 370
Unstable isotopes can spontaneously decay to lower energy states,
releasing energy in the process. This radioactive decay can result in Iodine-125 (125I) 60 days 28
the emission of therapeutically useful photons, electrons, or other Palladium-103 (103Pd) 16.97 days 21
decay products. The degree to which a sample is radioactive is called BETA
its activity and is defined as a number of decays per unit time. The Phosphorus-32 (32P) 14.3 days 1710
activity of a sample depends both on the amount of the isotope
Strontium-90/yttrium-90 28.5 yr/2.7 days 550/2280
and how quickly the isotope decays. The historical unit of activ-
(90Sr/90Y)
ity is the curie (Ci), which is defined as 3.7 × 1010 atomic decays
per second, corresponding to the decay rate of 1 g of radium-226. Tungsten-188/rhenium-188 69.4 days /17 h 350/2120
Activity is also specified in becquerels (Bq), defined as one decay (188W/188Re)
per second. Rhenium-186 (186Re) 3.8 days 1070
Because the rate of disintegration is proportional to the number Zinc-62/copper-62 (62Zn/62Cu) 9.3 h/9.7 min 660/2930
of nuclei present, the absolute number of radioactive nuclei will Xenon-133 (133Xe) 5.2 days 360
decay exponentially. Activity is proportional to the number of nuclei,
Iodine-131 (131I) 8.0 days 600
so a sample’s activity, and therefore its ability to deliver dose, will
decay with the same exponential behavior. The decay is described by Strontium-89 (89Sr) 50.5 days 1495
A(t) = A0e−λt, where A is the current activity, A0 is the activity at Holmium-166 (166Ho) 26.8 h 1850
time zero, and λ is a decay constant for the isotope in question. The
decay rates for various isotopes are more commonly given as the time
required for one-half of the sample to decay away; this period of time
is called the half-life of the isotope.
Therapeutically useful isotopes vary in half-life and in energy
of emitted particles, as shown in Table 27.1. Isotopes emitting
higher-energy particles can deliver significant amounts of dose Delivery of Therapeutic Radiation
farther from the radioactive source than those emitting lower-energy
particles. One type of radioactive source, 60Co, emits photons The cytotoxic properties of ionizing radiation provide an opportunity
with an average energy of 1.25 MeV, which is sufficiently similar for tumor control, but also require that care be exercised to limit the
to photon energies found in linear accelerators that 60Co can be exposure of healthy tissue to radiation. For EBRT, linear accelerators
used as an external source to treat targets deep in a patient. Most are typically mounted on rotating gantries (Fig. 27.4) that allow beams
other therapeutically useful radioactive sources emit lower-energy to pass through the patient and the target from a variety of directions.
radiation with less penetrating power and must be placed in close By placing the area to be treated at or near the center of rotation,
proximity to the area to be treated. Sources are formed into small multiple beams can be made to overlap in the region of the tumor,
sealed seeds, typically 1 to 5 mm in size, and can be inserted into delivering a high dose to the overlap area and a comparatively low
the treatment area on a temporary or permanent basis. The dose rate dose to other areas. For treatment based on implanted radioactive
falls off very quickly with distance from a seed because of both rapid sources, a procedure known as brachytherapy, proper dose delivery
attenuation and the rapid spread of photons as they move away from consists of designing and delivering a three-dimensional (3D) distribu-
the source. tion of radioactive seeds within the volume to be treated, creating a
436 Part I: Science and Clinical Oncology

Incident particle
track

Chromatin
fiber 30 nm
“Spur”: 0–100 eV
Gantry (G)
Collimator (C)
C “Blob”: 100–500 eV
G Short track: 500–5,000 eV
Isocenter
Figure 27.5  •  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
T of chromatin is shown approximately to scale. (From Zeman EM. Biologic
basis of radiation oncology. In: Gunderson LL, Tepper JS, eds. Clinical Radiation
Oncology. 4th ed. Philadelphia: Elsevier; 2016.)

This quantity of ionization density, typically expressed in units of

Table (T) (patient support assembly) keV/µm, is termed the radiation’s linear energy transfer (LET). The
Figure 27.4  •  Layout for gantry-based radiation therapy machines. The concept of ionization density is illustrated graphically in Fig. 27.5 for
linear accelerator rotates around a single point called the isocenter. Patients radiations of differing LETs, using a segment of DNA-containing
are placed on a movable table to align the area to be treated and the chromatin drawn to scale as a representative biomolecule. Although
isocenter. most radiation therapy is done using low-LET x-rays, γ-rays, or
electrons, a few institutions do employ high-LET neutrons, or even
higher-LET heavy charged particles (heavy ions) such as carbon ions,
high-dose region that decreases rapidly beyond the treatment volume. for treatment. Lower total doses of these radiations are used to achieve
Both of the aforementioned treatment modalities require a 3D tumor control in keeping with their greater biologic potency, and
understanding of the patient anatomy, and require that: especially stringent limits are placed on the amount of normal tissue
incidentally irradiated, out of justifiable concern for an increased
1. The tumor be precisely located within the patient anatomy frequency of complications. The use of protons for radiation therapy
2. A treatment plan be customized for an individual patient is also popular, with dozens of treatment facilities in operation in the
3. The patient be reliably and reproducibly positioned relative to the United States; protons behave like other high-LET particles in terms
radiation sources such that the intended radiation pattern can be of their physical properties, although they are only marginally more
precisely delivered potent biologically than x-rays or electrons.
Whether the ionization of a particular molecule results in a measur-
able biologic effect depends on a number of factors including how
RADIOBIOLOGY OF RADIATION THERAPY important the molecule is to the continued survival and function of
Mechanisms of Radiation Damage to Cells the cell, how many copies of the molecule are normally present, and
to what extent and how the cell responds to the loss of working copies.
As discussed previously, ionizing radiation (in the form of photons DNA is arguably the most important cellular macromolecule, and
or particles) deposits energy as it traverses the absorbing medium one that is present only as a single, double-stranded copy, so an energy
through which it passes, with the most salient feature of this interaction deposition event occurring directly in DNA certainly could affect a
being the random and discrete nature of the energy deposition events. cell’s continued survival and functioning. Accordingly, much attention
Energy is deposited in increasingly energetic packets called quanta, has been focused historically on understanding radiation-induced DNA
each of which leaves anywhere from a few to several dozen ionized damage and its repair, and the consequences when that damage is
atoms in its wake. Assuming the absorbing medium is a biologic either irreparable or misrejoined. That said, many other molecules in
system, a mammalian cell for example, any and all biologic molecules the cell may be less crucial to survival yet are much more abundant
contained in that cell are potential targets for these highly localized than DNA and therefore have a much higher probability of being
energy deposition events. Secondary particles set in motion by the ionized. By far, the most abundant molecule in the cell is water. Free
original ionization event can themselves go on to produce collateral radicals formed by the radiolysis of water (the hydroxyl radical, •OH,
damage. This chain reaction continues until all the energy deposited in particular) are capable of adding to the DNA damage resulting
by the incident photon or particle is expended. from direct energy absorption, by migrating to the DNA and damaging
The total amount of energy imparted to a cell during the passage it indirectly, as illustrated in Fig. 27.6. This mechanism is referred to
of ionizing radiation (expressed in units of dose, gray [Gy], which in as indirect radiation action to distinguish it from direct radiation action,4
turn is expressed in units of energy deposited, joules per kilogram [J/ described earlier. Approximately 30% of the total DNA damage
kg]) is by itself insufficient to describe its biologic consequences. For produced by a given dose of x-rays is from the direct effect, and 70%
example, 1 Gy of x-rays and 1 Gy of neutrons deliver the same total from the indirect effect.4
energy to a cell macroscopically speaking, but do not produce equivalent Complex macromolecules such as DNA that have been ionized
biologic effects because it is the microscopic pattern of that energy undergo a series of chemical transmutations in an attempt to rid
deposition, the spacing or density of the discrete ionization events themselves of unpaired electrons, many of which involve the further
along the track of the photon or particle, that is key to determining breakage of chemical bonds. These broken bonds can result in the
biologic effectiveness. In this example, the 1 Gy of neutrons is much modification or loss of a DNA base or an entire nucleotide, a cross-
more potent biologically because the average energy deposited locally linking of the two DNA strands, or a scission of the sugar phosphate
along the length of each neutron’s track is higher than for the x-rays. backbone involving either one or both strands. Luckily, DNA is unique
 Basics of Radiation Therapy  •  CHAPTER 27 437

DNA repair and replication pathways, whereas others are unique to

specific types of repair. Some are not directly involved with repair per
se, but rather link DNA repair to other cellular functions including
Direct damage sensing, cell cycle checkpoint control, chromatin remodeling,
photon-DNA
interaction
and cell death.9 Inactivation or loss of any of these myriad proteins
can lead to dysfunction in the DNA damage response, which in
turn can precipitate diverse clinical syndromes of varying severity
including immunodeficiency, neurodegenerative disorders, infertility,
premature aging, hypersensitivity to DNA damaging agents, and cancer
proneness.10
H• Of particular interest is that most cancer cells harbor one or more
defects in the DNA damage response. Because under normal conditions
different DNA repair pathways can share common components and
eaq H2O
functions, and in some cases compensate for defects in other pathways,
it may be that the clinical strategy of DNA repair inhibition will have
•OH
a greater effect on the tumor than on normal tissues.10 The approach
of combining DNA repair inhibitors with radiation to produce selective
Indirect interaction tumor radiosensitization, termed synthetic lethality, is discussed in more
via water radiolysis detail later in the chapter.

Molecular Biology of Cellular Radiation Responses

It goes without saying that much more has been learned about the
Figure 27.6  •  DNA damage that occurs after radiation exposure is secondary radiation response of cells at the molecular level since the molecular
to two types of ionization interactions. The direct effect occurs when an
incident photon deposits energy directly into the DNA, ionizing it. The
biology and biotechnology revolutions of the 1980s. In fact, many
indirect effect occurs when water molecules are ionized, and the reactive of the radiobiologic phenomena carefully characterized decades ago
species that are created damage DNA indirectly. but necessarily couched in operational terms (e.g., clonogenic survival,
sublethal damage repair or recovery [SLDR], cell cycle age response)
(see later) now have solid molecular underpinnings. Of particular
interest to modern radiation biologists is the molecular basis of radiation
in that it has its own repair system, and most of this damage can be sensitivity, the pertinent aspects of which are summarized here. An
repaired efficiently and typically with very high fidelity. Under certain important ramification of our ever-growing understanding of the
circumstances, however, the cell’s attempts to repair these lesions may molecular workings of cells is the promise of being able to identify
result in large segments of DNA being lost, rearranged, exchanged, and target specific genes, proteins, or pathways for therapeutic gain,
or rejoined in inappropriate ways, so-called “misrepair.” In other cases, in the hopes of rendering tumors cells more radiosensitive or normal
the complex nature of the damage itself, particularly when both DNA cells more radioresistant.
strands are involved (e.g., a DNA double-stranded break), or its location A cell’s (normal or tumor) radiation response represents a complex
in the genome makes repair impossible. It is this residual DNA damage interplay between intrinsic properties and extrinsic factors imposed by
that manifests as chromosome aberrations the next time the cell attempts the cell’s microenvironment. Properties intrinsic to the cell include,
to go through mitosis and that usually leads to cell death. In fact, the for example, its capacity to recognize and repair DNA damage, its
radiation dose response for the production of asymmetric, exchange-type position in the cell cycle, and its response to being damaged—that
chromosome aberrations (e.g., a dicentric chromosome with concomi- is, to adapt and grow or to die. However, extrinsic, environmental
tant acentric fragment) mirrors the shape of the corresponding cell factors also contribute to cellular radiosensitivity. Examples include
survival curve.5 the availability of nutrients and oxygen, the ability to eliminate
Historically, much of what radiobiologists learned (or inferred) waste, and the presence or absence of cytokines, growth factors, or
about DNA damage and repair, its time course, and its implications other signaling molecules that instruct the cell how to respond to
for cell survival and radiotherapeutic response came at least two decades its injury.
before the complex molecular underpinnings and processes involved Normal mammalian cells have in common key molecular signaling
in the different types of mammalian DNA repair were elucidated. pathways that regulate growth, death, and differentiation, many of
It is now known that there are several different DNA repair pathways which are activated in response to radiation exposure. Many of these
in mammalian cells, including single-step reactions that directly reverse pathways also exist in tumor cells but are typically dysregulated—that
certain simple types of damage, single-step and multistep base excision is to say, hyperactive or hypoactive—secondary to the activation of
and resynthesis processes, and multistep pathways to “clean up,” oncogenes and/or the inactivation of tumor suppressor genes, or because
resynthesize, and ligate single- or double-stranded breaks in the DNA of epigenetic changes. Not surprisingly, the activity (or lack thereof )
backbone.6 Which one (or more) of these repair pathways is activated of these pathways can influence both cellular radiosensitivity and the
depends on a number of factors including the type of lesion produced, radiation responses of tissues as a whole.
the physical location of the lesion in the genome (e.g., in the coding The first activated oncogene identified to confer radiation resistance
region of a gene versus in noncoding DNA), the functional and temporal was RAS.11,12 Ras, the protein product of the RAS gene, belongs to a
location of the lesion (i.e., in an actively replicating or transcribing superfamily of related proteins and is a small, cell membrane–associated
gene versus an inactive one), and, critically, the overall repair competence GTPase activated by upstream receptor tyrosine kinases. Its role is to
of the cell in which the lesion was created.7 transduce signals to multiple, downstream cascades of protein kinases
For a more in-depth discussion of the molecular biology, biochem- that control crucial cellular processes including proliferation, differ-
istry, and regulation of DNA repair, please refer to Chapter 11. entiation, migration, and survival. When the Ras protein is mutated,
Many bacterial, yeast, rodent, and human genes involved in DNA however, as is the case in approximately 30% of all human cancers
repair processes have been identified and cloned,8 with many of the (including 90% of pancreatic cancers), these pathways become overactive
encoded proteins functioning as components of large repair complexes. and no longer responsive to the normal regulatory mechanisms that
Some of these proteins are interchangeable and participate in different antagonize the Ras pathway and reign in excessive proliferation. This
438 Part I: Science and Clinical Oncology

situation is exacerbated in many tumors by the concurrent loss of therapy, it would be remiss not to include arguably the most significant
function of tumor suppressor proteins. advance in cancer treatment in decades: immunotherapy, a form of
Ras became, accordingly, a desirable target for cancer drug develop- disease treatment that co-opts parts of the immune system to fight
ment.13 For nearly 30 years, the research approach to targeting Ras disease, including (but not limited to) cancer. Cancer immunotherapy
focused on its need for posttranslational modification through pre- aims to harness the patient’s own immune system to recognize and
nylation to become activated.14 Despite encouraging preclinical results attack tumor cells, with the earliest attempts to do so dating back to the
with use of a class of prenylation-inhibiting agents known as farnesyl late 19th century.28 Two general approaches to cancer immunotherapy
transferase inhibitors—drugs that when used alone or in combination include the use of agents that fine-tune the patient’s own immune system
with radiation produced sensitization of tumor cells with constitutively to work harder or better, or supplying the patient with engineered,
active Ras pathways—these drugs did not meet expectations in clinical preprimed immune system components that supplement or replace
trials, because of alternate prenylation pathways.13 However, because the existing immune system.
of the critical, central role Ras plays in signal transduction, and given To date, most immunotherapeutic approaches (e.g., nonspecific
that it is so commonly mutated in human cancers, the National Cancer immunostimulants, immune cell therapy, cancer vaccines) have not
Institute established the RAS Initiative in 2013, with the goal of achieved the hoped-for clinical efficacy; however, within the past
redoubling efforts to target this important protein by using innovative decade, one approach, the use of so-called immune checkpoint
approaches.15 inhibitors—even as single agents—has yielded impressive and durable
The difficulties targeting Ras spawned subsequent drug development responses in small subsets of patients with a growing number of cancer
focused on inhibiting proteins upstream of Ras, in particular members types.29,30 Immune checkpoint inhibitors act by reversing the ability
of the human epidermal growth factor receptor (EGFR) family of of tumor cells to evade host immune detection and destruction, a
receptor tyrosine kinases that transduce growth signals through Ras hallmark of most cancers. The exciting field of cancer immunotherapy
and other signaling proteins.16,17 These transmembrane glycoproteins is discussed in detail in Chapters 26 and 30.
are activated through binding of ligands belonging to the EGF family For the purposes of the present discussion, the concept of combining
of peptide growth factors. immune checkpoint inhibitors with radiation therapy will be the
Cetuximab (Erbitux), a human-murine chimeric immunoglobulin focus: how radiation can act as an immune system stimulant, and
G1 monoclonal antibody raised against EGFR, is among the more why the addition of a checkpoint inhibitor might further enhance
successful molecularly targeted drugs, yielding improved outcomes in radiation’s efficacy.
squamous cell head and neck cancers when combined with radiation Because of the way irradiated cells die (see later), they have the
therapy.18 Details of its mechanism of action and clinical use are potential to release subcellular contents into the extracellular space,
discussed later in this chapter. Other classes of drugs that target EGFR which not only serves to liberate large quantities of tumor-associated
include the small-molecule tyrosine kinase inhibitors (TKIs) gefitinib, antigens, but also elicits a local inflammatory response.31,32 This also
erlotinib, and lapatinib (Iressa, Tarceva, and Tykerb, respectively), causes the release of inflammatory cytokines and the loss of suppressor
which inhibit EGFR phosphorylation and its downstream cascade by T cells locally (because lymphocytes are especially radiosensitive),
blocking the intracellular catalytic domain of the receptor.19 These enhances antigen presentation and processing, and recruits nonlocal
have shown some efficacy in selected patients with treatment-refractory, effector T cells to the site of disease.33,34 Despite this, many, arguably
advanced non–small cell lung cancer.20 most, human tumors are not particularly immunogenic to begin with,
Another approach has been to target signaling proteins downstream nor do they become more immunogenic during the course of standard
of Ras, including B-RAF, MEK, ERK, and PI3K, among others. Of radiation therapy, presumably because of the immunosuppressive
these, drugs that target mutant B-RAF have received the most attention microenvironment characteristic of most tumors.35
to date, and some are already approved by the US Food and Drug The work of Formenti and colleagues31–33,36 has been instrumental
Administration (FDA) for the treatment of late-stage melanoma, in translating preclinical studies of basic tumor immunology, the action
wherein BRAF mutations are present in 80% of patients.21 Two such of immune checkpoint inhibitors, and the potential of radiation therapy
drugs, vemurafenib (Zelboraf ) and dabrafenib (Tafinlar) have dem- to elicit an antitumor immune response into clinical trials of combined
onstrated clinical efficacy—significantly improved response rates, along radiation and checkpoint inhibitors.
with progression-free and overall survival—in advanced melanoma.22,23 In animal models, and based on rare, anecdotal reports in human
However like many chemotherapy agents (targeted or otherwise), patients, radiation therapy can act as a pseudo–cancer vaccine—that
drug resistance often develops and limits their usefulness. The use of is, it can elicit an abscopal effect in nonirradiated tumor sites distant
combinations of agents that target different components of the signaling from the irradiated primary tumor. An antitumor immune response
pathway is considered a better clinical strategy.24 could, at least in part, explain this apparently systemic effect of
A second molecular target of interest is vascular endothelial growth localized radiation therapy. If an immune response is responsible for
factor (VEGF) and/or its cell surface receptor. VEGF is the most the radiation abscopal effect, it follows that the higher the radiation
potent of the proangiogenic endothelial cell proliferation stimulators dose, the greater the immune system stimulus would be because
and chemoattractants and plays a pivotal role in promoting tumor proportionally more cells would be killed and that many more
survival by stimulating the growth of new blood vessels, derived in tumor antigens released. Furthermore, the addition of an immune
most cases from the host vasculature. This phenotype of sustained checkpoint inhibitor could enhance this effect by reactivating the
angiogenesis is a hallmark property of cancer. There are several host’s otherwise suppressed immune system, increasing the “vaccine’s”
isoforms of VEGF that bind to corresponding receptors VEGFR1, effectiveness.
VEGFR2, and VEGFR3 (encoded, respectively, by the genes FLT-1, This line of reasoning has spawned clinical trials that combine
KDR, and FLT-4).25 high-dose, hypofractionated radiation therapy with one or more of
Bevacizumab (Avastin), a recombinant humanized monoclonal several immune checkpoint inhibitors currently approved for human
antibody, is the first molecularly targeted antiangiogenic drug to gain use, discussed in further detail later.
approval for clinical use by the FDA. This antibody binds to and
inactivates VEGF, with the net effect of eliminating signaling to vascular Cell Survival and Tissue Dose-Response Curves
endothelial cells to initiate angiogenesis.26,27 The clinical use of beva-
cizumab in combination with radiation therapy is discussed later in Tumor control is achieved only when essentially all clonogenic cells
this chapter. (the putative “tumor stem cells”) are killed, or otherwise rendered
In any discussion of the molecular aspects of cellular radiation unable to sustain tumor growth indefinitely. To estimate the likelihood
response or the use of targeted therapies in combination with radiation of cure, it is necessary to know, at least to a first approximation, how
 Basics of Radiation Therapy  •  CHAPTER 27 439

radiosensitive or resistant these cells are, through the use of some

measure of cell-killing efficiency per unit radiation dose. 100
Death as a permanent, irreversible cessation of vital functions is
not the same as what constitutes “death” to the radiation biologist or

Surviving fraction
oncologist. For proliferating cells, including those maintained in vitro 10:1
and the stem cells of both normal tissues and tumors in vivo, cell
death in the radiobiologic sense refers to a loss of reproductive integrity
or clonogenicity—that is, an inability to sustain proliferation indefi-
nitely. It is important to note that the term clonogenic death as first 10:2
described 60 years ago is operationally defined, today serving as a
catchall term encompassing various mechanistic ways that cells die,
all of which culminate in a cell losing its ability to divide indefinitely. 10:3
These modes of cell death include mitotic catastrophe (the most
common form of cell death after radiation exposure), apoptosis, 0 200 400 600 800 1000 1200
autophagy, necrosis or necroptosis, and senescence (and, strictly A Exposure (R)
speaking, differentiation as well, to the extent that differentiated cells
lose their ability to divide).37 Another noteworthy feature of clonogenic
death is that it does not necessarily preclude the possibility that a cell 100
may remain physically intact and metabolically active, continue its
tissue-specific functions, and even divide a limited number of times

Surviving fraction
after irradiation. 10:1
The first report of a quantitative measure of intrinsic radiosensitivity
for a human cell line (HeLa, derived from a cervical carcinoma) was
published by Puck and Marcus in 1956.38 For different doses of x-rays, 10:2
the reproductive integrity of HeLa cells was measured by their ability
to form macroscopic colonies of at least 50 cells (corresponding to
approximately six successful postirradiation cell divisions) on Petri
dishes. The HeLa cell survival curve, in which the log of the surviving 10:3
fraction of cells was plotted as a function of the radiation dose, was 0 200 400 600 800 1000 1200
characterized by a roughly exponential dose response at intermediate Dose (cGy)
to-high doses, and a bending, “shoulder” region at low doses where
cell killing was less effective. This is illustrated graphically in the upper Hewitt and Wilson: CBA mouse leukemia
Puck and Marcus: human carcinoma
panel of Fig. 27.7. Radiation survival curves for hundreds of cell types McCulloch and Till: mouse bone marrow
derived from mammalian tumors and normal tissues have been gener- Mutants (e.g., A-T)
ated in the years since the pioneering work of Puck and Marcus,38 B
and most are qualitatively similar to the original HeLa survival curve Figure 27.7  •  X-ray or γ-ray single-dose survival curves for mammalian
(see lower panel of Fig. 27.7). cells. (A) The first such survival curve (for HeLa cells, obtained from a patient,
Mathematical models were developed to fit the cell survival data, Henrietta Lacks, with cervical adenocarcinoma) was published in 1956 by
with survival curve theory originating in a consideration of the physics Puck and Marcus.38 (Note that the dose is expressed in roentgens [R], which
of energy deposition in matter by ionizing radiation. An assumption for cells x-irradiated while adherent to glass Petri dishes must be multiplied
inherent to target theory was that a biologic response (cell killing in by approximately 1.4 to obtain the dose in cGy.) (B) A family of survival
this case) resulted from critical “targets” receiving random “hits”39 curves for other types of mammalian cells. The dashed lines encompass the
in a probabilistic manner. Furthermore, for cell survival curves with radiosensitivity range for wild-type cells, whereas the steepest curves show the
shoulders, each target was envisioned as requiring more than one range more typical of hypersensitive mutants, such as cells from patients with
the disease ataxia-telangiectasia.
hit to elicit the response—that is, that “sublethal” damage had to
accumulate first before the cell would be killed. One mathematical
expression derived from target theory that provided a good fit to survival
data was:
A different and more biology-based interpretation of the dose
S = 1 − (1 − e − D D0 )n response for radiation-induced cell killing was proposed by Kellerer
and Rossi41 and by Chadwick and Leenhouts.42 The linear-quadratic
(LQ) or “alpha/beta” equation,
In this equation, S is the fraction of cells that survive a given dose
D, D0 is the dose increment that reduces the cell surviving fraction 2

to 37% (1/e) of an initial value on the exponential portion of the S = e −( αD+βD )

curve, and n, the extrapolation number, is the back extrapolation of
the exponential portion of the survival curve to zero dose. was shown to fit cell survival data quite well, particularly in the low-dose
Over time it became apparent that some features of this model region of the curve where the target theory model often failed.40 In
were inadequate,40 not the least of which was that its basis was the this expression, S is again the fractional cell survival following a dose
probabilistic nature of energy deposition in matter by ionizing radia- D, α is the rate of cell kill by a single-hit process, and β is the rate
tion, and not anything biologically based. For example, target theory of cell kill by a two-hit mechanism. Implicit in the LQ model was
was not concerned per se with which biomolecules in the cell were that—borrowing the language of target theory for comparative
the purported “targets” of radiation damage, what the nature of the purposes—DNA (or a chromosome) was the target, and the hits
damage was in a molecular sense, or how the cell responded to it. corresponded to irreparable or misrejoined lesions produced by either
(Of course, it was not lost on radiation biologists of the day that one or two radiation tracks traversing the cell nucleus (Fig. 27.8).
at least one cellular target was likely to be the DNA contained in A comparison of the features and parameters of the target theory
chromosomes.38) and LQ survival curve models is shown in Fig. 27.9.
440 Part I: Science and Clinical Oncology

To bridge the gap between the radiation responses of single cells survival curve assay, but in which the animal essentially served as its
grown in culture and tissues or tumors in a laboratory animal or own Petri dish. One classic example of an in vivo clonogenic assay is
human patient, several ingenious methods were developed to measure, the spleen colony assay of Till and McCulloch,44 originally developed
or at least estimate, the radiation sensitivity of intact normal tissues as a model system for the study of bone marrow transplantation.
and tumors in vivo.43–45 Some of these assays employed the reproductive These authors determined that lethally irradiated mice could be
integrity of cells as an end point, similar in principle to the in vitro “rescued” by a bone marrow transplant from a nonirradiated mouse,
and that the transplanted, viable bone marrow stem cells were noted
to form discrete nodules or colonies in the spleens of the irradiated
animals. By extension then, a mouse’s spleen could be used as a
Y= αD + βD2 pseudo–Petri dish, with the number of clonogenic bone marrow colonies
countable as a function of the radiation dose that the donated bone
marrow received before transplantation. Assays such as this showed
e– that the radiosensitivity of individual cells (tumor or normal) was
largely unchanged whether the cells were irradiated in relative isolation
e–
in Petri dishes or as parts of a more complex tissue containing many
different, interacting cell types in 3D contact.
In vivo clonogenic assays necessarily involved the killing of the
animal, so they are obviously not applicable for clinical use. Further-
e– more, such assays are labor-intensive and involve long waiting periods
before results are obtained, adding to their impracticality. A second
type of in vivo radiosensitivity assay is nonclonogenic, using a tissue
structural or functional end point as a surrogate for cell survival. Data
derived from nonclonogenic assays and plotted as a function of radiation
+ dose are properly called dose-response curves rather than cell survival
curves, because cell survival is not the end point being assessed.
Regardless, cell survival curves and dose-response curves are often
analyzed and interpreted similarly—that is, a mathematical model is
commonly used to fit the data, and parameters are calculated.
Figure 27.8  •  Chromosome aberration production can be modeled by Two examples of nonclonogenic assays, one for normal tissues and
using the relationship Y = αD + βD2, where Y is the average chromosome one for tumors, are worth mentioning, especially because aspects of
aberration yield per cell and D is the dose delivered. The single-track αD both are used routinely in the clinic, if not in the exact same way as
component is shown on the left, where a single electron track is envisioned the laboratory assay. One of the first nonclonogenic methods developed
as producing a break in each of two different chromosomes which, if rejoined to assess normal tissue radioresponse was the skin reaction assay.46
incorrectly, produce a dicentric chromosome and an acentric fragment. These
exchange-type chromosome aberrations can also be formed as a consequence (Pigs were used in the original studies because their skin is similar to
of two different electron tracks, which accounts for the βD2 component, as that of humans in several key respects, although rodents have also
shown on the right. (From Wilson PF, Bedford JS. Radiobiologic principles. been used.) An ordinate scoring system was used to quantify the
In: Hoppe RT, Phillips TS, Roach M, editors. Leibel and Phillips textbook of severity of the skin reaction; for example, a skin score of 1 might
radiation oncology. 3rd ed. Philadelphia: Saunders; 2010.) correspond to mild erythema, whereas a score of 4 might correspond

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 provides a framework
for current isoeffect modeling used in radiation therapy treatment planning.
 Basics of Radiation Therapy  •  CHAPTER 27 441

100
100
RBE0.5~5.6
Surviving fraction

10–1 10–1
RBE0.05~3.6

Surviving fraction
10–2
Neutrons X-rays
10–2
10–3
RBE0.0005~2.8
10–4
10–3
0 2 4 6 8 10 12 14
Dose (Gy) 10–5
0 2 4 6 8 10 12 14
High LET (alpha particles) Dose (Gy)
Intermediate LET (15 MeV neutrons)
Low LET (250 kVp x-rays) Figure 27.11  •  Representative cell survival curves for x-rays and neutrons,
illustrating the increase in relative biologic effectiveness (RBE) with decreasing
dose. This occurs because higher linear energy transfer radiations preferentially
Figure 27.10  •  Dose-response curves for radiations of differing linear decrease or eliminate the shoulder on cell survival curves.
energy transfer (LET). The relative biologic effectiveness of neutrons or alpha
particles relative to that of x-rays is defined as the ratio of doses (x-rays/
neutrons) to yield the same biologic effect.
lacking in oxygen is that oxygen readily participates in the free radical
reactions that occur in the microseconds to milliseconds after irradiation
to confluent moist desquamation over more than half of the irradiated and has the net effect of enhancing the radiation damage to cellular
area. Then, when different time, dose, and fractionation schedules macromolecules. Poorly oxygenated cells experience less enhancement
were compared, any combination that resulted in the same skin reaction of radiation injury and are therefore more radiation resistant. This is
score was assumed to correspond to an equivalent amount of cell termed the oxygen effect. The relative resistance of poorly oxygenated
killing. In this way, and by collecting information for different severities cells versus well-oxygenated ones can be expressed in terms of an
of skin reactions, a dose-response curve could be generated. A common oxygen enhancement ratio (OER). The OER is the ratio of doses to
nonclonogenic assay of tumor response to radiation therapy is the produce the same biologic effect under low versus normal conditions
regrowth delay assay.47 In this assay, the tumor’s dimensions (or volume) of oxygenation. The OER typically ranges between 2.5 and 3.0 for
are measured periodically as a function of time after irradiation, with large single doses of x- or γ-rays, and 1.5 to 2.0 when multiple small
the degree of tumor shrinkage assumed to be a reflection of the fraction dose fractions are used.34 Furthermore, the oxygen effect is reduced
of clonogenic tumor cells killed. Dose-response curves are generated or eliminated as the LET of the type of radiation increases; OERs of
by plotting the average amount of growth delay (in days) as a function 1.5 to 2.0 are obtained for radiations of intermediate LETs, and 1.0
of radiation dose. (i.e., no oxygen effect) for high-LET radiations. Representative radiation
survival curves generated in the presence or relative absence of oxygen
Modifiers of Radiation Sensitivity are shown in Fig. 27.12.
Hypoxic cell radiosensitizers, exogenous chemicals that mimic the
As discussed previously, factors both intrinsic and extrinsic to the cell radiation damage-enhancing effects of oxygen, have been used clinically
can alter its radiosensitivity. In addition to the intrinsic, genetic in an attempt to combat the relative radiation resistance of tumors
determinants of radiation sensitivity, other physical and chemical that contain a clonogenic fraction of poorly oxygenated, hypoxic cells.
modifiers can also play important roles. The type of radiation used A second approach to the problem posed by tumor hypoxia is to
for treatment can be considered a physical modifier of radiosensitivity combine radiation therapy with a drug that, rather than sensitizing
to the extent that high-LET types of radiation (neutrons, heavy ions) hypoxic cells, kills them outright. These drugs are said to be bioreductive
are more biologically effective per unit dose than low-LET types (x-rays, because their toxic effects only occur secondary to the reductive
electrons). Representative dose-response curves for radiations with metabolism common in cells relatively lacking in oxygen.35,36 These
different LETs are shown in Fig. 27.10. In light of these differences are discussed further later.
in biologic potency, the term relative biologic effectiveness (RBE) has With few exceptions, clinical trials over several decades involving
been coined to compare and contrast two radiation beams of different such hypoxia-directed therapies have been unsuccessful, in no small
LETs. RBE is defined as the ratio of doses of a known type of low-LET part because there was no way to preselect patients whose tumors
radiation (historically, 250-kVp x-rays were the standard, but others contained sizeable hypoxic fractions and who therefore might be
can also can be used) to the dose of a higher-LET radiation, to yield expected to reap the most benefit from the use of a hypoxic cell
the same biologic end point. RBE is highly variable and depends on radiosensitizer. In fact, there was no way to directly measure hypoxia
several parameters including the type of radiation, the total dose, the in human tumors until the late 1980s.
dose rate or dose fractionation pattern, and the biologic effect being One of the first studies demonstrating an association between
assessed. An example of how RBE values are obtained from cell survival directly measured oxygen tension in tumors and clinical outcome was
curves is shown in Fig. 27.11. published in 1988 by Gatenby and colleagues.47a An oxygen-sensing
Chemical modifiers of radiation response are also important, and electrode was inserted into patients’ tumors (advanced squamous cell
perhaps the “chemical” of greatest significance in this regard is molecular carcinomas of the head and neck), and multiple readings of partial
oxygen, a potent radiosensitizer. Mechanistically speaking, the reason pressure of O2 were taken at different depths along the probe’s track;
well-oxygenated cells are more radiation sensitive than cells relatively the arithmetic mean Po2 value for each tumor positively correlated
442 Part I: Science and Clinical Oncology

1.0 carbonic anhydrase IX (CA-9 or CAIX),59 glucose transporter-1

(GLUT1),60–62 and osteopontin.63
OER ≈ 1.5−2.0
for small doses
Fig. 27.13 illustrates the potential of deriving “geographic” informa-
tion about extent and location of hypoxia in six different human
tumors with use of the exogenous marker pimonidazole hydrochloride.
Simultaneously marking other tumor features, the location of blood
vessels and proliferating cells in these examples, provides additional
Surviving fraction

information about the tumor microenvironment.

0.1
CLINICAL RADIATION ONCOLOGY
Therapeutic Ratio
The use of radiation therapy is heavily dependent on the concept of
OER ≈ 2.5−3.0 the therapeutic ratio. Given a high enough dose of radiation, virtually
for high doses any cancer will be destroyed with radiation therapy. Increasing the
dose of radiation increases the likelihood of tumor control within the
0.01
radiation therapy field. However, if an excessive dose is delivered, it
0 2 4 6 8 10 12 14 16 18 20 22 24 will produce an unacceptably high rate of complications in normal
Dose (Gy) tissue. The likelihood of a complication increases as the radiation dose
increases and as the volume of normal tissue irradiated increases. The
Figure 27.12  •  For x-rays, cells irradiated in the presence of oxygen are physics and technical aspects of radiation therapy are designed to
more radiosensitive than cells that are maintained under hypoxic conditions deliver the prescribed dose in such a way as to avoid or minimize the
(where the partial pressure of oxygen is greater than zero but less than about amount of radiation delivered to nearby normal tissues while maximizing
10 mm Hg). The ratio of doses that produce the same level of biologic damage the dose to the tumor. Another way to accomplish this is to exploit
in the absence of oxygen versus the presence of oxygen is known as the oxygen biology rather than physics to produce the differential effect between
enhancement ratio (OER). At high doses, the OER has a value of approximately cell killing in the tumor and that in the normal tissues.
2.5 to 3.0; however, its value is close to 1.5 to 2.0 for doses (or doses per
fraction) below about 2 Gy. The concept of therapeutic ratio attempts to strike a balance between
complication and tumor control in a given situation. At a given dose,
these probabilities can be estimated (although usually not very accurately
in clinical practice). Advances in radiation oncology can be made by
with local control rate, as did the tumor volume-weighted Po2 value. moving the normal tissue complication curve to the right (as illustrated
A high tumor oxygen tension was associated with a high complete in Fig. 27.14) so as to produce fewer complications at the same radiation
response rate, and vice versa. Several years later, comparable oxygen dose, or by moving the tumor control curve to the left so that a lower
electrode results for uterine cervix cancers were obtained by Höckel physical dose is needed to control the tumor (while also producing
and colleagues.48 They made the important discovery that tumor fewer complications).
hypoxia was a negative prognostic indicator in general, regardless of Historically, much progress has been made in moving the normal
whether the patient had received radiation therapy or not, suggesting tissue complication curve to the right by improving radiation delivery
that radiation resistance was only one facet of the hypoxia problem. techniques and taking advantage of the biology associated with dose
A large meta-analysis of the relationship between tumor oxygenation fractionation. The use of modern radiation therapy techniques
status measured with oxygen electrodes and clinical outcome was (described later) along with improved imaging to enhance tumor
published more recently for advanced head and neck tumors,49 with localization has made a major difference in decreasing the morbidity
comparable findings of improved overall survival in patients whose of therapy while improving tumor control. The ability to move the
tumors were less hypoxic. tumor control curve to the left can be accomplished primarily by the
Another method to directly identify and quantify hypoxic cells in use of radiation sensitizing compounds that are given concurrently
tumors is through the use of hypoxia markers. Both exogenous and with radiation therapy or by altering fractionation. Although there
endogenous markers for tumor hypoxia are available and can be studied has been a huge effort in this area, the major sensitizers that have
in relation to each other, the tumor vasculature, or other markable been effective are chemotherapeutic drugs that have both a radiation
features of the tumor microenvironment (e.g., proliferation status of sensitizing ability as well as an independent cytotoxic effect on the
tumor cells). Exogenous markers consist of injectable drugs or chemicals tumor. Examples include drugs such as 5-fluorouracil (5-FU), cis-
that are bioreducible only under hypoxic conditions, causing them platinum, and mitomycin C, used to treat, among others, head and
to bind to cellular proteins. These bound metabolites can be marked neck squamous cell carcinomas, uterine cervix cancers, and multiple
radioactively or detected with antibodies and visualized by means of gastrointestinal (GI) tumors. Although there has been great interest
several different techniques, such as autoradiography40 or fluorescence in using biologic agents as radiation sensitizers, with the exception of
immunohistochemistry.50 Two exogenous markers studied extensively the EGFR inhibitor cetuximab discussed earlier, these approaches
in both preclinical cell and animal systems, as well as in human patients, have not made their way into standard clinical practice.
are pimonidazole hydrochloride (Hypoxyprobe)51,52 and EF-5.53 Both
are of the chemical class known as nitroimidazoles that were originally Biology of Fractionation
studied as potential radiosensitizers of hypoxic cells54,55 (see later), but
were serendipitously found also to have the property of bioreduction In the earliest days of radiation therapy around the turn of the 20th
and binding to cellular macromolecules under hypoxic conditions. century, both x-rays (generated by applying an electric current across
This facilitated their use as hypoxia markers. Endogenous markers, an x-ray tube1) and radium (a naturally occurring radioactive element2)
on the other hand, consist of proteins that are upregulated as part of were used for cancer treatment. Because of the greater availability and
the cellular stress-adaptive response to hypoxic conditions, and whose radiation output of x-ray tubes, delivering one or a few large doses
expression levels can, with caveats, be used as surrogates for tissue in short treatment times was convenient and efficient. This “massive
oxygenation status.56,57 Commonly studied endogenous hypoxia markers dose technique”64 was a common way of administering radiation therapy
include the hypoxia-inducible factor 1α (HIF-1α),58 the enzyme from about 1900 through the 1920s. Unfortunately, normal tissue
 Basics of Radiation Therapy  •  CHAPTER 27 443

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-IdUrd marker only
incorporated by cells in S phase of the cell cycle), and hypoxia (green, anti-pimonidazole marker metabolized by cells only under hypoxic conditions). Differences
are evident among the tumors in terms of the amount, intensity, and pattern of staining with the hypoxia marker, and its location relative to proliferating
cells and blood vessels.

complications were severe, and to make matters worse, the rates of many small dose increments spread over several weeks became the
local tumor control were poor. standard of care, and has largely remained so to the present day.
Radium therapy was used more extensively in France. Because of Therapy using radioactive sources (such as the aforementioned radium
the low-activity sources available, radium applications involved longer therapy pioneered by the French) also has continued to the present
overall treatment times in order to reach comparable total doses as day, evolving into today’s practice of brachytherapy using both high-
used in x-ray therapy. Although extended treatment times were less and low-activity radioactive sources capable of delivering a range of
convenient, clinical results were frequently superior. Perceiving that dose rates.
the lengthening of the overall time was the critical factor and armed What was lacking in these early days of radiation therapy however,
with the results of animal experiments that convincingly demonstrated and arguably, for decades thereafter, was a biologic basis for dose rate
the superiority of longer treatment times,65 French physicians began and dose fractionation effects. Radiobiologists studied dose rate effects
to experiment with the use of multiple, smaller x-ray doses delivered extensively in the laboratory in an attempt to better elucidate the
over extended periods in human patients.66 Clinical outcomes were biologic factors involved in radiation therapy response; however, the
improved to such an extent that fractionated radiation therapy using clinical community was often unaware of this body of work. This
444 Part I: Science and Clinical Oncology

lack of cross talk between biologists and clinicians began to change

with the publication in 1975 of a seminal paper entitled The Four R’s Repair
of radiation therapy.67 The paper was an attempt to explain the biologic The tenets of target theory suggested that the shoulder region of the
basis of fractionation by describing in simple terms the key radiobiologic radiation survival curve indicated that “hits” had to accumulate before
phenomena thought to affect the outcome of fractionated radiation cell killing. Elkind and Sutton68 sought to better characterize how
therapy: repair, repopulation, reoxygenation, and redistribution. this damage accumulated and how the cell processed it. Even in the
absence of detailed information about DNA damage and repair at
that time—the structure of DNA had only been elucidated a few
years earlier—a few facts could be gleaned. First, those hits that were
part of the damage accumulation process yet did not in and of
100 themselves produce cell killing were, by definition, sublethal. Fur-
thermore, this sublethal damage (SLD) became lethal only if and
when it interacted with additional SLD. Elkind and Sutton conducted
experiments that deliberately interfered with the damage accumulation
process by delivering part of the intended radiation dose, inserting a
radiation-free interval, and then delivering the remainder of the dose
Response (%)

in what was called a “split-dose” experiment.

The overall surviving fraction of cells after a moderate to high
radiation dose was higher if that dose was split into two fractions
with a time interval in between, than if it was delivered as a single
dose. This is illustrated graphically in Fig. 27.15B. This suggested
that the cells that survived the initial dose fraction had “repaired”
Tumor some of the damage during the radiation-free interval. Therefore this
Normal tissue damage was no longer available to interact with the damage inflicted
0
by the second dose fraction, so a higher cell surviving fraction resulted.
Had the total dose been delivered as a single fraction, more damage
Radiation dose (Gy)
in total would have accumulated, some SLD would have be converted
to lethal damage, and the cell surviving fraction would have been
Figure 27.14  •  Graphical illustration of the concept of therapeutic ratio, lower. The results of split-dose experiments turned out to be crucial
which describes the relationship between the normal tissue tolerance and to the understanding of why and how fractionated radiation therapy
tumor control dose-response curves. In this example, very good tumor control
can be achieved for total dose D (vertical dashed line); however, that same works the way it does—that is, that fractionation and protraction of a
dose produces an unacceptably high normal tissue complication rate. Optimizing total radiation dose reduces its toxicity, in large part because of SLDR.
this therapeutic ratio as much as possible—through manipulation of the This phenomenon is termed the dose fractionation or dose rate effect
radiation physics and/or radiobiology—for each patient being treated with and occurs after low-LET radiation exposure in an undiminished
curative intent is the major goal of radiation therapy. manner regardless of the number of dose fractions.

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 fraction.
(A) The shoulder of the radiation survival curve is regenerated during the radiation free interval between the first and second D/2 doses. (B) SLDR demonstrated
in a plot of surviving fraction after the total dose, D, as a function of the time between the two dose fractions, D/2. Most SLDR occurs within the first 2
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. SLD, Sublethal damage.
 Basics of Radiation Therapy  •  CHAPTER 27 445

When considering complete cell survival curves, SLDR manifests characteristic of tumors73,74 (see also Chapter 8). One consequence is
as a return of the low-dose, shoulder region of the radiation survival that tumors can develop microregions relatively lacking in nutrients
curve. After an initial radiation dose and an adequate time interval and oxygen. Although prolonged oxygen deprivation, anoxia, will
for repair to occur, the response of surviving cells to graded additional eventually kill even the hardiest of tumor cells, hypoxia—a state of
doses is nearly identical to that obtained from cells without previous very low tissue oxygenation on the order of 0.5% oxygen or less
radiation exposure. This is illustrated in Fig. 27.15A. (corresponding to a partial pressure of oxygen of about 10 mm Hg)75—is
Bedford and Hall69,70 generated in vitro survival curves for HeLa potentially survivable, particularly when it is intermittent or cyclic in
cells irradiated at various dose rates, and found that the killing effective- nature. In contrast, the structure and function of the vasculature of
ness per unit dose decreased as the dose rate decreased, to a point. A normal tissues is such that in nearly all cases the development of such
limit to this dose rate effect was reached, however, and further lowering gradients of oxygen and nutrients is specifically avoided. Thus hypoxia
of the dose rate did not produce a further decrease in toxicity. This has a built-in specificity for tumors, which, ironically, is an attractive
finding is consistent with the idea that survival curves have negative feature clinically, whereby differences between normal tissues and
initial slopes, as described by the α component of the LQ survival tumors might be exploitable.
curve equation. A further implication is that small differences in initial Unfortunately, as previously discussed, maintenance under hypoxic
slopes of survival or dose-response curves for different tissues could conditions renders cells more radiation resistant by upward of a factor
be magnified into large differences when many small dose fractions of three (i.e., three times the total dose would be required to achieve
or continuous low dose rates were employed. the same biologic end point). A tumor containing even the smallest
fraction of clonogenic, hypoxic cells could easily make or break the
Repopulation success of radiation therapy, which is necessarily limited by the response
The sparing effects of fractionated external beam and brachytherapy of the aerobic, and therefore more radiosensitive, normal tissues.76
are largely attributed to SLDR; however, other factors can be involved. Many types of experimental solid tumors in laboratory rodents, and
Repopulation is defined as a compensatory increase in cell proliferation spontaneous tumors in veterinary patients and humans show an average
in tissues in response to an injury that results in a large amount of pretreatment hypoxic fraction of approximately 15% to 20%, although
cell killing. Stem cells of normal tissues and tumors can begin to the range of values is quite broad,55,77 as might be expected given
proliferate during and after a course of radiation therapy,71 although intratumor and intertumor heterogeneity.
the mechanism(s) the tissue uses to affect this process and the time Of course, tumor hypoxia would not constitute a barrier to clinical
it takes to commence varies with the tissue. Some tissues, however, success if, during the course of fractionated radiation therapy, the
do not seem to be able to mount a repopulation response, or at least fraction of clonogenic hypoxic cells decreased, ideally to zero. This
not a prompt or robust one, presumably because they possess only process is called reoxygenation and has been studied extensively in
very small numbers of stem cells, if any. experimental rodent tumors,78 and to some extent in human tumors.74
Repopulation is desirable in normal tissues because it facilitates the The reoxygenation process can be either slow (days to weeks) or
healing of common radiation therapy complications that can develop fast (minutes to hours), and complete or incomplete, depending on
during or soon after treatment (e.g., oral mucositis in patients receiving the type and extent of hypoxia present in the tumor. Slower reoxy-
radiation therapy for head and neck cancer). Repopulation of tumor cells, genation might be expected when the type of hypoxia is chronic, such
on the other hand, is quite undesirable because it has the net effect of as might occur in cells that are multiple cell diameters away from
counteracting the toxicity of ongoing radiation therapy. After radiation vasculature and near or beyond the diffusion distance of oxygen
therapy is complete, repopulation also can lead to tumor recurrence. (approximately 70 µm34,54). Physiologically speaking, the ways in which
In intact tissues, it can be difficult to tease apart the relative contribu- chronically hypoxic cells can reoxygenate are for aerobic cells closer
tions of repair and repopulation to the overall dose rate effect, although to vasculature to decrease their oxygen consumption, which would
generally speaking, repair-related effects occur over a timescale of occur if such cells were killed in large numbers by the radiation, and
hours to a day whereas proliferative effects usually do not come into for the tumor mass as a whole to shrink in size, which would have
play for days or weeks (or more) after the start of radiation therapy. the net effect of bringing the chronically hypoxic cells closer to the
In normal tissues capable of mounting a proliferative response, molecular existing vasculature. Some, although not all, human tumors shrink
signals associated with the radiation injury seemingly need to reach at least somewhat during the course of radiation therapy. Conversely,
a certain threshold before repopulation begins in earnest, and for most when hypoxia is intermittent or cyclic, reoxygenation could occur on
tissues this takes a minimum of a week, and more commonly several the order of minutes to hours, as has been noted for many experimental
weeks. Tissues that exhibit a prompt and robust response to radiation rodent tumors.79,80
injury (during or within a couple of months of treatment) and begin
to repopulate are said to be early responding, and those that show a Redistribution
delayed (more than 6–9 months after irradiation) proliferative response, Tumors that contain a sizeable fraction of actively proliferating cells will
if any, are referred to as late responding. necessarily contain subsets of cells in different phases of the cell cycle,
For tumors, especially carcinomas, the prevailing view (although much more so than for normal tissues in which cells are differentiated,
not without its detractors) is that compensatory repopulation does no longer able to proliferate, and reside in G0 phase. And even for those
not begin until approximately a month into the course of treatment.72 normal tissues that do contain stem cell compartments consisting of
One clinical implication is that overall treatment times should be kept undifferentiated, proliferating cells, these tend to be few in number
as short as practically possible, because treatment time much longer compared with the tissue as a whole, and they do not necessarily
than a month would allow for more tumor cell repopulation and proliferate rapidly. Thus tumors are much more heterogeneous than
therefore less treatment effectiveness. Some clinical data (mostly culled normal tissues with respect to cell cycle phase distribution.
from fractionation studies involving treatment of head and neck cancers) The pioneering work of Terasima and Tolmach81 during the 1960s
suggest that up to a third of a typical 1.8- to 2.0-Gy daily dose fraction led first to the development of a relatively simple method of obtaining
is wasted because of repopulation,72 and that for each day of treatment populations of cells synchronized with respect to cell cycle phase,
beyond the time repopulation begins, as much as 1% of local tumor followed by the generation of radiation survival curves for each phase.
control is lost. Following a single dose of approximately 7 Gy of x-rays, Chinese
hamster V79 cells in culture were noted to be most radioresistant in
Reoxygenation (late) S phase. Cells in G1 phase were of intermediate radiosensitivity
Tumor blood vessels tend to be abnormal structurally, functionally, (i.e., more resistant at the beginning of the phase, but somewhat more
and physiologically—a consequence of the dysregulated angiogenesis sensitive toward the end of the phase), and G2 cells were increasingly
446 Part I: Science and Clinical Oncology

1.0
7.1 Gy
0.2
0.1 0.1

Surviving fraction
0.05

0.02
0.01 0.01
0.005
Late S
0.001 Early S M G1 S G2
G1
G2/M Cell cycle phase

5.0 10.0 15.0

A Dose (Gy) B
Figure 27.16  •  The age response through the cell cycle. (A) Cell survival curves for synchronized populations of Chinese hamster cells irradiated in
different phases of the cell cycle. (B) Illustration of how these radiosensitivity differences translate into age response patterns. Cells in S phase (especially late
S phase) are the most radiation resistant, and cells in G2 and M phases the most radiosensitive.

sensitive as they moved toward the most radiosensitive M phase. This because the production of new cells outpaces the cytotoxic action of
was termed the cell cycle age response for ionizing radiation81 and is radiation therapy.
a general feature of mammalian cell radiation response.82 (Terasima Radiosensitizers and radioprotectors can be defined generically as
and Tolmach’s original work81,83 also showed this to be true for human any chemical or pharmacologic agent that increases or decreases,
HeLa cells.) Differences in radiosensitivity for cells in each phase were respectively, the cytotoxicity of ionizing radiation. “True” radiosensitizers
largely attributable to changes in the shoulder regions of their respective and protectors meet the stricter criterion of being relatively nontoxic
survival curves, with late S phase cells characterized by broad survival in and of themselves, acting only to potentiate or ameliorate radiation
curve shoulders, and mitotic cells showing strictly exponential cell toxicity. “Apparent” radiosensitizers and protectors still produce the
killing with no survival curve shoulders (Fig. 27.16). However, when net effect of making tumors more sensitive or normal tissues less so,
high-LET radiations such as neutrons are used in place of x-rays, the yet their mechanisms of action are not necessarily synergistic, and the
age response variation through the cell cycle is significantly reduced agents are not necessarily nontoxic when given alone.
or eliminated. Finally, it is important to realize that the use of any chemical
Because of the age response through the cell cycle for low-LET modifier of radiation response is only as good as it is selective, or at
radiations, an initially asynchronous population of cells surviving a minimum partially selective, for either tumors or normal tissues; agents
dose of radiation becomes enriched with more resistant cells (S phase, that show little or no differential effect between tumors and normal
and to a lesser extent, G1 phase cells). This partial synchrony decays tissues do not improve the therapeutic ratio and therefore may not
rapidly, however, in part because of radiation-induced perturbations be clinically useful.
in cell cycle progression, and also because of natural variations in cell
cycle phase durations. Such cells are said to have “redistributed,”84 with Traditional Radiosensitizers
the net effect of sensitizing the population as a whole to subsequent Sensitizers of proliferating cells
dose fractions compared with what would have been expected had Halogenated analogues of the DNA precursor thymidine, such as
the cells remained in their resistant phases. The redistribution process bromodeoxyuridine (BrdUdR) and iododeoxyuridine (IdUdR), can
can be demonstrated in rapidly growing cells in vitro but tends to be incorporated into the DNA of actively proliferating S phase cells
be dampened in vivo because of the longer (and dispersed) cell cycle in place of thymidine because of close structural similarities between
times and lower fractions of actively proliferating cells in tumors. the compounds. Cells containing DNA substituted with these com-
Attempts to take advantage of redistribution clinically, however, pounds are more radiosensitive than their counterparts without substitu-
such as by carefully timing each dose fraction to correspond to times tion, with the amount of sensitization proportional to the fraction of
when tumor cells would be expected to be most radiosensitive, have thymidine replaced.86 In general, the radiosensitization takes the form
been unsuccessful.85 In fact, it has been difficult to demonstrate that of a decrease in or elimination of the shoulder region of the radiation
redistribution has occurred in tumors (or normal tissues for that survival curve. The molecular basis of the ability of BrdUdR and
matter) at all, other than by indirect inference—that is, that increasing IdUdR to radiosensitize those cells that incorporate the drugs into
resistance to each subsequent dose fraction during radiation therapy does their DNA remains somewhat unclear. It is likely, however, that both
not occur. the formation of more complex radiation-induced lesions caused by
the presence of the halogen atoms and an interference with DNA
Radiosensitizers and Radioprotectors repair are involved.87
The clinical use of halogenated pyrimidines began in the late 1960s
The use of radiosensitizing or radioprotective compounds in combina- with a major clinical trial in head and neck cancer.88 Although BrdUdR
tion with radiation therapy is predicated on the idea that tumors did improve the tumor response to radiation therapy, it also produced
contain one or more radioresistant (or effectively so) subpopulations severe oral mucositis, as might have been expected in retrospect given
of cells that threaten the success of treatment. Historically, three such that the mucosa also contains rapidly proliferating cells that would
subpopulations in tumors that fit this description are inherently have been radiosensitized. As a result, the therapeutic ratio did not
radioresistant cells, hypoxic cells, and rapidly proliferating cells. Rapidly improve. Subsequently, these drugs were evaluated in more appropriate
proliferating cells may not be radioresistant per se, but rather have disease sites such as brain tumors and sarcomas, consisting of rapidly
the net effect of making the tumor seem less responsive to treatment growing tumor cells against a background of slowly proliferating or
 Basics of Radiation Therapy  •  CHAPTER 27 447

nonproliferating cells of the surrounding normal tissues.89,90 Unfor- techniques that allow better sparing of these dose-limiting tissues, the
tunately, these drugs did not improve outcomes sufficiently to warrant use of amifostine during radiation therapy has decreased.
their adoption for routine clinical use.
Chemotherapy Drugs as Radiosensitizers
Sensitizers of hypoxic cells A major change that has occurred in the clinical practice of radiation
The increased radiosensitivity of cells in the presence of oxygen is due therapy over the past few decades is the increasing percentage of
to oxygen’s affinity for the electrons produced by the ionization of patients who are treated with concurrent radiation therapy and
biomolecules. Molecules other than oxygen also have this chemical chemotherapy. This combination is used in two ways: chemotherapy
property, known as electron affinity91; some of these molecules are not used independently for its cytotoxic effect on the tumor, and chemo-
consumed by the cell for other purposes as oxygen is. Assuming that therapy used to enhance the effect of the radiation therapy through
such an oxygen-mimetic compound is not otherwise used by the cell, a drug sensitization effect. This second approach is discussed here. As
it should diffuse further from blood vessels and reach hypoxic regions mentioned earlier in this chapter, the value of radiation sensitization
of a tumor, sensitizing the hypoxic cells to radiation. is dependent on producing a differential sensitization of the tumor
One class of compounds that represented a reasonable trade-off compared with the adjacent normal tissue. There is little value if a
between efficiency as a radiosensitizer (as compared with oxygen) and drug’s only effect is to decrease the amount of time for which the
diffusion effectiveness was the nitroimidazoles, which include the radiation therapy machine is turned on.
drugs misonidazole, etanidazole, and nimorazole, all of which were It has been known for decades that certain pharmaceuticals can
the subjects of intensive preclinical and clinical studies over several increase the tumor cell kill produced by radiation therapy.105 One of
decades. Unfortunately, the nitroimidazoles were found to cause side the early, and still commonly used, approaches is the combination
effects in normal tissues—in particular, peripheral neuropathy—that of a fluoropyrimidine (typically 5-FU, or more recently capecitabine)
curtailed their clinical usefulness.92,93 In fact, the only member of this with radiation therapy for a variety of tumors, but especially those
class of compounds currently approved for clinical use is nimorazole, of the GI tract, including esophageal, gastric, pancreatic, rectal, and
which is used in Europe for subgroups of patients with advanced head anal cancers.106 The underlying mechanism(s) of action of these
and neck cancer.94 fluorinated pyrimidines as radiation sensitizers is still not completely
Another class of hypoxic cell radiosensitizers does not sensitize clear; however, it most likely involves some combination of the drug’s
cells per se, but rather kills them outright. This also produces the selective toxicity to otherwise radioresistant S phase cells, interference
net effect of sensitization of the tumor as a result of the elimina- with DNA synthesis and repair, and ability to dysregulate the cell
tion of an otherwise radioresistant subpopulation of cells. Agents cycle.105 In the past, the combination was also used to treat head and
selectively toxic to hypoxic cells are termed bioreductive drugs, with the neck and uterine cervix squamous cell carcinomas, although that practice
organic nitroxide tirapazamine (formerly, SR 4233)95,96 being the lead is much less common today. The details of these combinations are
compound. described more fully in the individual disease site chapters. It should
In preclinical models, tirapazamine was shown to outperform the be noted that local control has been consistently improved by this
nitroimidazole radiosensitizers with use of clinically relevant fractionated approach, and it has had a beneficial effect on survival in some of
radiation therapy97 and with some chemotherapy drugs either alone these diseases.
or in chemo radiation therapy regimens.98 In humans, more than 20 Another drug commonly used with concurrent therapy is cisplatin,
clinical trials are ongoing or complete, including randomized phase an inorganic compound consisting of a coplanar complex capable of
II and III trials with tirapazamine combined with radiation therapy producing both inter- and intra-strand DNA and protein crosslinks.105
and/or chemotherapy (particularly, cisplatinum) for advanced head and The cross-linking produced by cisplatinum most likely interferes with
neck, cervix, and lung cancers. Tirapazamine has improved outcomes cellular repair of radiation damage, particularly DNA double-stranded
for some standard regimens, but results overall have been mixed.99,100 breaks, resulting in radiation sensitization,107 although as in the case
Thus, although the drug has not become a staple of clinical practice, of the fluoropyrimidines, additional mechanisms of action have also
its activity against some tumors warrants further investigation, as been proposed.105 This combination is routinely used for head and
does the search for more effective agents from the same or a similar neck and uterine cervix cancers,108,109 with a major impact on long-term
chemical class. outcome. Mitomycin C is routinely used in the therapy of anal cancer.110
The use of temozolomide is standard practice in therapy of high-grade
Traditional Radioprotectors gliomas,111 and various other combination therapies have also been
In theory, if normal tissues could be made to tolerate higher total explored.
doses of radiation through the use of radioprotectors, then the relative
radioresistance of hypoxic tumor cells would no longer be treatment Molecularly Targeted Drugs and Biologics
limiting. One such agent, amifostine (Ethyol), is a thiol-containing There is great interest in the use of biologic therapies in combination
compound developed by the US Army for use as a radiation protector with radiation therapy. Although preclinical data have been gener-
for soldiers on a nuclear battlefield and subsequently repurposed for ated for quite a few of these agents, with even newer compounds
clinical use. Chemically, amifostine is an analogue of naturally occurring constantly in development, the only two that have gone through
radioprotective sulfhydryl compounds found in cells, such as cysteine, substantial clinical testing and entered the treatment mainstream are
cysteamine, and glutathione.101 Like those antioxidant compounds, anti-EGFR inhibitors used to treat squamous cell carcinomas of the
amifostine’s mechanism of action involves the scavenging of free radicals head and neck,18 and anti-VEGF therapies for the treatment of GI tract
produced by ionizing radiation, radicals that otherwise could go on tumors.112
to damage other cellular macromolecules, or react with oxygen and The use of cetuximab (Erbitux), a monoclonal antibody raised
“fix” damage that has already been registered. Amifostine can also against EGFR, has been shown to improve outcomes in head and
detoxify other reactive species, and because of this the drug can also neck cancers when combined with radiation therapy18 and is being
be used as a chemoprotective agent.102 explored in a variety of other clinical situations. Cetuximab competi-
Amifostine is approved for use in patients receiving radiation therapy tively binds to the extracellular domain of EGFR, preventing activation
for head and neck cancer, for reducing xerostomia secondary to exposure of the receptor by endogenous ligands; this abrogates its near-constant
of the parotid glands.103 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 non–small cell lung cancer.104 With the advent EGFR expression relative to the overexpression often displayed by
of 3D conformal and intensity-modulated radiation therapy (IMRT) diseases such as squamous cell cancers of the head and neck.
448 Part I: Science and Clinical Oncology

Bevacizumab (Avastin) exploits a different cancer hallmark, namely III clinical trials of PARP inhibitors are currently underway for several
the ability of tumors to continuously recruit new blood vessels from tumor types, including breast, ovarian, and pancreatic cancers.128,129
surrounding normal tissues. This is accomplished by tumor cells One drug, olaparib (Lynparza) has already received FDA approval for
producing and releasing into their microenvironment large quantities use in BRCA-mutated advanced ovarian cancer.
of (among other proangiogenic factors) VEGF, the principal stimulant As discussed earlier in the chapter, the use of immune checkpoint
of endothelial cells of the host vasculature to reproduce and migrate inhibitors in combination with radiation therapy is an area of consider-
into the tumor mass, forming new—if immature and aberrant—blood able clinical interest and excitement. Indeed, there is a body of clinical
vessels. The observation that tumors cannot grow beyond a size of evidence that radiation, particularly for the higher, acute doses that
approximately 2 mm3 without the support of neovascularization113 would be used for hypofractionation (defined as the use of one or a
has led to accelerated development of angiogenesis-inhibiting agents, few large doses delivered over short treatment times; see also later),
many of which target either VEGF or its endothelial cell surface can induce in vivo priming of T cells and produce objective (partial
receptor.114,115 or complete) abscopal responses in tumor metastases distant from the
Bevacizumab is a humanized monoclonal antibody raised against irradiated site, although this occurrence is quite rare with present day
VEGF.116 The binding of the antibody to VEGF prevents it from techniques. This has been shown for subsets of patients with metastatic
binding to its receptor on the surface of vascular endothelial cells, melanoma and non–small cell lung cancer receiving radiation therapy
which has the net effect of inhibiting the downstream signaling events combined with the immune checkpoint inhibitor ipilimumab (Yervoy),
that cause these cells to begin proliferating and forming vessel “sprouts” which blocks the cytotoxic T-lymphocyte antigen 4 (CTLA4) receptor
that migrate toward the tumor mass. At first blush, therapy that blocks on T cells and prevents the binding of inhibitory tumor cell ligands
new blood vessel formation might be expected to create more tumor thus causing these cells to “reactivate”).130,131 At present, more than
hypoxia, and therefore more radiation resistance. However, both a dozen phase I and II clinical trials of combined radiation therapy
preclinical and clinical studies with bevacizumab and related inhibitors and ipilimumab are ongoing, mostly for patients with advanced
of angiogenesis most often have shown that these agents promote melanoma, but also for lung, cervix, and head and neck cancers.32
radiation (and chemotherapy) sensitivity, not resistance. One hypothesis Despite these tantalizing early results, only a small subset of patients
to explain this observation is that antiangiogenic therapy actually with these cancers respond to this type of treatment (typically, less
“normalizes” tumor vasculature117 by selectively pruning away small, than 20%), and even among those who do respond, drug resistance
immature, abnormal tumor blood vessels, leaving the larger, more can develop.132
normal-seeming vessels behind. This would lead to improved tumor However, with FDA approval of other checkpoint inhibitors target-
oxygenation and better access of chemotherapy agents. ing different components of tumor immunosuppressive pathways,
Bevacizumab had been shown to prolong both overall survival such as pembrolizumab (Keytruda) or nivolumab (Opdivo), which
and progression-free survival in patients with advanced colorectal block the PD-1 receptor on T cells and thus prevent the binding of
cancer when added to a standard chemotherapy regimen consisting of the inhibitory ligand PD-L1 expressed by tumor cells, it is hoped that
irinotecan, 5-FU and leucovorin.118,119 In rectal cancer,120 bevacizumab future trials of these drugs (either alone or in combination) combined
has been evaluated in combination with radiation therapy, and although with radiation therapy will be forthcoming. Also, because it is thought
initial reports were encouraging, with excellent early responses, the by many that radiation works in this situation by stimulating neoantigen
combination does not appear to improve clinical efficacy. Also, despite release from the tumor, there is the possibility of enhancing antigen
prolonged progression-free survival, no clear overall survival benefit of presentation to further augment this effect.
bevacizumab was seen in large clinical trials for non–small cell lung
cancer,121 renal cell carcinoma,122 and metastatic breast cancer.123 In Normal Tissue Toxicity
response to the disappointing results in metastatic breast cancer, the
FDA withdrew its approval of bevacizumab as a first-line therapy, In the delivery of radiation therapy, an understanding of the biology
concluding that the drug’s benefit did not outweigh its adverse of normal tissue response to injury is critical. Normal tissue complica-
side effects, which can include hypertension, proteinuria, bleeding tions that arise during or after radiation therapy are the result of the
episodes, and thrombotic events.124 Nevertheless, there continues to killing of critical target cells crucial for the tissue’s continued functional
be interest in trying to exploit vascular normalization in a variety of and/or structural integrity. These irradiated cells die either directly or
tumor types. indirectly; however, the process that culminates in the complication
Many newer biologic agents have been shown to have radiation is both complex and dynamic, involving oxidative stress, radiation-
sensitizing properties in vitro and in animal systems, and there is a inducible gene expression (including production of cytokines and
great interest in translating this information to the clinic. For example, growth factors), cellular signaling cascades, different modes of cell
one class of drugs is the poly (ADP-ribose) polymerase (PARP) inhibi- death, and compensatory proliferative responses. For example, the
tors. Proteins in the PARP family participate in a number of cellular hyperproliferation of fibroblasts and deposition of collagen after a
functions, including detecting the presence of DNA strand breaks tissue injury can culminate in the replacement of a large proportion
and activating signaling pathways that recruit and mobilize DNA of that tissue’s parenchymal cells, resulting in fibrosis—a common
repair proteins to the site of the damage.125 PARP1 is by far the most complication of radiation therapy.
abundant member of this family and has been most frequently targeted
for inhibition. PARP inhibitors have been evaluated in preclinical Tolerance Doses
models as potential radiation sensitizers, given that unrepaired or Several important considerations in determining tolerance doses for
misrejoined DNA double-strand breaks are the lethal lesions with different tissues include the radiosensitivity of the tissue’s component
respect to the cytotoxic effects of radiation, and that PARP inhibition cells, the proliferative organization of the tissue (that determines the
might enhance this damage and increase toxicity. earliness or lateness of the tissue response to radiation), the volume
DNA repair inhibition will be clinically useful only insofar as it of the tissue irradiated, and the tissue’s fractionation sensitivity.
is selective for tumors, because inhibiting repair in irradiated normal Accordingly, tolerance doses for particular complications in particular
tissues could have adverse results. Fortunately, PARP inhibition has tissues are necessarily average values that take all of these factors
shown some selectivity for tumors, in particular those whose cells are into consideration. Furthermore, these doses have been determined
already defective in at least one DNA repair pathway, as is the case by pooling clinical outcomes data on thousands of patients over
for cells that carry mutations in the BRCA1 or BRCA2 genes.126,127 long periods of time (decades, typically). Bearing this in mind,
As cells from normal tissues have intact alternate or salvage pathways several general findings about normal tissue tolerance are worth
for DNA repair, the PARP inhibitors should be less toxic. Phase II/ mentioning.
 Basics of Radiation Therapy  •  CHAPTER 27 449

First, because tissues and organs contain, by definition, more than

one cell type (each with its own inherent radiosensitivity), it follows Radiation Carcinogenesis
that one tissue could manifest more than one complication after With increasing numbers of long-term cancer survivors, one late normal
radiation therapy, with the severity of each determined by the radio- tissue complication of radiation therapy that is particularly concerning
sensitivity of the particular target cell whose death precipitates the is the production of second malignancies. Leukemia accounts for
complication, and by the time-dose-fractionation schedule employed. about 20% of these second cancers, with the remainder being solid
In addition, the severity of one complication is not necessarily predictive tumors that develop in and around the previously irradiated site.133,134
of the severity of another complication, even within the same tissue. Large epidemiologic studies have assessed the breast and lung cancer
Using skin as an example, an early effect of treatment might consist risk in Hodgkin lymphoma survivors,135,136 and leukemia and sarcomas
of dry or moist desquamation (killing of basal cells of the epidermis), in cervical cancer survivors.137 Certain subpopulations of previously
whereas late effects might include fibrosis (loss of tissue parenchymal irradiated patients are at an even higher risk than the majority, including
cells and some dermal fibroblasts, resulting in overproliferation of children and young adults (who would be expected to live long enough
survivors) or telangiectasia (damage to small blood vessels in the dermis, for such second cancers to develop, and, in the case of children, who
resulting in abnormal regrowth). are more radiosensitive than adults to begin with), immunocompromised
Second, although it is generally true that tissues known to be individuals, and those with a known genetic predisposition to cancer.
composed of radiosensitive cells have lower tolerance doses (e.g., the Large studies of previously irradiated patients have demonstrated that
tolerance dose for a 5% risk of radiation-induced bone marrow aplasia the risk of late cancer developing in an incidentally irradiated organ
within 5 years of treatment [TD5/5] is approximately 2.5 Gy), compared will very roughly double the baseline risk.121 Fortunately, the baseline
with the tolerance doses for tissues containing more radioresistant risk in an individual organ is quite low, so the absolute impact of a
cells (TD5/5 for rectal stenosis or fistula formation is approximately radiation-induced cancer is also low, assuming there is clinical benefit
60 Gy),54 this is not universally the case because radiosensitivity is in the original therapy. However, the impact of a second cancer
not the sole determinant of radiation response. occurring many years after a prior cancer developed can be severe.
Tolerance dose data for representative early- and late-responding
normal tissues are shown in Table 27.2, with data included from Volume Effects
three seminal publications (with about 20 years between publications) Normal organs can be viewed as having “serial” or “parallel” structural
that compiled such information based on exhaustive reviews of the organization, by analogy with electrical circuits.138 A serial organ is
literature and updated to reflect new knowledge about the etiology of one in which an injury at any anatomic point in the structure will
normal tissue complications and changes in treatment technique over produce a severe functional loss. The classic example of this is the
the years. spinal cord. If there is major damage to the cord at any level, from a

Table 27.2  Radiation Tolerance Dose and Complication Frequency Data for Select Normal Tissues

Early or Irradiation and Volume Tolerance Dose or Complication

Tissue Late End Point Details Frequency Author
LUNG Early Pneumonitis Conventional fractionation; less TD5/5 ≅ 20 Gy Rubin and Casarett
than one-half of organ irradiated
Conventional fractionation; TD5/5 ( 13) ≅ 45 Gy Emami
one-third or whole organ TD5/5 (whole) ≅ 17.5 Gy
irradiated
Conventional fractionation; 7 Gy ≅ 5% complication frequency QUANTEC
3D-CRT; whole organ irradiated 20 Gy ≅ 20% complication frequency
27 Gy ≅ 40% complication frequency
RECTUM Late Ulcer, perforation, Conventional fractionation TD5/5 ≅ 65 Gy Rubin and Casarett
fistula, stricture
Conventional fractionation; TD5/5 ≅ 60 Gy Emami
100-cm field
Conventional fractionation; V50 <50%: <15% complication frequency QUANTEC
3D-CRT V65 <25%: <15% complication frequency
V75 <15%: <15% complication frequency
SPINAL CORD Late Myelopathy Conventional fractionation; 5- to TD5/5 ≅ 50 Gy Rubin and Casarett
10-cm field
Conventional fractionation; 5- or TD5/5 (5 cm) ≅ 50 Gy Emami
20-cm field TD5/5 (20 cm) ≅ 47 Gy
Conventional fractionation; Dmax = 50 Gy: <1% complication QUANTEC
3D-CRT; partial organ irradiation, frequency
including full cord cross-section Dmax = 60 Gy: 6% complication frequency
Dmax = 69 Gy: 50% complication
frequency

Conventional fractionation is equal to 1.8 to 2.0 Gy per fraction, one fraction per day, 5 days per week.
3D-CRT, Three-dimensional, conformal radiation therapy; Dmax, maximum radiation dose (Gy) to the irradiated volume; TD5/5, total radiation dose that results in approximately
a 5% risk of a complication within 5 years of treatment; V50, V65, V75, volume (%) of irradiated organ receiving ≥50, ≥65, or ≥75 Gy.
Data from Rubin P, Casarett GW. Clinical Radiation Pathology. Vol 1. Philadelphia: WB Saunders; 1968; Emami B, Lyman J, Broun A, et al. Tolerance of normal tissue to
therapeutic irradiation. Int J Radiat Oncol Biol Phys. 1991;21:109–122; 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–S19.
450 Part I: Science and Clinical Oncology

small dosimetric hot spot, for example, all function can be lost below
that level. Skin and many tubular or saclike organs (e.g., GI tract) Table 27.3 Representative α/β Ratios for Human
also behave as if their tissue components are arranged in series. Examples Normal Tissues and Tumors
of parallel organs include the kidneys and the lungs. Radiation injury
to a portion of one of these organs will in general just decrease its α/β Ratio (±95%
function by an amount approximately equal to the percent of the Tissue Type and End Point Confidence Interval)
organ that is destroyed, but often will not produce a major functional EARLY-RESPONDING NORMAL TISSUES
deficit unless the irradiated volume is large. Skin Erythema 10.6 (1.8–22.8) Gy
Some organs behave as if they have both a serial and a parallel Desquamation 11.2 (8.5–17.6) Gy
component. The liver can be viewed in this manner; the hepatic Lung Pneumonitis ≤90 days >8.8 Gy
parenchyma functions as a parallel structure, but the biliary system after radiation therapy
near the hilum functions as a serial structure. Thus the radiation
Oral mucosa Mucositis 8–15 Gy
oncologist can design radiation therapy fields that totally destroy
portions of the parenchyma of the liver without a clinical problem LATE-RESPONDING NORMAL TISSUES
to the patient, but damage to any tubular structure of the biliary Skin Telangiectasia ~2.7 (-0.1–8.1) Gy
system can produce severe consequences; obstruction of the common Fibrosis 1.7 (0.6–3.0) Gy
bile duct is a major complication that can affect the whole organ.
Breast Poor cosmesis 3.4 (2.3–4.5) Gy
Fractionation Sensitivity Fibrosis 3.1 (1.8–4.4) Gy
During the 1960s and 1970s, research interest among radiobiologists Lung Pneumonitis >90 days 4.0 (2.2–5.8) Gy
focused on the shape of the shoulder region of cell survival curves, after radiation therapy
the nature of dose rate and dose fractionation effects, and their relevance Bowel Perforation or stricture 3.9 (2.5–5.3) Gy
to the practice of radiation therapy. This research was timely, given Spinal cord Myelopathy <3.3 Gy
the growing appreciation clinically that tissue tolerances varied,
TUMORS
sometimes widely, depending on the exact time, dose, and fractionation
pattern used for treatment. This research ultimately led to the replace- Head and neck Nasopharynx 16 (−11 to 43) Gy
ment of the target theory model of cell survival with the LQ model, Vocal cord ~13 Gy
as well as the use of the LQ model as a framework for a new approach Tonsil 7.2 (3.6–∞) Gy
to clinical isoeffect modeling. Larynx 14.5 (4.9–24) Gy
In multifraction experiments assessing skin reactions in mice, Lung Squamous cell carcinoma ~50–90 Gy
Douglas and Fowler139 analyzed their data by using what was then a Cervix Squamous cell carcinoma >13.9 Gy
novel method that allowed the derivation of values for the ratio α/β, Skin Squamous cell carcinoma 8.5 (4.5–11.3) Gy
parameters of the LQ formula. This new approach to isoeffect analysis Melanoma 0.6 (−1.1 to 2.5) Gy
focused on the shape of dose-response curves, particularly in the Prostate 1.1 (−3.3 to 5.6) Gy
low-dose region, and by extension the fact that the critical parameter
in radiation therapy planning was the size of the dose per fraction. Breast (early-stage invasive ductal, lobular, 4.6 (1.1–8.1) Gy
and mixed)
More widespread use of this technique in subsequent years revealed
that in most cases there was a systematic difference between early- and
Data from Joiner and van der Kogel.55 Table excerpted from Zeman EM. Biologic basis
late-responding normal tissues and tumors in their responses to different of radiation oncology. In: Gunderson LL, Tepper JS, eds. Clinical Radiation Oncology.
fractionation patterns. The α/β ratios tended to be low for late- 3rd ed. Philadelphia: Saunders; 2012:3–42.
responding normal tissue end points (on the order of 1–6 Gy, with
an average of about 3 Gy), and high for early-responding normal
tissue and tumor end points (usually 7–20 Gy, with an average of
about 10 Gy). Table 27.3 shows α/β ratios determined for a variety
of human normal tissues and tumors.
Representative dose-response curve shapes for tissues characterized
by low or high α/β ratios are shown in Fig. 27.17. The curve with Mild Tumor and early-
the low α/β ratio has a shallow initial slope at low doses, but curves responding tissue
Late-responding tissue
downward rather abruptly as the dose increases. Conversely, the curve
with the high α/β ratio has a steeper initial slope and bends more
(Log of) Response

gradually as the dose increases.

In parallel with the fractionation experiments used to determine
tissue α/β ratios, other investigators140 quantified the fractionation
sensitivity of experimental tumors and normal tissues by using a plot
of the log of the total dose to achieve a particular tissue end point
versus dose per fraction; this is called an isoeffect curve, a method for
plotting tolerance dose data in common use in radiation oncology
since the 1940s.141 Plotted in this way, the curves for slowly proliferating
or nonproliferating normal tissues such as kidney and spinal cord
were found to be steeper than those for more rapidly proliferating,
Severe
early-responding tissues, such as skin and gut epithelium, and most
tumors.140,142 Taken together, the low α/β ratio and steep isoeffect Dose
curve suggest that late-responding tissues are more sensitive to changes
in dose per fraction, experiencing greater sparing with decreasing Figure 27.17  •  Putative dose-response curve shapes for tissues characterized
fraction size than their early-effects counterparts. This is illustrated by low (yellow line) or high (pink line) α/β ratios. The α/β ratio for most
graphically in Fig. 27.18. It was immediately evident that this could late-responding normal tissues averages about 3 Gy, and for most early-
be exploited for clinical benefit. responding normal tissues and tumors, about 10 Gy.
 Basics of Radiation Therapy  •  CHAPTER 27 451

80 Skin necrosis
Skin
70 desquamation
60 Skin
contraction Lung
)
50 sis (LD50 pneumonitis)
aly
ar
(p
Total dose for various isoeffects (Gy) 40
or
d cells
c nc rypt
in al colo
Sp s of Kidney (LD50)
30 Los
)
onia
rm atog
o f spe Loss of jejunal crypt cells
oss
tis (l
20 Tes

Loss of control of fibrosarcoma

Vertebral growth inhibition

10
Bone marrow ablation (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 suggests that with use of 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. LD50, The total dose required to kill 50% of the mice secondary
to radiation pneumonitis.

Clinical Application of the Linear-Quadratic where D is the total dose actually delivered, and d is the dose per
Isoeffect Model fraction actually used. When comparing clinical trial data from multiple
institutions, EQD2 doses can be used rather than the actual doses,
The shapes of tissue and tumor isoeffect curves and their calculated which makes the pooling of data with varying fractionation schedules
α/β ratios have a number of clinical applications. One is to use α/β more manageable, with the caveat that the results will apply only to
ratios to generate alternate treatment schedules employing different-sized the tissue of interest with its unique α/β ratio.
doses per fraction in order to match the probability of causing a tissue Another important implication of the steeper isoeffect curves for
injury. Making such a calculation assumes that the overall treatment late-responding tissues compared with those for tumors is that it might
times are similar in both schedules or that the tissue at risk of a be possible to increase the therapeutic ratio by using larger numbers
complication is relatively insensitive to treatment duration.143 The of smaller fractions (less than about 1.8 Gy) to a somewhat higher
equation total dose than conventionally used.144 This is called hyperfractionation.
Although such treatments would be expected to exacerbate early effects
in some normal tissues (undesirable, but usually manageable) and in
D 2 D1 = (α β + d 1) (α β + d 2)
the tumor (desirable), late effects would be spared preferentially (also
desirable).
can be used for this purpose, where D1 and d1 are, respectively, the Hypofractionation, the use of one or a few large dose fractions
total dose and dose per fraction of one radiation therapy treatment delivered over short periods of time (as would be the case for stereotactic
plan, D2 and d2 are the total dose and dose per fraction for an radiosurgery [SRS], stereotactic body radiation therapy [SBRT], or
alternate treatment plan intended to be biologically equivalent for a intraoperative radiation therapy [IORT], discussed further later), is
particular tissue effect, and with the fractionation sensitivity of that also an option, and one that is increasingly popular. Indications for
tissue defined by its α/β ratio. One example of the use of this approach hypofractionation include situations in which the complete ablation
is to express particular time-dose-fractionation schedules in terms of of small tumors is the goal; the radiation fields are small and not
equivalent total dose if the treatment had been given in 2-Gy fractions perilously close to critical tissues prone to complication when large
(EQD2), doses are used; radiation therapy is used in combination with immu-
notherapy; and/or in the relatively unusual circumstance in which
EQD 2 = D[( d + α β ) (2 + α β)] the tumor has a low, rather than high, α/β ratio. Prostate cancer and
452 Part I: Science and Clinical Oncology

melanoma appear to be tumor types that meet this criterion (see Table Radiation therapy can also be used in this manner when a patient
27.3), as does, to a lesser extent, breast cancer.130,145 is too frail for a surgical procedure or has declined surgical interven-
With particularly aggressive tumors that proliferate rapidly, another tion. Examples from this category include treatment of early-stage
clinical strategy has been suggested, although not explicitly derived cancers of the head and neck and cervix, prostate cancer (particularly
from the LQ model. Multiple treatments per day might also be useful early-stage prostate cancer), and selected basal cell carcinomas of
in order to decrease the overall treatment time, thereby allowing less the skin. Radiation therapy alone is used much less often for locally
time for repopulation of clonogenic tumor cells.146 Treatment with advanced disease, not only because it is now combined with concur-
multiple daily fractions of approximately standard size and number rent chemotherapy, but also because modern surgical procedures
(and to about the same total dose), but in shorter overall times, has can be performed even for extensive local-regional disease.
been called accelerated fractionation. In practice, however, a combination 2. Preoperative or postoperative radiation therapy. The treatment of many
of accelerated and hyperfractionated treatment is most often used.147 tumors requires surgery, yet surgery alone can leave residual disease
Of course, determining the best treatment schedule for a particular either in the tumor bed or in regional lymphatics that are not
patient is not simply a matter of avoiding a normal tissue complication completely resected. Radiation therapy in this situation is often given
or delivering a curative dose to the tumor, but rather, how the prob- with concurrent chemotherapy in order to exploit the chemotherapy’s
abilities of both change in comparing different treatment possibilities. radiation sensitizing effects. Examples include soft tissue sarcomas,
The biologically effective dose (BED) method,148 another derivative certain cancers of the head and neck, intermediate- and high-grade
of the LQ model, attempts to address this. BEDs are theoretical doses gliomas, and early-stage breast cancers.
to achieve a particular effect under conditions where fractionation 3. Primary radiation therapy with concurrent chemotherapy. For many
consists of an infinite number of infinitely small dose fractions. BEDs tumors, surgery is not an option because a grossly complete resection
would be quite large for tissues characterized by low α/β ratios and cannot be performed, so radiation therapy becomes the primary
steep isoeffect curves (such as many late-responding normal tissues), local therapy. Chemotherapy can be added either concurrently as
and appreciably smaller for tissues characterized by high α/β ratios a radiation sensitizer to enhance local control or before or after
and shallower isoeffect curves (such as most tumors and early-responding radiation therapy for control of systemic disease. Examples include
normal tissues). BEDs are not real doses, but extrapolations based on all anal cancers and locally advanced tumors of the cervix, esophagus,
the shapes of dose-response curves characterized by particular α/β pancreas, and head and neck.
ratios. For this reason, the units used to describe these theoretical, 4. Trimodality therapy. Often all three primary therapeutic modalities—
extrapolated doses are, for example, “Gy3s” or “Gy10s,” rather than surgery, radiation therapy, and chemotherapy—are needed for
“Gys,” where the subscripts 3 and 10 refer to the α/β ratios for the control of local, regional, and systemic disease. The timing of the
tissues at risk. While two radiation therapy treatment schedules can therapies is dependent on the individual clinical situation. This is
be compared qualitatively on the basis of their respective Gy3 or Gy10 perhaps the most common approach at the present time. Examples
“dose,” Gy3s and Gy10s cannot be intercompared. include a large group of tumors including esophageal cancer,
Even with the BED concept being only semiquantitative at best, glioblastoma, and cancers of the head and neck, pancreas, breast,
its use for treatment planning purposes over the past three decades and rectum.
has changed the radiation therapy standards of care for several tumor
types and provided a wealth of clinical data that has allowed a better Radiation Therapy Delivery Techniques
definition of what is or is not tolerable for particular normal tissues,
in terms of Gy3s or Gy10s. Using head and neck cancer as an example, The radiation oncologist has multiple tools that can be used for radiation
Fowler and colleagues146 suggested that for acute mucosal reactions, therapy delivery, depending on the specific circumstances. Because
the maximally tolerated BED is in the range of 59 to 61 Gy10, and there are many possible combinations, only a general framework is
for brain necrosis, approximately 110 to 115 Gy3. described here; the technical issues were described earlier in the chapter.
Often, combinations of techniques are used to optimize therapeutic
Radiation Therapy Delivery Approaches delivery.

Historically, radiation therapy was used as a single treatment modality, External Beam Fractionated Radiation Therapy
either for very early-stage disease in which radical surgery would be External beam fractionated radiation therapy is by far the most common
overtreatment (such as a total laryngectomy for early-stage glottic technique used clinically. Radiation beams usually are delivered through
cancer), or for advanced disease in which surgery would be insufficient multiple angles of approach to the lesion, with each one of the beams
for control of the disease extent (lung cancer with mediastinal disease shaped and altered in intensity to maximize the delivery of dose to
or stage III cervical cancer). Treatments also focused heavily on the the tumor while minimizing the dose to normal tissues. External beam
use of radiation therapy for organ preservation. In these situations, therapy can be delivered with conformal radiation therapy techniques
radiation therapy would rarely be combined with chemotherapy. (shaping the beams based on 3D reconstructions of the tumor size
However, there have been substantial changes over the years in the and shape as well as the location of nearby normal tissues). IMRT
conceptual use of radiation therapy. changes the intensity of each small segment (“beamlet”) of an individual
Although it is still used for the reasons described earlier, at the beam to obtain even more precise dose localization and avoidance of
present time radiation therapy is routinely combined with concurrent normal tissue irradiation.
chemotherapy (either cytotoxic or “targeted”). It is commonly combined In general, these treatments involve use of either low-energy
with surgery as either a preoperative or a postoperative approach, (6 MV) or high-energy (approximately 10–15 MV) x-rays, but they
and the timing of radiation therapy with surgery and chemotherapy can also be delivered with electrons of various energies, with the
can vary. higher energies having a greater depth of penetration into tissue. The
Radiation therapy has the substantial benefit of being able to provide radiation oncologist decides the proper treatment based on estimates
organ preservation in many clinical situations and to be able to sterilize of tolerance doses for normal tissue complications and curative doses
residual microscopic disease when used in conjunction with surgery. for tumors for different fractionation schedules. A balance is required
Thus we can categorize the use of radiation therapy as follows: in trying to give the highest probability of tumor control with the
lowest reasonable level of clinically significant normal tissue injury.
1. Radiation therapy alone. This is often used for small tumors where Often, depending on the individual anatomy and tumor extent,
surgery would be excessive either because of the precise location radiation doses will need to be modified from what is considered
of the tumor or because of the limitations of surgical resection. standard.
 Basics of Radiation Therapy  •  CHAPTER 27 453

The radiation fields used with EBRT often target areas of presumed
subclinical disease (such as nodal drainage regions) as well as the
clinically apparent tumor. This makes it critical that the radiation
oncologist have an excellent understanding of the natural history of
each disease and its specific spread pattern. Radiation treatments are
usually given daily, 5 days a week, and can extend in duration from
1 week (or less) for certain types of palliative therapy to courses
extending for 7 to 8 weeks of daily treatment. Total doses can vary
from close to 80 Gy over 8 to 9 weeks to 20 Gy in 1 week, to 8 Gy
delivered as a single fraction for palliation.

Simulation, treatment planning, and delivery of external

beam radiation therapy
After diagnosis, and after a decision has been made to irradiate the
tumor, the first step in designing and delivering radiation therapy to
a patient is called simulation. Simulation is a process for determining Figure 27.19  •  Isocenter selection in the center of a lung tumor allows
the proper selection and orientation of beams such that they properly beams from any gantry angle to be centered on the lesion. Skin markers placed
overlap a target and avoid normal tissue. Simulation requires the at centroid of the anterior and lateral beams can be aligned with treatment
determination of patient dimensions for dose calculation, and the room lasers to assist in placing the patient in the proper treatment position.
determination and/or creation of identifiable reference points to ensure
that beams are being aimed correctly. Historically, patient dimensions
were determined by methods as simple as forming a lead wire or avoidance of normal structures takes place on the CT scan acquired
plaster cast around the patient. Target volumes and patient anatomy at the time of treatment planning but may be supplemented by other
were identified and located by examining bony structures on a series imaging modalities, such as magnetic resonance imaging (MRI), PET,
of radiographs. These radiographs were typically acquired with a device or ultrasonography. Normal structures are typically defined at their
called a simulator. Originally, the simulator was a diagnostic x-ray anatomic boundaries. The volume to be treated, defined as the target
source configured to mimic the geometric beam delivery configuration volume in ICRU 60,149 is created by combining three structures: the
of a radiation therapy linac. The x-ray source is mounted on a rotating gross tumor volume (GTV), the clinical tumor volume (CTV), and
gantry, similar to a linear accelerator, with a detector rotating in the the planning target volume (PTV). The GTV includes all gross disease
opposite position on the far side of the patient. This allows fluoroscopic detectable by imaging, including visible primary tumor and involved
imaging from multiple angles, which facilitates positioning the patient lymph nodes. The CTV is an expansion of the GTV that includes
such that the center of gantry rotation can be placed in the tumor regions of possible or probable microscopic disease, including both
area. Once this position, called the isocenter, is selected, radiographs adjacent tissue and draining lymph nodes. The PTV is a further
are taken from all desired beam angles. These radiographs are taken expansion of the CTV to account for anatomic motion and expected
as a record for comparison with future portal films (taken during variations in patient daily setup. Expansions from GTV to CTV to
treatment), and as an aide for the physician in refining each beam PTV vary with disease, technique, and patient history, although
shape. Finally, room-mounted lasers indicate the location of the isocenter expansion numbers from CTV to PTV are usually on the order of
on the patient’s skin, allowing these points to be marked by a small 1 cm or less. Expansion from GTV to CTV is entirely dependent on
tattoo or similar marking. These markings can later be aligned with the biology of the clinical situation. At times, there is no GTV (such
identically placed lasers in the linear accelerator treatment room to as treatment in a postoperative setting), in which case the CTV is
position the patient on each treatment day. based entirely on the assumed high-risk areas for residual disease.
Poor soft tissue contrast from fluoroscopic imaging means that, Once target and avoidance structures have been identified and
on a conventional simulator, treatment parameters such as isocenter defined on patient images, a specific strategy for dose delivery can be
and beam boundaries can be defined only relative to visible landmarks, developed. The essential task of treatment planning is to select, arrange,
such as bony anatomic features. Subsequent techniques were developed and characterize a group of radiation beams to deliver high dose to
to use dedicated computed tomography (CT) scanners for “virtual” the tumor while keeping dose to normal structures below acceptable
simulation, replacing conventional simulators in many radiation limits. The treatment plan must be specified in terms of the total dose
oncology departments. Virtual simulation is based solely on the CT and the number of fractions in which the dose will be delivered.
scan of a patient and is made possible by the ability to reproduce any Individual beams can be customized by specifying the beam energy,
arbitrary radiograph from a CT data set. In virtual simulation, the orientation, and shape. Beams are typically shaped to match the cross
patient is placed in the orientation and position to be used for treatment section of the PTV plus some small margin in order to maximize
delivery. A CT scan is acquired, and, with the patient still positioned overlap with the tumor while limiting the amount of normal tissue
on the scanning table, the physician uses the superior soft tissue contrast directly exposed to the beam. Historically, this was accomplished by
of the CT scan to select a location for isocenter within the target area designing a customized block made from an easily cast metal alloy
(Fig. 27.19). An integrated laser system then moves to indicate the such as Cerrobend, but on modern machines is typically performed
position of the physician-selected isocenter on the patient surface, by using automated beam-shaping devices such as a multileaf collimator
allowing the external markers or tattoos to be placed for future align- (MLC; Fig. 27.20). Use of multiple beams that converge on the tumor
ment with the linear accelerator vault laser systems. This approach site helps maximize the dose received by the tumor. The appropriate
allows improved tumor localization and beam selection compared number, orientation, and relative weighting of beams in a treatment
with fluoroscopy-based conventional simulators. plan depend on geometric factors, such as the tumor’s location and
After simulation is completed, the CT scan and other images are proximity to normal structures, as well as clinical factors, such as prior
sent to a computer-based planning workstation, where the team of or planned surgery, overall patient health, prior radiation therapy,
physicians, dosimetrists, and physicists can begin the treatment planning likelihood of future irradiation, and the effects of concurrent
process. Treatment planning includes the identification of target volumes chemotherapy.
and normal structures requiring dose tracking, and the selection and A sample treatment plan must be evaluated for likely treatment
modification of beams to achieve specified dosimetric goals. The efficacy of the tumor as well as for possible toxicity to normal structures.
contouring process of identifying the boundaries of all treatments and Dosimetry can be evaluated by examining isodose lines and dose
454 Part I: Science and Clinical Oncology

A Figure 27.21  •  Four-field treatment plan for a thoracic lesion. A combina-

tion of anteroposterior and oblique fields produce isodose lines that keep the
90% dose region (yellow isodose line) away from the spinal cord and the 50%
Source dose region (blue isodose line) out of the lung.

100

Tumor
80 Liver
Spinal cord
Volume (%)

60

Multileaf collimator 40

20

0
0 20 40 60 80 100
Dose (%)

Figure 27.22  •  Dose-volume histogram expressed in terms of what percent-

age of the structure volume receives at least what percentage of the total dose.
In this example, only 10% of the spinal cord receives 15 Gy or more, whereas
Projected field almost 100% of the tumor receives 100% of the target dose.

B
Figure 27.20  •  (A) Multileaf collimator device on a linear accelerator. imposed on treating lung lesions is to limit the total volume of lung
(B) The individual collimator leaves can be adjusted to form arbitrarily shaped receiving 20 Gy or more to 30%.150 Determining appropriate dose
fields. constraints for normal structures from clinical data is critical; compila-
tions of tolerance doses for different normal tissue effects are generated
periodically as clinical data accrue, and have most recently been
volume histograms. Isodose lines are a 3D representation of dose aggregated in the QUANTEC publications.150
gradients superimposed on the patient image, and indicate regions of
high and low dose on any user-selected plane. As shown in Fig. 27.21, Intensity-Modulated Radiation Therapy
isodose lines correlate dose with anatomic location, can be used to In conventional radiation therapy, treatment plans are designed to
identify regions of insufficient or excessive dose, and depict beam deliver a roughly homogeneous dose distribution to the tumor region.
arrangements and weightings that can better meet the dosimetric goals This is most easily accomplished by covering the target with overlapping
for the plan. Aggregate dose to contoured structures is expressed as homogeneous beams. For this reason, most modern linear accelerators
dose-volume histograms, which display the percentage or absolute are designed to deliver such flat dose distributions. Attaining a
volume of the structure receiving at or below a specified dose (Fig. homogeneous dose distribution across a target can be complicated by
27.22). Most dose constrains applied to treatment planning are expressed multiple factors. For example, geometric concerns such as beam
in terms of dose-volume histograms. For example, a typical constraint obliquity or irregular patient surfaces commonly lead to uneven dose
 Basics of Radiation Therapy  •  CHAPTER 27 455

distributions across a given beam depth. In other cases, the presence and delivered in sequence without requiring the intervention of a
of a sensitive normal structure in the vicinity of the target region radiation technologist. The widespread implementation of MLCs has
might necessitate that the photon intensity be lessened across all or allowed IMRT to grow from an experimental procedure practiced at
part of a given beam. Varying the intensity of multiple radiation a small number of academic centers in the 1990s to a standard technique
beams in a manner that improves the overall homogeneity of the dose applied in clinics around the world.
to the target and helps to decrease dose to normal tissue is referred Calculating the proper intensity distributions for multiple intersect-
to as intensity-modulated radiation therapy.151 ing beams is too complex a task for human hand calculations. Rather
The simplest form of intensity modulation, wedge filters, has been than having the physician and physicist create a treatment plan by
in use in radiation therapy since the 1960s. A wedge is an angled manually selecting beam orientations and field shapes, IMRT fields
piece of high-density material that preferentially attenuates a photon are designed with computer algorithms called optimizers. The treatment
beam on its thick end, resulting in a dose gradient across the beam. planners specify the hoped-for dose distribution, expressed as dose
Wedges are often used to flatten the dose distribution for beams goals and toxicity limits, and the optimizer uses mathematical techniques
striking sloped surfaces, as illustrated in Fig. 27.23. More recently, to alter the intensity profile of each beam until the dose goals are met
complex intensity distributions have been created by combining multiple to the greatest extent possible. The first optimizers considered only
beamlets of varying intensity into a single beam having an intensity purely dosimetric goals, but efforts have been made to include biologic
profile customized to meet the needs of a specific patient (Fig. 27.24). end point models in optimization functions, such as effective uniform
The delivery of multiple beamlets for IMRT is made practical by the dose (EUD), tumor control probability (TCP), and normal tissue
development of the MLC, which allows each beamlet to be formed complication probability (NTCP). IMRT optimization has been used
in a variety of clinical circumstances and has been shown to have
clinical benefits for treatments in many anatomic sites, such as
prostate,152 lung,153 and head and neck cancers.154
Once the treatment plan has been completed, approved, peer
reviewed, and passed through a rigorous quality assurance program,
the patient is ready to begin treatment. On each treatment day the
patient must be positioned in an orientation identical to that used
during simulation, and the position within the patient designated
as the isocenter must be placed matching the center of rotation of
the linear accelerator. Rough alignment can be accomplished by
aligning the tattoos from the simulation step with in-room lasers
in the accelerator vault. For more precise alignment of the patient,
image-guided radiation therapy (IGRT) techniques can be used.
Global patient positioning can be refined using video imaging of
the patient surface155 or two-dimensional (2D) imaging of bony
anatomy (MV portal films or kV radiographs). Techniques to image
soft tissue structures to improve patient alignment include the use
of in-room CT scanners, linac-mounted cone beam CT scans,156 or
implantable fiducial markers detectable by radiograph, radiofrequency
signal157 or ultrasound.158 Adjustments to patient position based on
these techniques can be made before radiation delivery. To ensure
that the patient moves as little as possible between positioning and
Figure 27.23  •  Wedges in the opposing lateral beams for treatment of the delivery of radiation, several forms of patient immobilization may
the larynx. The thick ends of the wedges provide extra beam attenuation
where the patient is thinnest. be used.
During the delivery of radiation, the patient lies as motionless as
possible while the linear accelerator rotates around the patient from
position to position, delivering the beams specified during the treatment
planning. Treatments are delivered and supervised by radiation thera-
pists, who operate the linear accelerator and monitor the patient and
linac positions to ensure that both are in the proper orientation. A
typical treatment session lasts 10 to 15 minutes, although some cases
involving extra imaging or delivery of higher doses can last one or
more hours. Radiation delivery is undetectable by the patient because
the actual energy deposited in tissue for a typical 2-Gy fraction, although
sufficient to cause irreparable cellular damage, will raise the temperature
of the tissue by only 0.001°F.
Brachytherapy
Although not used as commonly as in the past, the use of radioactive
implants is still a standard part of the tool kit that the radiation
oncologist has at his or her disposal to deliver radiation dose precisely
where the tumor is located. This technique is most commonly used
in gynecologic tumors as well as in the treatment of prostate cancer.
For gynecologic malignancies such as cervical cancer, external radiation
therapy is initially used to treat the primary tumor in the pelvis and
Figure 27.24  •  Sample intensity-modulated radiation therapy beams for the draining lymphatics. Then an implant is used to give an even
treatment of a head and neck cancer patient. Each of the seven beams has a higher dose of radiation to the primary tumor through the use of
computer-optimized intensity distribution that combines with the other beams tubes that are placed in the uterus and vagina and subsequently loaded
in such a way as to produce highly conformal dose distributions. with radioactive sources. Although in the past it was very common
456 Part I: Science and Clinical Oncology

to use “low–dose rate” sources for the brachytherapy, delivering the to the treatment area, although in this case the sources are placed on
prescribed radiation dose continuously (in an inpatient setting) over an exterior surface. For the treatment of malignant (e.g., choroidal
2 to 4 days, it is now more common to use high–dose rate sources melanoma) and some benign conditions (e.g., pterygium) of the eye,
for therapy in which the applicators are inserted daily or weekly surface application is common. Intravascular brachytherapy deploys
and treatment is delivered over 10 to 15 minutes for approximately a radioactive seed(s) through a catheter placed in a blood vessel. This
five sessions. technique has been used to treat tumors in the liver via the hepatic
Temporary implants are also used for treatment of selected head artery where the radioactive particles are placed on special beads that
and neck squamous cell carcinomas, melanomas of the choroid in the are then embolized in the hepatic vasculature, effectively limiting the
eye, and occasionally for tumors at other anatomic sites where it is dose to the tumor area in the liver.
difficult to otherwise deliver the desired radiation dose.
Prostate brachytherapy is delivered by placing permanent radioactive Stereotactic Radiosurgery and Stereotactic Body
seeds into the prostate. Depending on the radioisotope, the treatment
is delivered over the course of months with the implanted radiation Radiation Therapy
sources continuously delivering therapy until they decay to the point Although attempts at stereotactic delivery of radiation therapy have
of barely being radioactive. Fortunately, the radiation energy deposited been considered for decades, only over the last few years has there
by these isotopes is low and the range short, so there is minimal public been a marked increase in use of this approach. Whereas conventional
health risk or risk to family members. This is probably the most EBRT is designed to preserve the normal tissue that is being irradiated,
cost-effective way to definitively treat early-stage prostate cancer and the intent with radiosurgical approaches is to fully ablate a small
is very effective because of the high dose of radiation therapy delivered amount of tissue that includes the tumor. Depending on the precise
to the prostate. location, if the volume irradiated to a high, ablative dose is small, the
likelihood of clinically significant injury is low, similar to what would
Simulation, treatment planning, and delivery of brachytherapy be expected with surgical excision. This technique is entirely dependent
The short range of radiation from most brachytherapy sources confines on very precise dose localization and the use of many radiation beams
the majority of the dose to the immediate vicinity of the sources so that only the tumor and immediately adjacent tissues receive a
themselves, allowing highly conformal dose distributions through the high dose.
careful placement of sources within or near the target volume. This The reason this approach has an advantage over surgery is that no
arrangement allows a degree of sparing of nearby normal structures surgical procedure (with its attendant risks) is actually required. In
that may be superior to that achievable with EBRT. Because of the addition, radiosurgery can often ablate tumors that are not easily
high degree of conformity involved, brachytherapy is most effective accessible by conventional surgery. Treatment is usually given in one
for relatively small, well-localized tumors. The majority of radionuclides to five sessions, although more can be used in special situations.
used for radiation therapy use γ-ray photon emission as the primary Typically, very large doses (often 20 Gy) are used for single-fraction
source of therapeutic energy. Early brachytherapy procedures used therapy, doses that otherwise could not be used for standard external
radium or radon sources, but these have been almost completely beam therapy with larger treatment volumes because of the high risk
replaced by safer, artificially produced radionuclides such as cesium-137, of normal tissue complications. For multifraction therapy, common
iridium-192, iodine-125, and palladium-103 (see Table 27.1). fractionation schemes include three fractions of 7 to 15 Gy each, or
Brachytherapy sources are typically surrounded by multiple layers of four or five fractions of 5 to 12 Gy or more.
inert material. The inert layers prevent leakage of the radioactive Stereotactic radiosurgery refers to a single-fraction delivery of a
material and, for photon sources, absorb unwanted decay products high dose to an intracranial target. The term radiosurgery was coined
such as alpha particles and electrons. Brachytherapy can either be in 1951160 by a neurosurgeon named Lars Leskel, who developed
delivered over a short period of time (temporary implant) or gradually the original techniques for SRS in the 1940s by using orthovoltage
over the lifetime of the seeds (permanent implant). x-rays. Since that time, patients undergoing SRS have been treated
Brachytherapy treatments are delivered with either interstitial or with heavy charged particles, megavoltage x-rays, and γ-rays from
intracavitary techniques. In interstitial brachytherapy, radioactive seeds radioactive sources. The Gamma Knife was the first widely used
are surgically placed within the tumor volume, with the seed placement technique, using a large number of 60Co sources. Over the subsequent
being either temporary or permanent. Permanent seeds are deposited decades, the use of SRS has been documented in more than 4000
in the tumor volume with needles. Temporary seeds are placed and publications161 demonstrating the effectiveness of the technique in
removed from the tumor volume through implanted catheters. Early- treating primary and metastatic brain lesions, as well as nonmalignant
stage prostate cancer is commonly treated with a permanent interstitial functional disorders such as arteriovenous malformations and trigeminal
implant composed of approximately 100 iodine-125 seeds, each the neuralgias.
size of a grain of rice. A temporary interstitial implant typically uses Although the first radiosurgical approaches were designed for
fewer seeds—for example, MammoSite therapy for partial breast treatment of intracranial lesions, the same technique is now used for
irradiation, which employs a single iridium-192 seed applied through multiple anatomic sites, termed stereotactic body radiation therapy
a catheter.159 (SBRT). The ability to deliver radiation in this manner is critically
Intracavity treatment is the other common technique used for dependent on the development of hardware and computer software
brachytherapy. In this form of brachytherapy, seeds are placed in to design a large number of radiation beams that intersect at the
existing body cavities in the vicinity of the tumor volume. Radioac- tumor. There are now a number of different approaches using linear
tive seeds are deployed in catheters arranged in specially designed accelerators for delivering x-rays stereotactically.
applicators that are inserted into the appropriate cavity. Intracavitary The uses of SRS and SBRT, including treatment of brain metastases
treatment is most commonly used for treatment of gynecologic cancers and other intracranial tumors, and of isolated lesions in the lung,
but may also be used in other sites such as the nasopharynx, the liver, kidney, prostate, and vertebral bodies, are increasing as the
biliary tree, or the esophagus. Intracavitary brachytherapy treatments technology and our understanding of the biology of ablative radiation
are always temporary, ranging in duration from a few minutes to doses both improve. One area of great interest in this regard is the
several days. treatment of oligometastatic disease—characterized by only a small
Two additional brachytherapy techniques include surface application number of metastatic sites—in either the liver, lung, or brain or
and intravascular brachytherapy. Surface application of brachytherapy elsewhere. It is now clear that many patients can be cured by eradication
sources is conceptually similar to intracavitary treatment, in that the of oligometastatic disease (or conversely, a few foci of primary tumor).
radioactive sources are placed in an applicator and positioned adjacent Stereotactic approaches are ideal for this type of therapy.
 Basics of Radiation Therapy  •  CHAPTER 27 457

Physics of stereotactic radiosurgery and stereotactic Nevertheless, all these techniques increase the uncertainty of beam
body radiation therapy delivery, meaning larger margins around the GTV and consequently
As previously discussed, the long fractionation schemes used in EBRT larger volumes of irradiated normal tissue. In part, this explains why
(e.g., 2-Gy doses delivered in 30–40 daily fractions) are designed to SBRT treatments are typically delivered in three to five fractions rather
give normal tissue a chance to recover while still delivering a clinically than as single doses.
useful dose to the tumor. While this approach helps minimize normal
tissue toxicity, tumor control could be increased further by using large Intraoperative Radiation Therapy
doses in fewer fractions. These large doses, however, are highly toxic In oncologic surgery, it is not always possible to remove all cancer-
to normal tissues as well as tumors, so hypofractionated treatments ous tissue during the procedure. Presumed microscopic infiltration
such as SRS and SBRT can be delivered safely and within normal of cancer cells into the tumor bed and/or portions of the tumor left
tissue tolerance only under the following conditions: unresected because of excessive risk of morbidity can be treated in
the operating room with short-range radiation. IORT was attempted
1. Well-circumscribed tumors (minimal or no CTV expansion) as early as 1909163 but did not become a mature treatment modality
2. Minimal treatment margin around the lesion (minimal PTV until the 1980s. In IORT, a large, single dose of radiation is delivered
expansion) to an exposed tumor or tumor bed for the purpose of improving
3. Rapid dose fall-off away from the target area the probability of local control. Performing the irradiation during
4. Very precise (1–5 mm) targeting and localization of the tumor the surgical procedure allows sensitive normal structures to be surgi-
cally moved out of the beam path, minimizing the dose received by
The single-fraction doses in SRS are sufficient to sterilize any healthy tissue.
tissue, cancerous or otherwise, so great care must be taken to produce Radiation oncologists have been delivering radiation therapy in
a high-dose region that is tightly conformal to the target area, and to conjunction with surgery for many years; techniques to best accom-
deliver the dose to the correct location in the patient. As shown in plish this continue to evolve. The use of electrons (or sometimes
Fig. 27.25A, highly conformal dose distributions can be created using orthovoltage x-rays) delivered intraoperatively, when a tumor or
100 to 200 overlapping beams or by delivering dose continuously as tumor bed is exposed, has the potential to allow direct visualiza-
a linear accelerator moves around the patient in one or more arcs tion of the tissues that need to be treated as well as the ability to
(Fig. 27.25B). Positioning the patient correctly relative to the beams control the depth of penetration of the radiation beam by varying the
requires much stricter immobilization than is typically used for EBRT. electron energy.
Traditionally, patients would be placed in a rigid stereotactic head frame IORT usually requires a dedicated irradiator in the operating room,
which would then be positioned relative to the radiation beams by and so is available only at specialized centers. It is best suited for the
affixing the frame to either the treatment table or a room-mounted treatment of deep-seated tumors, but where there are severe limitations
pedestal. The frame, which is affixed to the patient’s skull before on the ability of the surgeon to excise completely all the tissues at
patient imaging, provides a known offset between radiation isocenter high risk of tumor involvement. Radiation is delivered in a single
and the tumor location, allowing dose delivery with an accuracy of session at a dose on the order of 10 to 15 Gy. This is often preceded
approximately 1 mm. Newer SRS immobilization techniques have or followed by a course of standard EBRT, with the intraoperative
been able to approach the accuracy of stereotactic frames without component viewed as a radiation boost. IORT has been used most
requiring fixation to the patient’s skull, having the advantages of commonly for intraabdominal tumors, and especially for recurrent
being less invasive and more reproducible if fractionation is war- tumors in the pelvis, such as recurrent rectal cancer. It may have a
ranted. Examples of these techniques include vacuum-based frame role in the treatment of retroperitoneal sarcomas and has been evaluated
fixation to the hard palate, and IGRT-intensive frameless radiosurgery. for the treatment of pancreatic and breast cancers. In addition, IORT
SRS can be delivered to multiple tumor sites in the brain during has been delivered using low-energy (orthovoltage), low-penetrability
a single treatment and is generally limited to well-defined lesions x-rays to the tumor bed of small or superficial cancers, and in combina-
2 cm or smaller. tion with brachytherapy techniques.
SBRT is hypofractionated treatment applied to extracranial targets, In a typical IORT treatment, the surgeon performs the opening
such as in the abdomen or pelvis or the spine. SBRT has a much incision and removes as much of the suspected cancerous tissue as
shorter history than SRS; the first clinical outcomes for SBRT were possible. The patient is then moved into position under the linac,
reported in 1995.162 Early SBRT studies focused on the treatment of and the appropriate electron beam energy is selected based on the
lung and liver lesions, but more recent efforts have included studies desired depth of treatment. An applicator cone is attached to limit
of spine, prostate, kidney, pancreas, and gynecologic cancers. The the beam to the intended area; the tumor bed and other high-risk
delayed development of SBRT relative to SRS is largely due to difficul- tissues are aligned with the beam and then irradiated. After the desired
ties with target localization. For example, whereas intracranial lesions dose has been delivered, the patient is moved away from the linac,
can be expected to maintain a constant position relative to the patient’s and the surgical team completes the operation.
skull, soft tissue lesions in the body can move relative to bony anatomy
or any external markers used for patient setup. Minimizing this Specialized Radiation Therapy Techniques and Facilities
uncertainty requires the use of in-room imaging to ensure accurate There is great interest in the use of protons, neutrons, or other high-
beam delivery. Soft tissue imaging can be facilitated by implanting energy particles for radiation therapy. Although treatment with photon
radiographically visible fiducial markers in the region of the tumor. beams is the most common form of radiation therapy, particle beam
Today, in-room imaging (IGRT) has largely replaced the use of ste- therapy also has many clinically useful properties.
reotactic body frames for SBRT. As discussed earlier in this chapter, light charged particles such as
Tumors in the thoracic or abdominal cavity also move during beam electrons lose their energy gradually, depositing dose approximately
delivery because of respiratory motion. Techniques for minimizing evenly as the beam passes through tissue. This continues until all
this include: energy is expended, at which point the dose delivery stops abruptly, as
illustrated in Fig. 27.3. Therapeutic electrons are limited to treatment
1. Gating, in which dose is only delivered during a small portion of depths of 5 to 6 cm, meaning they can be used only for relatively
the breathing cycle shallow lesions. Furthermore, electrons can scatter at large angles,
2. Tracking, in which the beam delivery device moves with the target causing the beam to spread as it passes through tissue, blurring
3. Immobilization, in which patient breathing is regulated or limited the edges of the dose distribution. This makes precision dosimetry
to reduce the degree of tumor motion difficult.
458 Part I: Science and Clinical Oncology

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 linac-based arc therapy. (A) Gamma Knife consists of more than 200 cobalt-60 sources arranged and collimated to overlap at a single point. (B) Linac-based
radiosurgery uses a head frame or other device to immobilize the patient’s skull such that the target is located as close as possible to isocenter. The linac delivers
beam continuously as the gantry rotates in an arc around the patient, producing an effect similar to a large number of overlapping beams.
 Basics of Radiation Therapy  •  CHAPTER 27 459

These limitations can be overcome through the use of heavier

charged particles, such as protons, neutrons, or heavy ions. The use
Modulated
of heavier particles has several advantages: proton beam SOBP
100
1. Heavier particles scatter at smaller angles, allowing less blurring
and more precise dose delivery.
2. They typically have a higher LET, leading to greater biologic 80

Relative dose (%)

effectiveness than an equivalent energy deposition from standard
photon or electron beams. 10-MV x-rays
3. For particles such as protons, the distal end of the dose distribution 60
is very sharp, allowing much more accuracy in avoiding irradiation
of normal tissues deep to the tumor.
40
Protons
Protons are charged particles that can be accelerated and directed into
20 Unmodulated
tissue where they deposit their energy. Proton therapy is the most proton beam
common type of heavy particle radiation therapy. The advantage that
protons have over conventional x-rays is that they deliver a low dose
0
to superficial (normal) tissues, a high radiation dose at depth where
the tumor is, and then virtually no exit dose to normal tissues beyond 0 4 8 12 16
the tumor. This is the opposite of what happens with x-rays, Depth in tissue (cm)
where the highest dose (from a single beam) is delivered to more
superficial tissues. The RBE for protons is approximately 1.1, so they Figure 27.26  •  Depth-dose comparison of 10-MV x-rays and unmodulated
are only slightly more biologically effective than x-rays or electrons; and modulated proton beams. Monoenergetic (unmodulated) proton beams
this means that the principal advantage of proton therapy is improved produce narrow regions of high dose, often requiring beam modulation to
dose distributions. spread the dose distribution over a wider range. Both unmodulated and
Proton beams are produced by accelerating ionized hydrogen in a modulated proton beams compare favorably to photon beams for minimizing
cyclotron or synchrotron to energies in excess of 160 MeV. These dose both upstream and downstream of the target area. SOBP, Spread-out
machines are considerably larger and more expensive than conventional Bragg peak.
linear accelerators, so they tend to be incorporated into stand-alone
facilities (although research into smaller-scale proton irradiators is
ongoing). Unlike electrons, which lose energy roughly evenly across
the range of therapeutic energies, protons lose their energy at an discussed; these interactions can cause low-energy protons and heavier
increasing rate as the beam loses energy with depth. This effect cul- ions to be ejected during collisions between neutrons and target nuclei.
minates in a region of rapid dose deposition near the depth of maximum These ejected particles cause biologic damage in accordance with their
penetration, called the Bragg peak (see Fig. 27.25). The depth of the LET. Neutron beams therefore have an energy-dependent, average
Bragg peak increases with beam energy, allowing careful energy selection RBE that can vary between 5 and 20 depending on the biologic or
to ensure that the highest dose is delivered to the tumor volume, with clinical end point, meaning that they are more potent biologically
lower doses upstream of the target, and negligible doses downstream and are characterized by a lower OER.
of the target. The width of the Bragg peak is virtually always narrower Neutrons have no dose distribution advantage over x-rays and in
than the region to be targeted, requiring a range of proton energies fact have a disadvantage in dose delivery, but they do have the potential
to “paint” high, uniform doses across the target. This widened dose to more effectively destroy certain tumors that are relatively radiore-
distribution, known as a spread-out Bragg peak (SOBP), can be created sistant and/or slow growing, including melanomas, sarcomas, and
either by varying the proton beam energy in a synchrotron or by salivary gland tumors. There have been many clinical studies of neutron
using a spinning modulator of varying thickness to selectively vary radiation therapy, yet it has been difficult to find a clear-cut advantage
the beam energy, shown in Fig. 27.26. to this approach over more conventional treatment methods.
The largest clinical experience with the use of proton radiation
therapy has been for the treatment of prostate cancer. However, although Heavy ions
there is a theoretical advantage of proton therapy at this site, that There has been a long-standing interest in use of other heavy charged
advantage has never been demonstrated through clinical trials.164 Protons particles such as accelerated carbon or neon ions for therapeutic
are very appealing for the treatment of certain pediatric tumors because purposes, and that interest continues to the present day. These particles
the effects of unwanted irradiation of normal tissues can be severe. have the potential to combine both the biologic advantages of neutrons
In this context, protons have been used extensively in the treatment and the dose distribution advantage of protons. Machines to produce
of pediatric central nervous system tumors.165 Studies exploring the these particles and associated operating costs are very expensive, however,
use of protons for therapy of lung cancer and tumors at other anatomic and that has substantially limited their development and use to only
sites are ongoing. The cost of a proton irradiator (and its specialized a handful of facilities worldwide.166,167
facility) is far greater than for traditional x-ray and electron linear
accelerators, so it is incumbent on those who use protons for radiation FUTURE DIRECTIONS
therapy to demonstrate that the extra expense translates into better
tumor control rates and/or fewer normal tissue complications. The The practice of radiation therapy has advanced enormously over
lack of such Level I evidence to date has made many concerned about the last 25 years, allowing more accurate tumor localization and
the rapid proliferation of proton facilities. more precise dose delivery to the volume of interest while minimiz-
ing exposure to normal tissues. Most of these advances have been
Neutrons technologic, and in all likelihood more will be forthcoming. There
Neutrons are heavy particles that lack an electric charge. They are is, for example, growing interest in melding biology with therapy
also produced by specialized irradiators. Neutrons interact with matter in the form of improved biologic definition of the tumor by using
through different mechanisms than the photons and particles previously functional imaging. Further elucidation of tumor molecular subtypes
460 Part I: Science and Clinical Oncology

should allow us to define better which patients are at higher risk for in clinical practice in the future by enhancing the selective killing of
local recurrence and who therefore require additional local therapy, tumor cells.
or which patients will benefit from various combination treatments.
It is also clear that combinations of radiation therapy and biologicals The complete reference list is available online at
(as well as new cytotoxic agents) will have a substantially greater role ExpertConsult.com.

KEY REFERENCES
18. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy radiotherapy. J Natl Cancer Inst. 1968;40:441– phase III trial (AVAiL). Ann Oncol. 2010;21:1804–
plus cetuximab for squamous-cell carcinoma of the 451. 1809.
head and neck. N Engl J Med. 2006;354:567–578. 79. Chaplin DJ, Durand RE, Olive PL. Acute hypoxia 125. Chalmers AJ, Lakshman M, Chan N, et al. Poly
26. Ellis LM, Hicklin DJ. VEGF-targeted therapy: in tumors: implication for modifiers of radiation (ADP-ribose) polymerase inhibition as a model for
mechanisms of anti-tumour activity. Nat Rev Cancer. effects. Int J Radiat Oncol Biol Phys. 1986;12:1279– synthetic lethality in developing radiation oncology
2008;8:579–591. 1282. targets. Semin Radiat Oncol. 2010;20:274–281.
27. Ebos J, Kerbel R. Antiangiogenic therapy: impact 81. Terasima T, Tolmach LJ. Changes in x-ray sensitivity 134. Tubiana M. Can we reduce the incidence of second
on invasion, disease progression, and metastasis. Nat of HeLa cells during the division cycle. Nature. malignancies occurring after radiotherapy? A critical
Rev Clin Oncol. 2011;8:210–221. 1961;190:1210–1211. review. Radiother Oncol. 2009;91:4–15.
31. Pilones KA, Vanpouille-Box C, Demaria S. Com- 93. Dische S. Chemical sensitizers for hypoxic cells: 135. Travis LB, Hill DA, Dores GM, et al. Breast cancer
bination of radiotherapy and immune checkpoint a decade of experience in clinical radiotherapy. following radiotherapy and chemotherapy among
inhibitors. Semin Radiat Oncol. 2015;25:28–33. Radiother Oncol. 1985;3:97–115. young women with Hodgkin’s disease. JAMA.
38. Puck TT, Marcus PI. Action of X-rays on mammalian 94. Overgaard J, Hansen HS, Overgaard M, et al. 2003;290:465–475.
cells. J Exp Med. 1956;103:653–666. A randomized double-blind phase III study of 136. De Bruin ML, Sparidans J, Van’t Veer MB, et al.
46. Fowler JF, Morgan RL, Silvester JA, et al. Experi- nimorazole as a hypoxic radiosensitizer of primary Breast cancer risk in female survivors of Hodgkin’s
ments with fractionated x-ray treatment of the skin radiotherapy in supraglottic larynx and pharynx lymphoma: lower risk after smaller radiation
of pigs. I. Fractionation up to 28 days. Br J Radiol. carcinoma. Results of the Danish Head and Neck volumes. J Clin Oncol. 2009;27:4239–4246.
1963;36:188–196. Cancer Study (DAHANCA) Protocol 5-85. Radiother 138. Withers HR, Taylor JMG, Maciejewski B. Treatment
47. Thomlinson RH, Gray LH. The histological Oncol. 1998;46:135–146. volume and tissue tolerance. Int J Radiat Oncol Biol
structure of some human lung cancers and the 96. Brown JM. SR 4233 (Tirapazamine): a new Phys. 1988;14:751–759.
possible implications for radiotherapy. Br J Cancer. anticancer drug exploiting hypoxia in solid tumors. 140. Thames HD, Withers HR, Peters LJ, Fletcher G.
1955;9:539–549. Br J Cancer. 1993;67:1163–1170. Changes in early and late radiation responses with
48. Höckel M, Knoop C, Schlenger K, et al. Intratu- 105. Wilson GD, Bentzen SM, Harari PM. Biologic basis altered dose fractionation: implications for dose-
moral Po2 predicts survival in advanced cancer of for combining drugs with radiation. Semin Radiat survival relationships. Int J Radiat Oncol Biol Phys.
the uterine cervix. Radiother Oncol. 1993;26:45–50. Oncol. 2006;16:2–9. 1982;8:219–226.
49. Nordsmark M, Bentzen SM, Rudat V, et al. Prog- 106. Moertel CG. Chemotherapy for colorectal cancer. 142. Thames HD, Bentzen SM, Turesson I, et al. Time-
nostic value of tumor oxygenation in 397 head and N Engl J Med. 1994;330:1136–1142. dose factors in radiotherapy: a review of human
neck tumors after primary radiation therapy. An 110. Ajani JA, Winter KA, Gunderson LL, et al. Fluoro- data. Radiother Oncol. 1990;19:219–235.
international multi-center study. Radiother Oncol. uracil, mitomycin, and radiotherapy vs fluorouracil, 143. Fowler JF. The James Kirk Memorial Lecture. What
2005;77:18–24. cisplatin, and radiotherapy for carcinoma of the next in fractionated radiotherapy? Br J Cancer.
64. Bernier J, Hall EJ, Giaccia A. Radiation oncol- anal canal: a randomized controlled trial. JAMA. 1984;46(suppl):285–300.
ogy: a century of achievements. Nat Rev Cancer. 2008;299:1914–1921. 152. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose
2004;4:737–747. 111. Stupp R, Hegi ME, Mason WP, et al. Effects of intensity modulated radiation therapy for prostate
66. Coutard H. Roentgen therapy of epitheliomas of the radiotherapy with concomitant and adjuvant cancer: early toxicity and biochemical outcome
tonsillar region, hypopharynx and larynx from 1920 temozolomide versus radiotherapy alone on survival in 772 patients. Int J Radiat Oncol Biol Phys.
to 1926. AJR Am J Roentgenol. 1932;28:313–331. in glioblastoma in a randomised phase III study: 2002;53:1111–1116.
67. Withers HR. The four R’s of radiotherapy. In: 5-year analysis of the EORTC-NCIC trial. Lancet 161. Benedict SH, Yenice KM, Followill D, et al. Stereo-
Adler H, Lett JT, Zelle M, eds. Advances in Oncol. 2009;10:459–466. tactic body radiation therapy: the report of AAPM
Radiation Biology. vol. 5. New York: Academic 112. Willett CG, Duda DG, di Tomaso E, et al. Complete Task Group 101. Med Phys. 2010;37:4078–4101.
Press; 1975:241–271. pathological response to bevacizumab and chemo- 164. Shipley WU, Verhey LJ, Munzenrider JE, et al.
68. Elkind MM, Sutton H. X-ray damage and recovery radiation in advanced rectal cancer. Nat Clin Pract Advanced prostate cancer: the results of a randomized
in mammalian cells. Nature. 1959;184:1293–11295. Oncol. 2007;4:316–321. comparative trial of high dose irradiation boosting
71. Denekamp J. Changes in the rate of proliferation 113. Folkman J. Tumor angiogenesis: therapeutic with conformal protons compared with conventional
in normal tissues after irradiation. In: Nygaard O, implications. N Engl J Med. 1971;285:1182– dose irradiation using photons alone. Int J Radiat
Adler HI, Sinclair WK, eds. Radiation Research: 1186. Oncol Biol Phys. 1995;32:3–12.
Biomedical, Chemical and Physical Perspectives. New 120. Willett CG, Duda DG, Czito BG, et al. Targeted 165. Allen AM, Pawlicki T, Dong L, et al. An evidence
York: Academic Press, Inc.; 1975:810–825. therapy in rectal cancer. Oncology (Williston Park). based review of proton beam therapy: the report of
72. Withers HR, Taylor JMG, Maciejewski B. The hazard 2007;21:1055–1065. ASTRO’s emerging technology committee. Radiother
of accelerated tumor clonogen repopulation during 121. Reck M, von Pawel J, Zatloukal P, et al. Overall Oncol. 2012;103:8–11.
radiotherapy. Acta Oncol. 1988;27:131–146. survival with cisplatin-gemcitabine and bevacizumab 166. Jensen AD, Munter MW, Debus J. Review of clinical
78. van Putten LM, Kallman RF. Oxygenation status or placebo as first-line therapy for nonsquamous experience with ion beam radiotherapy. Br J Radiol.
of a transplantable tumor during fractionated non–small-cell lung cancer: results from a randomised 2011;84(suppl):S35–S47.
 Basics of Radiation Therapy  •  CHAPTER 27 460.e1

REFERENCES
1. Roentgen WC. Uber eine neue art von strahlen. combined dabrafenib and trametinib. N Engl J 48. Höckel M, Knoop C, Schlenger K, et al. Intratu-
Sitzgsber Physik-Med Ges Wuerzburg. 1895;137: Med. 2015;372:30–39. moral Po2 predicts survival in advanced cancer of
132–141. 25. Zhong H, Bowen JP. Recent advances in small the uterine cervix. Radiother Oncol. 1993;26:45–50.
2. Becquerel H. Emission of the new radiations by metal- molecule inhibitors of VEGF and EGFR signaling 49. Nordsmark M, Bentzen SM, Rudat V, et al. Prog-
lic uranium. CR Acad Sci. 1896;122:1086–1088. pathways. Curr Top Med Chem. 2011;11:1571–1590. nostic value of tumor oxygenation in 397 head and
3. Curie P, Curie MS. Sur une substance nouvelle 26. Ellis LM, Hicklin DJ. VEGF-targeted therapy: neck tumors after primary radiation therapy. An
radioactive, contenue dans la pechblende. CR Acad mechanisms of anti-tumour activity. Nat Rev Cancer. international multi-center study. Radiother Oncol.
Sci. 1898;127:175–178. 2008;8:579–591. 2005;77:18–24.
4. Hutchinson F. Molecular basis for action of ionizing 27. Ebos JM, Kerbel RS. Antiangiogenic therapy: impact 50. Zeman EM, Calkins DP, Cline JM, et al. The
radiations. Science. 1961;134:533–538. on invasion, disease progression, and metastasis. Nat relationship between proliferative and oxygenation
5. Cornforth MN, Bedford JS. A quantitative com- Rev Clin Oncol. 2011;8:210–221. status in spontaneous canine tumors. Int J Radiat
parison of potentially lethal damage repair and 28. Mellman I, Coukos G, Dranoff G. Cancer immu- Oncol Biol Phys. 1993;27:891–898.
the rejoining of interphase chromosome breaks in notherapy comes of age. Nature. 2011;480:480–489. 51. Kennedy AS, Raleigh JA, Perez GM, et al. Pro-
low passage normal human fibroblasts. Radiat Res. 29. Hodi FS, O’day SJ, Mcdermott DF, et al. Improved liferation and hypoxia in human squamous cell
1987;111:385–405. survival with ipilimumab in patients with metastatic carcinoma of the cervix: first report of combined
6. Friedberg EC, Walker GC, Siede W, Wood RD, melanoma. N Engl J Med. 2010;363:711–723. immunohistochemical assays. Int J Radiat Oncol Biol
Schultz RA, Ellenberger T. DNA Repair and 30. Brahmer JR, Pardoll DM. Immune checkpoint inhibi- Phys. 1997;37:897–905.
Mutagenesis. Washington, DC: ASM Press; 2006. tors: making immunotherapy a reality for the treat- 52. Nordsmark M, Loncaster J, Aquino-Parsons C, et al.
7. Borchiellini D, Etienne-Grimaldi MC, Thariat J, ment of lung cancer. Cancer Immunol Res. 2013;1: Measurements of hypoxia using pimonidazole and
Milano G. The impact of pharmacogenetics on 85–91. polarographic oxygen-sensitive electrodes in human
radiation therapy outcome in cancer patients. A 31. Pilones KA, Vanpouille-Box C, Demaria S. Com- cervix carcinomas. Radiother Oncol. 2003;67:35–44.
focus on DNA damage response genes. Cancer Treat bination of radiotherapy and immune checkpoint 53. Evans SM, Hahn S, Pook DR, et al. Detection of
Rev. 2012;38:737–759. inhibitors. Semin Radiat Oncol. 2015;25:28–33. hypoxia in human squamous cell carcinoma by EF5
8. Wood RD, Mitchell M, Lindahl T. Human DNA 32. Vatner RE, Cooper BT, Vanpouille-Box C, et al. binding. Cancer Res. 2000;60:2018–2024.
repair genes. Mutat Res. 2005;577:275–283. Combinations of immunotherapy and radiation in 54. Hall EJ, Giaccia AJ. Radiobiology for the Radiologist.
9. Kastan MB, Bartek J. Cell-cycle checkpoints and cancer therapy. Front Oncol. 2014;4:325. 7th ed. Philadelphia: Lippincott Williams & Wilkins;
cancer. Nature. 2004;432:316–323. 33. Demaria S, Pilones KA, Vanpouille-Box C, et al. 2012.
10. Jackson SP, Bartek J. The DNA-damage The optimal partnership of radiation and immu- 55. Joiner M, van der Kogel A, eds. Basic Clinical
response in human biology and disease. Nature. notherapy: from preclinical studies to clinical Radiobiology. 4th ed. London: Hodder Arnold;
2009;461:1071–1078. translation. Radiat Res. 2014;182:170–181. 2009.
11. Fitzgerald TJ, Daugherty C, Kase K, et al. Activated 34. Ishihara D, Pop L, Takeshima T, et al. Rationale 56. Vordermark D, Brown JM. Endogenous markers
human n-ras oncogene enhances x-irradiation repair and evidence to combine radiation therapy and of tumor hypoxia: predictors of clinical radiation
of mammalian cells in vitro less effectively at low immunotherapy for cancer treatment. Cancer resistance? Strahlenther Onkol. 2003;179:801–811.
dose rate. Implications for increased therapeutic Immunol Immunother. 2016;Oct 14. [Epub ahead 57. Hoogsteen IJ, Marres HA, Bussink J, et al. Tumor
ratio of low dose rate irradiation. Am J Clin Oncol. of print.]. microenvironment in head and neck squamous cell
1985;8:517–522. 35. Formenti SC, Demaria S. Systemic effects of local carcinomas: predictive value and clinical relevance
12. Sklar MD. The ras oncogenes increase the intrinsic radiotherapy. Lancet Oncol. 2009;10:718–726. of hypoxic markers. A review. Head Neck. 2007;29:
resistance of NIH 3T3 cells to ionizing radiation. 36. Demaria S, Golden EB, Formenti SC. Role of local 591–604.
Science. 1988;239:645–647. radiation therapy in cancer immunotherapy. JAMA 58. Vordermark D, Katzer A, Baier D, Kraft P, Flentje
13. Rusconi P, Caiola E, Broggini M. RAS/RAF/ Oncol. 2015;1:1325–1332. M. Cell type-specific association of hypoxia-inducible
MEK inhibitors in oncology. Curr Med Chem. 37. Galluzzi L, Vitale I, Abrams JM, et al. Molecular factor-1 alpha (HIF-1α) protein accumulation and
2012;19:1164–1176. definitions of cell death subroutines: recommenda- radiobiologic tumor hypoxia. Int J Radiat Oncol Biol
14. Berndt N, Hamilton AD, Sebti SM. Targeting tions of the nomenclature committee on cell death Phys. 2004;58:1242–1250.
protein prenylation for cancer therapy. Nat Rev 2012. Cell Death Differ. 2012;19:107–120. 59. Olive PL, Aquino-Parsons C, Macphail SH, et al.
Cancer. 2011;11:775–791. 38. Puck TT, Marcus PI. Action of X-rays on mammalian Carbonic anhydrase 9 as an endogenous marker
15. Thompson H. Us National Cancer Institute’s cells. J Exp Med. 1956;103:653–666. for hypoxic cells in cervical cancer. Cancer Res.
new RAS project targets an old foe. Nat Med. 39. Lea DE. Actions of Radiation on Living Cells. 2001;61:8924–8929.
2013;19:949–950. Cambridge: Cambridge University Press; 1946. 60. Airley R, Loncaster J, Davidson S, et al. Glucose
16. Bernier J. Drug insight: cetuximab in the treat- 40. Alper T. Keynote address: survival curve models. transporter glut-1 expression correlates with tumor
ment of recurrent and metastatic squamous cell In: Meyn RE, Withers HR, eds. Radiation Biology hypoxia and predicts metastasis-free survival in
carcinoma of the head and neck. Nat Clin Pract in Cancer Research. New York: Raven Press; 1980: advanced carcinoma of the cervix. Clin Cancer Res.
Oncol. 2008;5:705–713. 3–18. 2001;7:928–934.
17. Dequanter D, Shahla M, Paulus P, et al. The role of 41. Kellerer AM, Rossi HH. The theory of dual radiation 61. Airley R, Loncaster J, Raleigh JA, et al. GLUT-1 and
EGFR-targeting strategies in the treatment of head action. Curr Top Radiat Res Q. 1972;8:85–158. CA-IX as intrinsic markers of hypoxia in carcinoma
and neck cancer. Onco Targets Ther. 2012;5:127–131. 42. Chadwick KH, Leenhouts HP. A molecular theory of the cervix: relationship to pimonidazole binding.
18. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy of cell survival. Phys Med Biol. 1973;18:78–87. Int J Cancer. 2003;104:85–91.
plus cetuximab for squamous-cell carcinoma of the 43. Hewitt HB, Wilson CW. A survival curve for cells 62. Cooper R, Sarioglu S, Sokmen S, et al. Glucose trans-
head and neck. N Engl J Med. 2006;354:567–578. irradiated in vivo. Nature. 1959;183:1060–1061. porter-1 (GLUT-1): a potential marker of prognosis
19. Vecchione L, Jacobs B, Normanno N, et al. EGFT- 44. Till JE, McCulloch EA. A direct measurement of the in rectal carcinoma? Br J Cancer. 2003;89:870–876.
targeted therapy. Exp Cell Res. 2011;317:2765–2771. radiation sensitivity of normal mouse bone marrow 63. Bache M, Kappler M, Said HIM, et al. Detection
20. Cho BC, Im CK, Park MS, et al. Phase II study cells. Radiat Res. 1961;14:213–221. and specific targeting of hypoxic regions within solid
of erlotinib in advanced non–small-cell lung 45. Withers HR. The dose-survival relationship for tumors: current preclinical and clinical strategies.
cancer after failure of gefitinib. J Clin Oncol. irradiation of epithelial cells of mouse skin. Br J Curr Med Chem. 2008;15:322–338.
2007;25:2528–2533. Radiol. 1967;40:187–194. 64. Bernier J, Hall EJ, Giaccia A. Radiation oncol-
21. Mandala M, Voit C. Targeting BRAF in melanoma: 46. Fowler JF, Morgan RL, Silvester JA, et al. Experiments ogy: a century of achievements. Nat Rev Cancer.
biological and clinical challenges. Crit Rev Oncol with fractionated x-ray treatment of the skin of pigs. 2004;4:737–747.
Hematol. 2013;87:239–255. I. Fractionation up to 28 days. Br J Radiol. 1963;36: 65. Regaud C, Ferroux R. Discordance des effets de
22. Chapman PB, Hauschild A, Robert C, et al. 188–196. rayons x, d’une part dans le testicule, par le peau,
Improved survival with vemurafenib in melanoma 47.  Thomlinson RH, Gray LH. The histological structure d’autre part dans la fractionnement de la dose. CR
with BRAF v600e mutation. N Engl J Med. of some human lung cancers and the possible Soc Biol. 1927;97:431–434.
2011;364:2507–2516. implications for radiotherapy. Br J Cancer. 1955;9: 66. Coutard H. Roentgen therapy of epitheliomas of the
23. Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib 539–549. tonsillar region, hypopharynx and larynx from 1920
in BRAF-mutated metastatic melanoma: a multi- 47a. Gatenby RA, Kessler HB, Rosenblum JS, et al. to 1926. AJR Am J Roentgenol. 1932;28:313–331.
centre, open-label, phase 3 randomised controlled Oxygen distribution in squamous cell carcinoma 67. Withers HR. The four R’s of radiotherapy. In:
trial. Lancet. 2012;380:358–365. metastases and its relationship to outcome of Adler H, Lett JT, Zelle M, eds. Advances in
24. Robert C, Karaszewska B, Schachter J, et al. radiation therapy. Int J Radiat Oncol Biol Phys. Radiation Biology. vol. 5. New York: Academic
Improved overall survival in melanoma with 1988;14:831–838. Press; 1975:241–271.
460.e2 Part I: Science and Clinical Oncology

68. Elkind MM, Sutton H. X-ray damage and recovery 91. Adams GE, Dewey DL. Hydrated electrons and anal canal: a randomized controlled trial. JAMA.
in mammalian cells. Nature. 1959;184:1293–11295. radiobiological sensitization. Biochem Biophys Res 2008;299:1914–1921.
69. Bedford JS, Hall EJ. Survival of HeLa cells cultured Commun. 1963;12:473–477. 111. Stupp R, Hegi ME, Mason WP, et al. Effects of
in vitro and exposed to protracted gamma irradia- 92. Brown JM. Clinical trials of radiosensitizers: what radiotherapy with concomitant and adjuvant
tion. Br J Radiol. 1964;39:896–900. should we expect? Int J Radiat Oncol Biol Phys. temozolomide versus radiotherapy alone on survival
70. Hall EJ, Bedford JS. Dose-rate: its effect on the 1984;10:425–429. in glioblastoma in a randomised phase iii study:
survival of HeLa cells irradiated with gamma-rays. 93. Dische S. Chemical sensitizers for hypoxic cells: 5-year analysis of the EORTC-NCIC trial. Lancet
Radiat Res. 1964;22:305–315. a decade of experience in clinical radiotherapy. Oncol. 2009;10:459–466.
71. Denekamp J. Changes in the rate of proliferation Radiother Oncol. 1985;3:97–115. 112. Willett CG, Duda DG, Di Tomaso E, et al.
in normal tissues after irradiation. In: Nygaard O, 94. Overgaard J, Hansen HS, Overgaard M, et al. Complete pathological response to bevacizumab and
Adler HI, Sinclair WK, eds. Radiation Research: A randomized double-blind phase III study of chemoradiation in advanced rectal cancer. Nat Clin
Biomedical, Chemical and Physical Perspectives. New nimorazole as a hypoxic radiosensitizer of primary Pract Oncol. 2007;4:316–321.
York: Academic Press; 1975:810–825. radiotherapy in supraglottic larynx and pharynx 113. Folkman J. Tumor angiogenesis: therapeutic implica-
72. Withers HR, Taylor JMG, Maciejewski B. The hazard carcinoma. Results of the Danish Head and Neck tions. N Engl J Med. 1971;285:1182–1186.
of accelerated tumor clonogen repopulation during Cancer Study (DAHANCA) Protocol 5-85. Radiother 114. Ferrara N, Kerbel RS. Angiogenesis as a therapeutic
radiotherapy. Acta Oncol. 1988;27:131–146. Oncol. 1998;46:135–146. target. Nature. 2005;438:967–974.
73. Dewhirst MW, Cao Y, Moeller B. Cycling hypoxia 95. Zeman EM, Brown JM, Lemmon MJ, et al. SR 115. Hicklin DJ, Ellis LM. Role of the vascular endo-
and free radicals regulate angiogenesis and radio- 4233: a new bioreductive agent with high selective thelial growth factor pathway in tumor growth and
therapy response. Nat Rev Cancer. 2008;8:425–437. toxicity for hypoxic mammalian cells. Int J Radiat angiogenesis. J Clin Oncol. 2005;23:1011–1027.
74. Dewhirst MW. Relationships between cycling Oncol Biol Phys. 1986;12:1239–1242. 116. Ranieri G, Patruno R, Ruggieri E, et al. Vascular
hypoxia, HIF-1, angiogenesis and oxidative stress. 96. Brown JM. SR 4233 (Tirapazamine): a new endothelial growth factor (VEGF) as a target of
Radiat Res. 2009;172:653–665. anticancer drug exploiting hypoxia in solid tumors. bevacizumab in cancer: from the biology to the
75. Alper T, Howard-Flanders P. The role of oxygen in Br J Cancer. 1993;67:1163–1170. clinic. Curr Med Chem. 2006;13:1845–1857.
modifying the radiosensitivity of E. coli B. Nature. 97. Brown JM, Lemmon MJ. Potentiation by the 117. Carmeliet P, Jain RK. Principles and mechanisms of
1956;178:978–979. hypoxic cytotoxin sr 4233 of cell killing produced vessel normalization for cancer and other angiogenic
76. Fowler JF, Morgan RL, Wood CAP. Pretherapeutic by fractionated irradiation of mouse tumors. Cancer diseases. Nat Rev Drug Discov. 2011;10:417–
experiments with the fast neutron beam from the Res. 1990;50:7745–7749. 427.
medical research council cyclotron. I. The biological 98. Adam M, Bayer C, Henke J, et al. Tirapazamine 118. Fernando NH, Hurwitz HI. Targeted therapy of
and physical advantages and problems of neutron plus cisplatin and irradiation in a mouse model: colorectal cancer: clinical experience with bevaci-
therapy. Br J Radiol. 1963;36:163–173. improved tumor control at the cost of increased zumab. Oncologist. 2004;9(suppl 1):11–18.
77. Wijffels KI, Kaanders JH, Rijken PF, et al. Vascular toxicity. J Cancer Res Clin Oncol. 2008;134:137– 119. Welch S, Spithoff K, Rumble RB, et al. Bevacizumab
architecture and hypoxic profiles in human head 146. combined with chemotherapy for patients with
and neck squamous cell carcinomas. Br J Cancer. 99. Le QT, Moon J, Redman M, et al. Phase II study advanced colorectal cancer: a systematic review.
2000;83:674–683. of tirapazamine, cisplatin, and etoposide and Ann Oncol. 2010;21:1152–1162.
78. Van Putten LM, Kallman RF. Oxygenation status concurrent thoracic radiotherapy for limited-stage 120. Willett CG, Duda DG, Czito BG, et al. Targeted
of a transplantable tumor during fractionated small-cell lung cancer: SWOG 0222. J Clin Oncol. therapy in rectal cancer. Oncology (Williston Park).
radiotherapy. J Natl Cancer Inst. 1968;40:441–451. 2009;27:3014–3019. 2007;21:1055–1065.
79. Chaplin DJ, Durand RE, Olive PL. Acute hypoxia 100. Rischin D, Peters LJ, O’Sullivan B, et al. Tirapaza- 121. Reck M, Von Pawel J, Zatloukal P, et al. Overall
in tumors: implication for modifiers of radiation mine, cisplatin, and radiation versus cisplatin and survival with cisplatin-gemcitabine and bevacizumab
effects. Int J Radiat Oncol Biol Phys. 1986;12: radiation for advanced squamous cell carcinoma of or placebo as first-line therapy for nonsquamous
1279–1282. the head and neck (TROG 02.02, HeadSTART): non–small-cell lung cancer: results from a ran-
80. Brown JM. Evidence for acutely hypoxic cells in a phase III trial of the Trans-Tasman Radiation domised phase III trial (AVAiL). Ann Oncol. 2010;21:
mouse tumours, and a possible mechnaism of Oncology Group. J Clin Oncol. 2010;28:2989–2995. 1804–1809.
reoxygenation. Br J Radiol. 1979;52:650–656. 101. Patt HM. Cysteine protection against x-irradiation. 122. Escudier B, Bellmunt J, Negrier S, et al. Phase iii trial
81. Terasima T, Tolmach LJ. Changes in x-ray sensitivity Science. 1949;110:213–214. of bevacizumab plus interferon alfa-2a in patients
of HeLa cells during the division cycle. Nature. 102. Schuchter LM, Glick J. The current status of with metastatic renal cell carcinoma (AVOREN):
1961;190:1210–1211. WR-2721 (amifostine): a chemotherapy and radia- final analysis of overall survival. J Clin Oncol.
82. Sinclair W. Dependence of radiosensitivity upon tion therapy protector. Biol Ther Cancer. 1993;3: 2010;28:2144–2150.
cell age. Proceedings of the Carmel Conference on 1–10. 123. Valachis A, Polyzos NP, Patsopoulos NA, Georgoulias
Time and Dose Relationships in Radiation Biology 103. Bourhis J, Rosine D. Radioprotective effect of V, Mavroudis D, Mauri D. Bevacizumab in meta-
as Applied to Radiotherapy. 1969;97-107. amifostine in patients with head and neck squamous static breast cancer: a meta-analysis of randomized
83. Terasima T, Tolmach LJ. Variations in several cell carcinoma. Semin Oncol. 2002;29:61–62. controlled trials. Breast Cancer Res Treat. 2010;
responses of hela cells to x-irradiation during the 104. Culy CR, Spencer CM. Amifostine: an update on 122:1–7.
division cycle. Biophys J. 1963;3:11–33. its clinical status as a cytoprotectant in patients with 124. Ratner M. FDA panel votes to pull Avastin in breast
84. Withers HR. Cell cycle redistribution as a factor in cancer receiving chemotherapy or radiotherapy and cancer, again. Nat Biotechnol. 2011;29:676.
multifraction irradiation. Radiol. 1975;114:199–202. its potential therapeutic application in myelodys- 125. Chalmers AJ, Lakshman M, Chan N, et al. Poly
85. Steel GG. Growth Kinetics of Tumours. Oxford: plastic syndrome. Drugs. 2001;61:641–684. (ADP-ribose) polymerase inhibition as a model for
Clarendon Press; 1977. 105. Wilson GD, Bentzen SM, Harari PM. Biologic basis synthetic lethality in developing radiation oncology
86. Szybalski W. Properties and applications of haloge- for combining drugs with radiation. Semin Radiat targets. Semin Radiat Oncol. 2010;20:274–281.
nated deoxyribonucleic acids. The Molecular Basis Oncol. 2006;16:2–9. 126. Bryant HE, Schultz N, Thomas HD, et al.
of Neoplasia (A Collection of Papers Presented at the 106. Moertel CG. Chemotherapy for colorectal cancer. Specific killing of BRCA-2 deficient tumours with
Fifteenth Annual Symposium on Fundamental Cancer N Engl J Med. 1994;330:1136–1142. inhibitors of poly (ADP-ribose) polymerase. Nature.
Research, 1961). Austin: University of Texas Press; 107. Milas L, Mason KA, Liao Z, et al. Chemoradio- 2005;434:913–917.
1962:147–171. therapy: emerging treatment improvement strategies. 127. Farmer H, McCabe N, Lord CJ, et al. Targeting
87. Cecchini S, Girouard S, Huels MA, et al. Single- Head Neck. 2003;25:152–167. the DNA repair defects in BRCA mutant cells as a
strand-specific radiosensitization of DNA by bro- 108. Cooper JS, Zhang Q, Pajak TF, et al. Long-term therapeutic strategy. Nature. 2005;434:917–921.
modeoxyuridine. Radiat Res. 2004;162:604–615. follow-up of the RTOG 9501/Intergroup Phase III 128. Rabenau K, Hofstatter E. DNA damage repair and
88. Bagshaw MA, Doggett RL, Smith KC. Intra-arterial trial: postoperative concurrent radiation therapy and the emerging role of poly (ADP-ribose) polymerase
5-bromodeoxyuridine and x-ray therapy. AJR Am J chemotherapy in high-risk squamous cell carcinoma inhibition in cancer therapeutics. Clin Ther.
Roentgenol. 1967;99:889–894. of the head and neck. Int J Radiat Oncol Biol Phys. 2016;38:1577–1588.
89. Kinsella T, Mitchell J, Russo A, et al. The use of 2012;84:1198–1205. 129. Murata S, Zhang C, Finch N, et al. Predictors and
halogenated thymidine analogs as clinical radiosensi- 109. Angioli R, Plotti F, Montera R, et al. Neoadjuvant modulators of synthetic lethality: an update on PARP
tizers: rationale, current status, and future prospects. chemotherapy plus radical surgery followed by inhibitors and personalized medicine. Biomed Res
Int J Radiat Oncol Biol Phys. 1984;10:139–146. chemotherapy in locally advanced cervical cancer. Int. 2016;2016:2346585.
90. Greenberg HS, Chandler WF, Ensminger WD, et al. Gynecol Oncol. 2012;127:290–296. 130. Golden EB, Demaria S, Schiff PB, et al. An abscopal
Radiosensitization with carotid intra-arterial bromo- 110. Ajani JA, Winter KA, Gunderson LL, et al. Fluoro- response to radiation and ipilimumab in a patient
deoxyuridine +/- 5-fluorouracil biomodulation for uracil, mitomycin, and radiotherapy vs. fluorouracil, with metastatic non–small cell lung cancer. Immunol
malignant gliomas. Neurology. 1994;44:1715–1720. cisplatin, and radiotherapy for carcinoma of the Res. 2013;1:365–372.
 Basics of Radiation Therapy  •  CHAPTER 27 460.e3

131. Postow MA, Callahan MK, Barker CA, et al. Immu- 145. Miles EF, Lee WR. Hypofractionation for prostate localized prostate cancer. Int J Radiat Oncol Biol
nologic correlates of the abscopal effect in a patient cancer: a critical review. Semin Radiat Oncol. Phys. 2006;65:528–534.
with melanoma. N Engl J Med. 2012;366:925–931. 2008;18:41–47. 158. Langen KM, Pouliot J, Anezinos C, et al. Evalu-
132. Kelderman S, Schumacher T, Haanen J. Acquired and 146. Fowler JF, Welsh JS, Howard SP. Loss of biological ation of ultrasound-based prostate localization for
intrinsic resistance in cancer immunotherapy. Mol effect in prolonged fraction delivery. Int J Radiat image-guided radiotherapy. Int J Radiat Oncol Biol
Oncol. 2014;8:1132–1139. Oncol Biol Phys. 2004;59:242–249. Phys. 2003;57:635–644.
133. Ng AK, Travis LB. Subsequent malignant neoplasms 147. Thames HD, Hendry JH. Fractionation in Radio- 159. Vicini F, Beitsch P, Quiet C, et al. Five-year analysis
in cancer survivors. Cancer J. 2008;14:429–434. therapy. Philadelphia: Taylor and Francis; 1987. of treatment efficacy and cosmesis by the American
134. Tubiana M. Can we reduce the incidence of second 148. Fowler JF. The linear-quadratic formula and Society of Breast Surgeons Mammosite Breast
malignancies occurring after radiotherapy? A critical progress in fractionated radiotherapy. Br J Radiol. Brachytherapy Registry Trial in patients treated with
review. Radiother Oncol. 2009;91:4–15. 1989;62:679–694. accelerated partial breast irradiation. Int J Radiat
135. Travis LB, Hill DA, Dores GM, et al. Breast cancer 149. ICRU 60: Prescribing, recording and reporting photon Oncol Biol Phys. 2011;79:808–817.
following radiotherapy and chemotherapy among beam therapy. 1993. 160. Leskel L. The stereotactic method and radiosurgery
young women with Hodgkin’s disease. JAMA. 150. Marks LB, Bentzen SM, Deasy JO, et al. Radiation of the brain. Acta Chir Scand. 1951;102:316–319.
2003;290:465–475. dose-volume effects in the lung. Int J Radiat Oncol 161. Benedict SH, Yenice KM, Followill D, et al.
136. De Bruin ML, Sparidans J, Van’t Veer MB, et al. Biol Phys. 2010;76(suppl):S70–S76. Stereotactic body radiation therapy: the report of
Breast cancer risk in female survivors of Hodgkin’s 151. Webb S. Intensity-Modulated Radiation Therapy. AAPM Task Group 101. Med Phys. 2010;37:4078–
lymphoma: lower risk after smaller radiation Bristol, United Kingdom: Institute of Physics 4101.
volumes. J Clin Oncol. 2009;27:4239–4246. Publishing; 2000. 162. Blomgren H, Lax I, Naslund I, et al. Stereotactic high
137. Kleinerman RA, Boice JD, Storm HH, et al. Second 152. Zelefsky MJ, Fuks Z, Hunt M, et al. High-dose dose fraction radiation therapy of extracranial tumors
primary cancer after treatment for cervical cancer. intensity modulated radiation therapy for prostate using an accelerator. Clinical experience of the first
Cancer. 1995;76:442–452. cancer: early toxicity and biochemical outcome thirty-one patients. Acta Oncol. 1995;34:861–870.
138. Withers HR, Taylor JMG, Maciejewski B. Treatment in 772 patients. Int J Radiat Oncol Biol Phys. 163. Beck C. On external roentgen treatment of internal
volume and tissue tolerance. Int J Radiat Oncol Biol 2002;53:1111–1116. structures (eventration treatment). NY Med J.
Phys. 1988;14:751–759. 153. Sidhu K, Ford EC, Spirou S, et al. Optimization of 1909;89:621–622.
139. Douglas BG, Fowler JF. The effect of multiple small conformal thoracic radiotherapy using cone-beam 164. Shipley WU, Verhey LJ, Munzenrider JE, et al.
doses of X-rays on skin reactions in the mouse and CT imaging for treatment verification. Int J Radiat Advanced prostate cancer: the results of a randomized
a basic interpretation. Radiat Res. 1976;66:401–426. Oncol Biol Phys. 2003;55:757–767. comparative trial of high dose irradiation boosting
140. Thames HD, Withers HR, Peters LJ, et al. Changes 154. Lin A, Kim HM, Terrell JE, et al. Quality of life after with conformal protons compared with conventional
in early and late radiation responses with altered dose parotid-sparing IMRT for head and neck cancer: a dose irradiation using photons alone. Int J Radiat
fractionation: implications for dose-survival relation- prospective longitudinal study. Int J Radiat Oncol Oncol Biol Phys. 1995;32:3–12.
ships. Int J Radiat Oncol Biol Phys. 1982;8:219–226. Biol Phys. 2003;57:61–70. 165. Allen AM, Pawlicki T, Dong L, et al. An evidence
141. Strandqvist M. Studien uber die kumulative wirkung 155. Bert C, Metheany KG, Doppke KP, et al. Clinical based review of proton beam therapy: the report
der roentgenstrahlen bei fraktionierung. Acta Radiol. experience with a 3D surface patient setup system of ASTRO’s Emerging Technology Committee.
1944;55(suppl):1–300. for alignment of partial-breast irradiation patients. Radiother Oncol. 2012;103:8–11.
142. Thames HD, Bentzen SM, Turesson I, et al. Time- Int J Radiat Oncol Biol Phys. 2006;64:1265–1274. 166. Jensen AD, Munter MW, Debus J. Review of clinical
dose factors in radiotherapy: a review of human 156. Jaffray DA, Siewerdsen JH, Wong JW, et al. experience with ion beam radiotherapy. Br J Radiol.
data. Radiother Oncol. 1990;19:219–235. Flat-panel cone-beam computed tomography for 2011;84(suppl):S35–S47.
143. Fowler JF. The James Kirk Memorial Lecture. What image-guided radiation therapy. Int J Radiat Oncol 167. Kamada T. Clinical evidence of particle beam therapy
next in fractionated radiotherapy? Br J Cancer. Biol Phys. 2002;53:1337–1349. (carbon). Int J Clin Oncol. 2012;17:85–88.
1984;46(suppl):285–300. 157. Willoughby TR, Kupelian PA, Pouliot J, et al.
144. Fowler JF. Non-standard fractionation in radiotherapy. Target localization and real-time tracking using the
Int J Radiat Oncol Biol Phys. 1984;10:755–759. Calypso 4D localization system in patients with