23 
Basic Principles in Gynecologic Radiotherapy
Catheryn M. Yashar, MD, FACR, FACRO
OUTLINE
Introduction to Electromagnetic Radiation
Radiation Units
Radiation Physics
Energy Deposition
Sources of Radiation
Photon Interactions
Radioactive Decay
Inverse Square Law
Depth Dose Characteristics of Radiation
Radiobiology
Structural Changes
Radiosensitivity
Radiosensitizers, Hypoxic Cell Sensitizers, and
Radioprotectors
Genetic Effects
Fetal Effects
Principles of Clinical Radiation Therapy
External-beam Radiation (Teletherapy)
Local Radiation (Brachytherapy)
KEY POINTS
1. Radiation therapy is used for the treatment of primary
and metastatic gynecologic carcinomas.
2. Radiation therapy depends on the differential
susceptibility of tumors to irradiation compared with
normal tissues, and research attempts to maximize the
therapeutic ratio are ongoing.
3. Photons, a nonparticulate form of radiation, are the
primary modality of therapeutic irradiation used in
gynecologic carcinomas.
4. Particulate irradiation with electrons and protons are also
used in many centers but have specialized indications.
5. Radiation is measured in international system (SI) unit of
centigray and Gray. A typical dose for therapeutic
irradiation for adjuvant therapy is 45 to 50 Gy and for
gross disease, as in cervical carcinoma, is 80 to 85 Gy.
6. Radiation is primarily generated from human-made
sources, as in a linear accelerator, called x-rays, or from
naturally radioactive decay, termed gamma rays.
Therapeutically, these are indistinguishable, although
photons or electrons may be the therapeutic source.
7. A variety of DNA lesions are produced by radiation
including base damage, DNA–protein crosslinking,
single-strand breaks, and double-strand breaks.
586
Normal Tissue Tolerance
Pelvic Organ Tolerance
Long-term Effects
New Radiation Modalities
Protons
Electrons
Fast Neutrons
Negative Pi Mesons and Other Heavy Ions
New Radiation Delivery Technology
Intraoperative Radiation
Hyperthermia
Three-dimensional Conformal Radiation Therapy
Intensity-modulated Radiation Therapy
Stereotactic Radiotherapy
Immune-tagged Radiation Therapy
Glossary
8. In general, radiation is delivered in two basic manners.
External-beam radiation therapy delivers radiation to the
body from an external source. Brachytherapy, a crucial
component to the safest and most effective treatment of
many gynecologic cancers, delivers radiation from sources
that are placed within the body.
9. An important concept, crucial to the delivery of
brachytherapy, is that the dose of radiation at a given
point is inversely proportional to the square of the
distance from the source of radiation (dose ∝ 1/
Distance2). This forms the basis of high therapeutic dose
directly to the tumor and safe doses to adjacent critical
organs. External methods of delivery cannot duplicate
this delivery. A level of expertise is absolutely crucial to
the delivery of this modality.
10. Low-dose-rate brachytherapy is being replaced in most
centers by high-dose-rate brachytherapy or pulse-dose-
rate brachytherapy.
11. Image guidance with computed tomography, magnetic
resonance imaging, or positron emission computed
tomography scans, in all aspects of radiation therapy
(planning, external and brachytherapy), appears to
increase the therapeutic ratio.
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 587
12. Concurrent therapies (radiosensitizers and protectors)
seek to increase this therapeutic ratio, each with its own
mechanism of action to be exploited.
13. The short- and long-term effects of irradiation are not
trivial, and a risk-to-benefit discussion is crucial to the
patient and multidisciplinary oncology team. During and
after therapy, a team approach best serves the patient.
A basic understanding of the principles of radiation oncol-
ogy is essential to gynecologic oncologists. Radiation therapy
is used in the curative treatment of locoregionally advanced
cervical and vaginal carcinoma. It is often an adjuvant therapy
prescribed for uterine or vulvar carcinoma and in inoperable
patients may be the only definitive therapy available. Last, it can
be used for the palliative treatment of gynecologic carcinomas.
INTRODUCTION TO ELECTROMAGNETIC
RADIATION
Radiant energy or radiation is an essential component of life on
earth. For example, sunlight provides heat, light, and energy for
plant photosynthesis, and radio waves provide a method of
communication. This electromagnetic radiation physically
consists of photons, or “packets” of energy without mass or
charge. The primary difference between the radiations is the
energy of the photons. The energy is proportional to frequency
(E = hν, where h is Planck’s constant and ν is frequency) and
inversely proportional to wavelength (Table 23.1). A common
analogy is to compare wavelength to the length of a person’s
stride when walking; the number of strides per minute is the
frequency of the wave.
Photons, a nonparticulate radiation, are only one form of
radiation. Another form of radiation is particulate radiation.
Particulate radiation consists of subatomic particles such as
electrons, protons, α particles, and neutrons.
Radiation is not harmful in ordinary quantities and is
actually helpful to life processes. In fact, exposure to radiation
is a constant phenomenon (Tables 23.2 and 23.3). However,
high-energy, or “ionizing,” radiation is not entirely harmless,
although it is commonly used for both diagnostic and thera-
peutic purposes. High-energy radiation can be injurious to
biologic material, and its use in oncology depends on the ability
of normal tissue to recover from the effects more effectively
TABLE 23.1  Electromagnetic Spectrum
Wavelength (M)
Radio >1 × 10−1
Microwave 1 × 10−3 − 1 × 10−1
Infrared 7 × 10−7 − 1 × 10−3
Visible 4 × 10−7 − 7 × 10−7
Ultraviolet 1 × 10−8 − 4 × 10−7
X-ray 1 × 10−11 − 1 × 10−8
Gamma ray <1 × 10−11
14. Intensity-modulated radiation therapy, image-guided
radiation therapy, and stereotactic radiation therapy are
all tools in an ever increasingly complex toolbox for the
radiation oncologist to use for increased local control,
survival, and palliation. Ongoing studies evaluate the
risk-to-benefit ratio and cost effectiveness of these new
and expensive technologies.
or efficiently than malignant tissue. Radiation causes both
reversible and irreversible changes in normal tissue, and these
effects are placed into two categories: acute effects (apparent
during or shortly after the radiation course) and long-term
effects (apparent from 6 months to years after completion of
therapy). Radiation effects may not be initially apparent except
by careful chemical or microscopic study. Indeed, the effects
may not be apparent for many years or may manifest only in
the offspring of the irradiated organism. The accepted position
regarding radiation exposure is that incidental environmental
radiation, diagnostic tests, and therapeutic radiation can all be
detrimental. Although in many cases the chance of injury from
diagnostic or environmental radiation is slight, the possibility
of damage from a known exposure must always be weighed
against the importance of the information to be gained or the
effect desired. Incidental exposure must be avoided through
control of environmental hazards whenever possible by fol-
lowing the ALARA (as low as reasonably achievable) principle.
There are many forms and sources of radiation, including
natural isotopes and human-made radiations. The natural
radiation emissions (gamma and beta rays) of isotopes such as
iridium, iodine, and cesium are used for therapeutic purposes
in many human malignancies (Table 23.4). In addition, during
the past 4 decades, increasingly sophisticated machines have
been manufactured to produce high-intensity, directed radia-
tion to treat both malignant and benign conditions. Modern
machines emit energies greater than 1 million electron volts
(1 MeV) and are termed supervoltage or megavoltage machines
(Table 23.5). The most commonly available are called linear
accelerators (linacs). Even these have recently become more
sophisticated to allow increasingly precise delivery of radiation
in the form of intensity-modulated radiation therapy (IMRT).
The newest generation models allow for real-time computed
tomography (CT) for position verification, termed image-
guided radiation therapy, or IGRT. Image guidance is also more
Frequency (Hz) Energy (J)
<3 × 109 <2 × 10−24
3 × 109 − 3 × 1011 2 × 10−24 − 2 × 10−22
3 × 1011 − 4 × 1014 2 × 10−22 − 3 × 10−19
4 × 1014 − 7.5 × 1014 3 × 10−19 − 5 × 10−19
7.5 × 1014 − 3 × 1016 5 × 10−19 − 2 × 10−17
3 × 1016 − 3 × 1019 2 × 10−17 − 2 × 10−14
>3 × 1019 >2 × 10−14
588 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

TABLE 23.2  General Population Radiation TABLE 23.6  Historical and International
Exposure System (SI) Units of Radiation
Average Annual Historical Conversion
Whole-Body Dose Quantity Unit SI Unit Factor
Radiation Source (millirem/yr) Exposure R C/kg 2.58 × 10−4 C/kg/R
Natural: cosmic 29 Absorbed dose Rad Gray (Gy) 10−2 Gy/rad
Terrestrial 29 Dose equivalent Rem Seivert (Sv) 10−2 Sv/rem
Radon 200 (used in radiation
Internal (eg, 40K, 14C) 40 protection)
Human made (diagnostic radiography, 64 Activity Curie (Ci) Becquerel (Bq) 3.7 × 1010 Bq/Ci
nuclear medicine, consumer products
such as smoke detectors)
All others (fallout, air travel, occupational) 2
Average annual total 360\ commonly used in brachytherapy, which historically used only
Tobacco smokers: add ~280 mrem two-dimensional imaging. With the advent of CT- and magnetic
resonance imaging (MRI)–compatible brachytherapy applica-
tors, imaging modalities are used to more precisely direct the
radiation to the tissues at risk while simultaneously avoiding
TABLE 23.3  Radiation Associated With
normal, uninvolved tissues. The acceleration in technology has
Common Activities
paralleled the advances in computer technology. In addition,
Activity Typical Radiation Dose simulations that combine radiation delivery planning with
Smoking 280 mrem/yr positron emission tomography (PET) and MRI are currently
Chest radiography 8 mrem/single radiograph being used at several centers.
Drinking water 5 mrem/yr
Cross-country airplane trip 5 mrem/yr
RADIATION UNITS
Those in training and in practice must familiarize themselves
TABLE 23.4  Radioactive Isotopes Used in with the international system (SI) of weights and measures used
Radiation Oncology today. The SI units and appropriate conversions are shown in
Table 23.6.
Element Isotope Emax (MeV) T1/2 Clinical Use When a radiation exposure occurs, the resultant ionizations
Radium 236
Ra 3.26 1600 yr Historical deposit energy in the air. If a patient lies in the path of the beam,
137
Cesium Cs 0.514, 1.17 30 yr Temporary energy will be deposited in the patient. This deposition of
intracavitary energy by radiation exposure is called radiation-absorbed
implants dose, measured in the acronym rad. One rad is equivalent to
192
Iridium Ir 0.38ave 74.2 d Temporary interstitial the deposition of 100 ergs of energy into each gram of the
implants and source
irradiated object. The SI unit of radiation absorbed dose is
for high dose rate
machine
the gray (Gy), and 1 Gy = 1 cGy =100 rads = 1 joule/kg. The
Iodine 125
I 0.028ave 60.2 d Permanent interstitial erg and joule are units of energy.
implants
Phosphorus 32
P None 14.3 d Permanent RADIATION PHYSICS
intracavitary
placement Energy Deposition
103
Palladium Pd 20KV 17 d Permanent prostate Radiation energy is deposited into the tissue in one of two ways:
seed implant direct or indirect ionization. Ionization is when an outer shell
electron is stripped from an atom, leaving a positive charge.
Direct ionization is the predominant mechanism of action of
TABLE 23.5  Radiation Delivery by Energy particles that possess charge, but photons can also cause direct
ionization. Examples of directly ionizing particles include par-
Modality Voltage Source ticulate radiation such as protons and neutrons. Indirect ioniza-
Low voltage (superficial) 85−150 keV X-ray tion produces free radicals of other molecules, namely water,
Medium voltage 180−400 keV X-ray which diffuse and damage critical targets (Fig. 23.1). A free
(orthovotage) radical has an unpaired outer shell electron that is chemically
Supervoltage 500 keV−8 MeV Linear accelerator, unstable and very reactive. The hydroxyl free radical (made by
60
Co machine
the lysis of H20) diffuses only about 1 nm and breaks the chemi-
Megavoltage Above supervoltage Betatron, linear
cal bonds in cellular proteins and other key substances such as
energy accelerator
DNA. Either form of energy deposition results in ionization of
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 589
Indirect action Direct action
Incoming
photon
Damage to DNA
H2O Free
radical
Damage to DNA
DNA
FIGURE 23.1  Direct and indirect actions of radiation. DNA, the
most lethal target of radiation is schematically shown in the
center. In direct action, the incident photon displaces an elec-
tron from the target (DNA) molecule. In indirect action, another
molecule, such as water, is ionized, and the displaced electron
diffuses to the target and damages the DNA.
target molecules. Scientists estimate that about two-thirds of
cell biologic damage is from indirect action by ionizing radia-
tion, from sources such as x-rays and gamma rays.
The electrons generated by penetrating photons lose their
energy slowly, resulting in a low energy deposition along the
electron track, or low linear energy transfer (LET; defined as
energy transferred per unit length of track, or keV/µm). High
LET radiations (neutrons, negative p mesons, or alpha particles)
deposit more energy per unit length, are more commonly
directly ionizing, and are less susceptible to perturbations such
as oxygen tension. This means that for the same reaction pro-
duced in healthy cells by all radiation modalities, high LET
radiation has a higher probability (1.5 to 2.5 times that of
x-rays) of killing those cells in less than ideal circumstances (ie,
hypoxic tumor cells, cells in a resistant part of the cell cycle).
Sources of Radiation
Gamma rays are the photons emitted from the atomic nuclear
decay of radioactive isotopes—for example, 137Cs (cesium) or
60
Co (cobalt). X-rays are photons electrically generated by
bombarding a target such as tungsten with electrons (how a
linear accelerator works). When these fast-moving electrons
approach the tungsten nuclear field, they are attracted to the
nucleus and thus veer from their original path. This change in
direction causes deceleration and kinetic energy is converted to
x-rays in the form of bremsstrahlung photons. These emitted
x-rays, or photons, vary in energy from zero to a maximum
determined by the kinetic energy of the bombarding electrons.
Machines such as the betatron and linear accelerator generate
electrons with high kinetic energy and thus produce high-
energy x-rays. In addition to bremsstrahlung photons, charac-
teristic photons are also produced as atoms seek to fill electron
orbital vacancies (see later discussion). Gamma rays and x-rays
can be collectively called photons, and what is of medical impor-
tance is the energy and delivery of the photon, not the source.
Photon Interactions
The interaction of photons with matter is accomplished through
six mechanisms: (1) Compton scattering, (2) photoelectric
absorption, (3) pair production, (4) triplet production, (5)
photodisintegration, and (6) coherent scattering (no energy
transfer). The Compton effect is the major interaction of
photons in tissue used in modern radiotherapy (Fig. 23.2).
When the photon from the linear accelerator interacts with
outer orbital atomic electrons, part of the photon energy trans-
fers to the electron as kinetic energy. The photon is deflected
with reduced energy. The ejected electron is propelled forward
and sets up a cascade of increasing energy deposition by dis-
placing more electrons. As a result of this initiation and subse-
quent buildup effect, megavoltage photon beams have a
skin-sparing effect not seen in older machines and therefore
produce less superficial tissue change.
The photoelectric effect is seen at lower energies. This effect
is the most important in diagnostic radiology. In this interac-
tion, the incident photon is absorbed completely by an inner
shell electron. The inner shell electron is ejected with kinetic
energy equal to the incident photon energy less the electron-
binding energy. An outer shell electron then drops into the
vacancy. As this electron changes orbit, its energy is reduced,
and the excess energy is given off in the form of a photon, called
a “characteristic photon.”
In pair production, photon energies greater than 1.02 MeV
interact with the strong electric field of the nucleus and lose all
incident energy. The incident photon energy is converted into
matter in the form of a positron–electron pair. If this happens
in the field of an orbital electron, three particles are produced in
the interaction, and the interaction is called triplet production.
Last, in photodisintegration, the high-energy photon enters
the nucleus and ejects a neutron, proton, or alpha particle. This
is important for shielding considerations in linear accelerators
that operate at energies above 15 MeV.
Radioactive Decay
Naturally radioactive substances decay to more stable sub-
stances by several methods: (1) beta decay (32P, 18F), (2) electron
capture (125I), (3) alpha decay (226Ra), and (4) isomeric transi-
tion (gamma emission and internal conversion). “Decay” is the
manner in which an isotope releases, or gains, matter, or energy
to become a more stable substance. The rate of decay of a
radionuclide is exponential and is termed the “activity.” The old
unit for activity was the Curie (Ci). The SI unit is the becquerel
(Bq) defined by 1 Bq = 1 dps (disintegration per second). The
half-life (T1/2) is the time required to disintegrate to half the
original activity. T1/2 of commonly used radioactive substances
is in Table 23.4.
137
Cs (Cesium-137), used in low dose rate (LDR) applica-
tions, is a byproduct of the fission process in a nuclear reactor
and decays via beta and gamma emission. In beta decay, a
neutron from the nucleus converts into a proton (positively
590 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

Compton effect Photoelectric effect

e-
Vacancy in k-shell

e- e-
Incident photon e-
e- Fast electron
e-
e-
e- e-
Fast electron e-

e- e-

Scattered photon e-
Characteristic x-rays
Incident photon

Pair production

e-

e-
Incident photon e-
Positron electron pair
e- e+
e-
e-

e-

FIGURE 23.2  The major photons interactions important in therapeutic and diagnostic radiation
oncology.

charged) and an electron. Again, to increase stability, a photon Cesium

is released, and the 127Cs becomes the more stable 137Ba (Fig.
137
23.3). 137Cs decays approximately 2%/year. Cs
192 55 0.51 MeV (95%)
Ir (iridium 192) is also produced in a nuclear reactor and
decays via beta decay (see earlier) and electron capture. In 137 m
Ba
electron capture, the nucleus “captures” an orbital electron and 56
1.17 MeV (5%)
converts a proton into a neutron. 192Ir then becomes the excit- 0.662 MeV
able 192mPt and 192mOs, which release gamma rays to stabilize. 137
192
Ir is the primary isotope used for high dose rate (HDR) Ba
56
applications and interstitial implants. It decays approximately
1%/day.
192
Inverse Square Law Iridium Ir
77
Another important physics concept in radiotherapy is the
4.4% 95%
inverse square law. This law states that the dose of radiation at
a given point is inversely proportional to the square of the 192 m 192 m
Os Pt
distance from the source of radiation (dose ∝ 1/distance2). This 76 78
rapid decrease in dose is very important in brachytherapy. It
underscores why the bladder and rectum can be relatively 192 192
Os Pt
protected from the high intracavitary doses of radiation, espe- 76 78
cially with good vaginal packing to maximize the distance from FIGURE 23.3  Decay diagram of 137
Cs and 192
Ir.
the source to the normal organ. It also underscores why good
geometry is critical when performing implants. Last, it explains
the reasoning behind standing at the door (increasing the dis-
tance) while conversing with a brachytherapy patient. As a
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 591

simplistic example, consider the following. The dose at point A
is 4. Two feet away the dose would be 4 divided by the square
of the distance (22) or 4/4 = 1. Another 2 feet away, the dose
would be 1/4 (4/42 = 4/16 = 1/4).
Depth Dose Characteristics of Radiation
The last physics concept to master is variation in radiation beam
characteristics based on energy. To that end, it is important
to realize that the energy and penetrating power of ionizing
radiation increase as the photon frequency increases and
wavelength decreases. In addition, as energy increases, the depth
of maximum dose increases (Dmax; remember the buildup
effect discussed earlier). For low energies, such as 250 keV, the
maximum dose is at the skin surface. For a 4-MeV (4 million
electron volts) accelerator, the Dmax is approximately 1 cm; for
6 MeV, Dmax is at 1.5 cm; for 22 MeV, Dmax is at 3.5 cm; and so
on. Knowing this, one can see why higher energy beams are
more suited to treat deeply seated tumors, such as in the uterine
or cervix. These higher energy beams differentially spare more
superficial tissues. Depths of maximum dose curves and isodose
distributions (areas receiving similar dose) for various energies
are shown in Fig. 23.4.
The reduced effect on skin of supervoltage radiation, com-
pared with orthovoltage (keV range) radiation, is based on a
physical characteristic of radiation. With higher energy, forward
movement of the energy cascade (in the direction of the primary
beam) is greater with reduced lateral scattering. As the energy
increases, it becomes more penetrating, and the photons and
resultant liberated electrons travel a greater distance into the
absorbing material. Therefore, the percentage of radiation at
any specific depth, compared with the surface dose, increases as
the energy increases.
In summary, above the energy of 400 to 800 keV, the advan-
tages to higher energy photons are less damage to the skin at
the portal of entry, greater radiation at depth relative to the
surface, and reduced lateral scatter of radiation in the tissues.
In addition, there is less photoelectric effect at higher energies
and therefore less absorption in bone.
RADIOBIOLOGY
The selective destruction of tissues forms the basis of therapeu-
tic radiation. Neoplastic cells are preferentially killed by radia-
tion compared with the surrounding normal tissues, primarily
as a result of differences in repair capabilities. This differential
radiosensitivity between normal and cancerous tissues deter-
mines in large part whether a radiated neoplasm is eradicated.
The ratio that defines the dose necessary to effect tumor kill

60Co
200 keV 6 MeV 20 MeV betatron
10  10 cm 10  10 cm 10  10 cm 10  10 cm
50 cm SSD 80 cm SSD 100 cm SSD 100 cm SSD
Surface Surface
Depth (cm) 5 0 5 5 0 5 5 0 5 5 0 5 Depth (cm)
100 100 100
95
2 90 2
90
80
80 90 100
4 70 4
60
6 70 80 90 6
50
8 10
40
10 8
60
70
10 30
80 10
50
12 20
60 12
70
14 14
40
5 5
50
16 16
10
18 30 60 18
40
20 20
22 22
50
24 20
24
30
26 5 10 10 26
5

28 20 20 28
10 40
10
30 5 5 20 20 30
10 10
5 5

FIGURE 23.4  Comparison isodose curves and depth-dose distribution through a single field.
Each machine is delivering photons of different energies. Note that higher energy machines
deliver radiation to a greater depth for the same surface dose. Note also the skin sparing with
6- and 20-MV equipment. Last, note the difference in lateral scattering—higher energy photons
are more “forward moving” with less lateral scatter.
592 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

100

90
Major complications
80

70
Cure rate (%) 60

50 Tumor
Normal tissue
40

30

20

10
Acceptable morbidity <10%
0
A B
Dose
FIGURE 23.5  Therapeutic ratio. Diagrammatic representation of a parallel tumor response and
normal tissue tolerance curve demonstrating the relationship between increasing dose, increas-
ing cure rate, and increasing morbidity. Under ideal circumstances (B), an 80% to 90% cure rate
can be achieved with 5% to 10% morbidity. Pushing the cure rate carries with it an increase in
morbidity. However, attempts to avoid all morbidity (A) significantly reduce the ability to cure.
Although the shape of these curves varies for various tumor types and dose rates, general
concepts are valid whenever radiotherapy is used to treat malignant lesions.

with the dose likely to cause normal tissue damage is the
therapeutic ratio, and modern radiotherapy is striving to
maximize this ratio (Fig. 23.5).
Structural Changes
Deposition of radiation energy in the cell can lead to a variety
of changes that alter normal function. Degradation, or breaking
into smaller units, and cross-linking are examples of structural
damage that can affect proteins, enzymes, and nucleic acids. The
initial chemical change occurs in a fraction of a second and is
rarely detected directly. Some changes are repaired almost
immediately, but others can never be repaired. Although various
morphologic and functional changes occur in irradiated cells,
the bulk of direct and indirect evidence suggests that the bio-
logic effects of radiation result principally from DNA damage.
For example, it has been calculated that 1 million cGy is required
to inactivate cell cytoplasmic enzyme systems, and doses of
1000 cGy are required to damage cell membranes. In contrast,
chromosomal aberrations and mutations can be produced by
very low doses of radiation. Because only a few hundred cGy
are needed to produce a high degree of lethality in cell tissue
culture, it seems logical that nuclear changes are responsible for
cell death.
Radiation-induced DNA damage destroys the cell by one of
several mechanisms. It may stimulate cell apoptosis, called
interphase death, which is visible by several methods, including
light microscopy and Western blot. Radiation may also cause
mitotic death. In this form of damage, the cell outwardly
appears normal but is sufficiently damaged so that cell division
is not possible. Actual death of the cell does not occur, however,
until cell division is attempted. This is why tumors may continue
to regress after completion of radiation.
A variety of DNA lesions are produced by radiation includ-
ing base damage, DNA–protein crosslinking, single-strand
breaks, and double-strand breaks (DSBs). Repairing even a
single nucleotide requires many genes and a series of steps. The
most toxic cellular lesion inflicted by ionizing radiation is the
DSB. In fact, the proficiency of repair of DSB correlates well
with radiation-induced lethality. The repair of DSB can occur
by several mechanisms. Religation of complementary DSB ends,
homologous recombination (HR), is efficient, and cells can
usually survive. The Mre11 protein is attracted when a DSB
occurs and may be the first sensor of the break and primarily
involved in repair through nuclease activity, unwinding DNA,
or removing hairpin loops. When the ends are not complemen-
tary, nonhomologous end joining (NHEJ) is used and can be
complicated by small DNA deletions or insertions. These errors
in turn can lead to cell death or mutation. Some of the necessary
proteins for NHEJ are Ku70, Ku80, DNA ligase IV, and XRCC4.
The Ku70/Ku80 complex binds to the DSB and unwinds the
strand while the DNA ligase IV/XRCC4 complex repairs DSBs.
Mammalian cells seem to repair more by NHEJ than HR.
Radiosensitivity
Radiosensitivity is the response of the tumor to irradiation
that can be measured by the extent of regression, rapidity of
response, and response durability. Radiosensitivity depends
on several factors. These factors include the ability to repair
damage, hypoxia, cell cycle position, and growth fraction. In
addition, the volume of the initial tumor has been demonstrated
to influence the ability to eradicate tumors.
Understanding that radiosensitivity and radiocurability are
not identical in meaning is essential. Relatively radioresistant
tumors accessible to high-dose local radiation therapy can be
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 593
cured, but radiosensitive tumors that are widely metastatic can
only be controlled locally. An excellent example of a relatively
radioresistant tumor is squamous cell carcinoma of the cervix;
however, this malignancy remains one of the most curable
tumors in humans because of its accessibility to high-dose
irradiation and the relatively radioresistant nature of the
hosting normal tissues (eg, cervix and vagina). The ability to
place radium or cesium in juxtaposition to the malignancy
within dose ranges tolerable to the surrounding normal tissue
is the key to success.
Many attempts have been made to develop an assay to predict
tumor radiosensitivity. However, no assay yet developed accu-
rately predicts the outcome in a given tumor. This is likely
secondary to tumors containing mixed cell populations with
differing sensitivities to chemotherapy and radiation. Sensi-
tive cells are eliminated, but resistant cells continue to grow.
This explains why many tumors initially respond to therapy
but are ultimately incurable.
In vitro models have been developed to predict and study
tumor cell radiosensitivity. Cellular radiosensitivity is generally
quantified by measuring the loss of reproductive capacity,
which can be plotted in a survival curve. Survival curves are
characterized by an initial slope, α, and the terminal slope, β. α
represents irreparable damage to the cell, and β represents the
repairable damage (Fig. 23.6). The α/β ratio is the dose at which
the contribution from alpha equals the contribution from beta
and is a measure of radiosensitivity. Large ratios are seen with
rapidly dividing cells and help predict the response of tumors
and the early effects of radiation. Low ratios characterize late
responding tissues.
In addition, the size of the shoulder (Dq) on a survival curve
relays valuable information because it represents the magnitude
of repair of sublethal damage (SLD). Broad shoulders have
small α/β ratios and good repair of SLD. This repair of sublethal
damage takes several hours (2–6 hours) to complete. The ability
of cells to repair SLD forms the basis for the use of fractionated
1 Normal
Surviving fraction
0.1 
Nonrepairable
0.01
Repairable
Dose
FIGURE 23.6  Cell survival curve. The initial slope, α, represents
irreparable damage, and the terminal slope, β, represents repa-
rable damage. The α/β ratio is the point on the curve where the
two are equal.
doses in clinical radiation therapy, in which differential capaci-
ties between normal tissue and tumor to repair a sublethal
injury can be exploited (Fig. 23.7). This differential repair
capacity also forms the basis for accelerated fractionation or
hyperfractionation in which the dose is given twice a day. This
approach works very well with rapidly growing tumors. Treated
twice a day, the normal tissues have sufficient time to repair, but
the tumor tissues, which are less organized, efficient, and accu-
rate, are differentially killed. Some cells have almost no shoulder,
indicating a limited ability to repair sublethal damage, and these
cells can be eradicated with relatively low doses of radiation. For
example, dysgerminomas are highly curable with relatively low
doses of radiation (20–30 Gy) compared with cervical cancer
tumors, which may require more than 70 Gy to obtain cure.
The availability of oxygen is of vital importance to the
radiosensitivity of the cell also. As radiation enters the cell, it
interacts with organic molecules (DNA). This molecule may
repair itself unless an oxygen molecule becomes attached,
thereby “fixing” the damage. The addition of O2 will enhance
low LET radiation (photons) but does not similarly affect high
LET radiation. The ability of oxygen to enhance radiation is
measured by the oxygen enhancement ratio, or oxygen enhance-
ment ratio (OER) (OER = Dose of XRT without O2 for a given
effect/Dose of XRT with O2 for the same effect). It takes at least
2% (17 mm Hg) tissue O2 to see the full oxygen effect.
Tumor cells with potentially unlimited capacity for growth
are limited as they outgrow the blood supply. In fact, tumors
above 200 µm have necrotic cores secondary to a limited dif-
fusion distance for oxygen. Oxygen may effectively penetrate
approximately 70 µm from the blood vessel (Fig. 23.8). Outside
this distance, tumor cells become deficient and enter a noncycling 
phase. They may become hypoxic or even anoxic and necrotic.
tissue
Surviving fraction
Tumor
tissue
Fractionated dose
FIGURE 23.7  Different capacities between normal tissue and
tumor to accumulate and repair sublethal injury from fraction-
ated doses result in differential survival. The normal tissue is
able to repair more efficiently and effectively.
594 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

M
Mitosis

O Capillary G2
2
Gap 2
G1
Gap 1

Aerated cell
Hypoxic viable cell
Anoxic necrotic cell G0
70 m S Noncycling
FIGURE 23.8  As the distance from the blood supply increases, Synthesis
cells become hypoxic and even anoxic. Hypoxic cells are more
radioresistant and therefore harder to sterilize. Oxygen diffuses FIGURE 23.9  Cell cycle.
about 70 µm from the capillary.

This is important from a radiobiologic standpoint because

noncycling cells exhibit a greater capacity to repair radia-
tion injury. Hypoxic cells are more resistant to the effects of
radiation than are cells with normal oxygen tension. Thus large
tumors can be difficult to control with radiation therapy, not
only because there is a greater number of cells to sterilize but
also because a proportion of these cells are hypoxic, noncycling, Late S
Cell survival

and radioresistant. As a clinical example, experience notes

that exophytic friable cervical lesions that hemorrhage easily
on contact respond better and more quickly than infiltrative
lesions. The blood supply and oxygenation vary considerably
between these two lesions, with the friable lesion better vas-
cularized and oxygenated and therefore more radiosensitive.
Unfortunately, attempts to overcome this differential sensitivity
by mechanisms such as hyperbaric oxygen and radiosensitizers
have been less than optimal to date.
Another factor important in radiosensitivity is the propor-
tion of mitotic or clonogenic cells in the tumor. Cycling cells
are more radiosensitive. In fact, mitotic counts have been shown
to correlate with the prognosis in many tumors. The position
in the cell cycle is also important (Fig. 23.9). Cells in late G2
and mitosis (M-phase) are the most sensitive to radiation, and
cells in late synthesis (S-phase) are the most resistant (Fig.
23.10). This is exploited with chemotherapies such as paclitaxel,
which arrests cells in mitosis and is a profound radiation
sensitizer.
Finally, the initial tumor volume greatly influences the ability
to sterilize a site. Generally, the smaller the tumor volume, the
less radiation is required to destroy all cells. As the volume
increases, the dose to obtain local control is increased. The
concept of treating with “shrinking” fields is to serially reduce
the size of the radiation portals to give a higher dose of radia-
tion therapy to the central portion of the tumor, where presum-
ably more hypoxic, radioresistant cells are present.
Historically, clinicians attempted to correlate radiation
tumor response and local tumor control. Generally, the faster
and more complete the tumor response at the completion of
Early S
G1
M G2
Dose
FIGURE 23.10  The survival curve for cells in mitosis, and G2
is steep and has no shoulder. The curve for cells late in S phase
is shallower and has a large shoulder. G1 and early S are
intermediate in sensitivity.
the therapy, the greater long-term control, assuming that no
distant metastasis occurs. Although this is not uniformly true,
it has been shown in cervical cancer that there is a good correla-
tion between local tumor control and complete or partial
regression of the cancer at the completion of radiation. In addi-
tion, Grigsby and associates have correlated posttreatment PET
tumor response (which measures glucose metabolism) with
survival.
Another factor limiting radiocurability is the normal tissue
toxicity with increasing radiation doses. Normal tissue effects
depend on total dose, dose fraction size, volume, and inherent
tissue radiosensitivity. The ultimate goal is to obtain maximal
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 595
curability with minimal side effects. Combining radiation
therapy with surgery or chemotherapy decreases normal tissue
tolerance to a given dose. Well-established port size, total dose,
and fractionation schemes have been identified but cannot
remain static. Variations are being investigated to increase
curability and decrease complications, including new che-
motherapeutic radiosensitizers, technological advances in the
delivery of radiation such as IMRT, and radioprotectors such  mucosa, esophagus, intestinal mucosa, kidney, and testes. It is
as Ethyol.
RADIOSENSITIZERS, HYPOXIC CELL
SENSITIZERS, AND RADIOPROTECTORS
Radiation sensitizers and protectors are being actively investi-
gated to increase the effectiveness of radiation or allow dose
escalation while minimizing side effects. Radiation sensitizers
increase the ability of radiation to cause permanent, lethal
damage. This therapeutic gain may be from a variety of mecha-
nisms, including selective uptake, targeting, or activation. To be
effective, sensitizers must have acceptable normal tissue side
effects. Known radiation sensitizers include chemotherapeutic
agents such as cisplatin, 5-fluorouracil, paclitaxel, Adriamycin,
and gemcitabine. Hypoxic cell sensitizers include the imidazole
drugs such as misonidazole and bioreductive agents such as
tirapazamine. Endogenous sulfhydryl compounds and Ethyol
afford radioprotection to normal tissues.
The advantages afforded by chemoradiation can be by several
mechanisms. Some agents (eg, cisplatin) inhibit the repair of
radiation damage, but others (eg, paclitaxel) block cells in a
radiosensitive cell cycle phase. Adriamycin, docetaxel, and
paclitaxel have unique effects when combined serially with
radiation because “radiation recall” is an uncommon but dis-
tressing phenomenon. After a course of radiation, the normal
tissue sensitization can be “recalled” when the chemotherapy is
initiated—this phenomenon is a reemergence of a prior radia-
tion burn that conforms exactly to the prior radiation portal.
The mechanism of this is unknown but well described for these
chemotherapies.
The nitroimidazoles such as metronidazole, misonidazole,
etanidazole, and nimorazole are electron affinic and increase
the sensitivity of radioresistant hypoxic cells to XRT. They
mimic oxygen and can diffuse into hypoxic areas. Unfortunately,
clinical studies to date have demonstrated significant toxicity
and little clinical utility with these drugs.
Tirapazamine is entering clinical trials as an adjunct to
radiotherapy. Gynecologic Oncology Group (GOG) trial 219
randomized chemoradiation for cervical cancer with and
without tirapazamine. Tirapazamine is bioactivated intracel-
lularly to a cytotoxic, active free radical that causes extensive
chromosomal breaks and inhibits DNA repair. The reaction
is driven by low tissue oxygen tension and when combined
with radiation may allow more effective destruction of tumors
with hypoxic cores. The GOG published a phase II trial for
advanced or recurrent cervical carcinoma using tirapazamine
and cisplatin and concluded that the combination was fairly
well tolerated. A subsequent phase III trial randomizing stages
Ib2 to IVa between standard cisplatin and radiation versus
cisplatin, radiation, and tirapazamine was opened but closed
for accrual in 2009.
Radioprotection has been proved in several sites with the use
of Ethyol. Amifostine (Ethyol; WR-2721) is an organic thio-
phosphate extensively studied by the Walter Reed Army Institute
of Research. Normal tissues noted to be protected included the
salivary glands, bone marrow, immune system, skin, oral
dephosphorylated to the active metabolite (WR-1065) in the
tissues.
It is believed that tissue versus tumor alkaline phosphatase
concentration variations provide the differential protective
effect. In addition, tissue pH differences afford selective tissue
versus tumor uptake of Ethyol. When given intravenously, the
plasma half-life is less than 10 minutes, but there is prolonged
retention of the drug in normal tissue. In the first 30 minutes,
drug uptake into normal tissues has been shown to be 100 times
that of tumor tissues. When inside the cell, the metabolite
scavenges oxygen free radicals and provides an alternative target
for alkylating agents, such as cisplatin.
There have been numerous studies of the protective effect of
Ethyol with no reported decrease in antitumor efficacy. A phase
III trial in head and neck cancer unequivocally established its
role in salivary gland protection, confirming earlier studies.
Other clinical trials have shown Ethyol protects from cisplatin-
induced renal, neurologic, and bone marrow toxicity. Liu
published a phase III randomized trial in rectal cancer patients
treated with pelvic radiation with and without Ethyol (340 mg/
m2). The toxicity in the mucous membranes and genitourinary
(GU) and gastrointestinal (GI) tracts was reduced by 50% in
the Ethyol arm. Moderate to severe late toxicities were seen in
14% of those treated without Ethyol compared with zero in the
Ethyol-treated patients.
Athanassiou and colleagues randomly assigned 205 patients
with pelvic radiation plus or minus Ethyol and demonstrated a
significant decrease in bladder and GI toxicity. Complete
responses to therapy and median survival were not significantly
different between the arms. The RTOG (Radiation Therapy
Oncology Group 0116) completed a two-arm trial using Ethyol
with chemoradiation for pelvic and paraaortic radiation with
concomitant cisplatin in cervical carcinoma. Arm 1 consisted
of cisplatin chemotherapy concomitant with paraaortic radia-
tion and demonstrated significant acute and late toxicity. Arm
2 again demonstrated significant acute and long-term toxicity,
with no significant benefit demonstrated with the addition of
Ethyol, although compliance to the medication was disappoint-
ing. Ethyol has been found to be useful in reducing early and
late toxicity with hypofractionated accelerated conformal radia-
tion by Koukourakis. Toxicities with intravenous administration
include hypotension and nausea. Data on subcutaneous admin-
istration demonstrate less hypotension but treatable nausea and
skin effects persist. There have been rare reports of Stevens-
Johnson syndrome.
Genetic Effects
It is not possible to generalize and assign a specific mutation
rate to a given radiation dose. Gene loci differ greatly in their
596 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

mutability, and the random damage exerted by irradiation on TABLE 23.7  Radiation Doses to Low
any particular chromosome makes predictability impossible. Pelvis From Diagnostic Scans
The mitotic stage, cell type, sex, species, and dose rate influence
the mutation rate as studied in lower animals and bacteria. Data Dose to Fetus
from lower animals are difficult to extrapolate to humans, and (First Trimester)
and Maternal
therefore prediction of mutation rates cannot be expected from
Examination Gonads (mcGy)
the evidence that has been accumulated from various types of
radiation exposure. Direct evidence of radiation-induced muta- Lower extremity radiography 1
Cervical spine radiography 2
tion in humans is lacking, although there is strong anecdotal
Chest radiography 8
evidence for carcinogenesis in those exposed to radiation. A few Chest fluoroscopy 70
examples are excess skin cancers seen in those exposed to x-rays Lumbar spine radiography 275
before safety standards were established, lung cancer in pitch- Hip radiography 100
blende miners, bone tumors in radium dial painters, and liver IVP 585
tumors in those exposed to Thorotrast contrast. The largest Upper GI 330
groups of humans available for study are survivors and descen- Lower GI 465
dants of those exposed in Hiroshima and Nagasaki. Although Chest CT 8
there has been no detectable effect on the frequency of prenatal Abdominal CT 800
or neonatal deaths or on the frequency of malformations in Pelvic CT 2300
subsequent generations, this does not mean that no hereditary CT, Computed tomography; GI, gastrointestinal; IVP, intravenous
effects were produced. The number of exposed parents was pyelography.
small, and dosages were so low that it would have been surpris- Modified from DiSaia PJ. In Scott JR, DiSaia PJ, Hammond CB,
Spellacy WN, eds. Danforth’s Obstetrics and Gynecology, 8th ed.
ing if an increase in mutation had been detected in such a brief
Philadelphia, 1999, JB Lippincott.
period. There has not been sufficient time for the several gen-
erations needed to reveal recessive damage.
Radiation does not produce new and unique mutations
but increases the incidence of spontaneous mutations. Based or less (roughly 0.5 cGy). Monthly exposures should not exceed
largely on experiments in mice, it is estimated that the doubling 0.05 rem. If a pregnant patient receives 10 cGy in the sensitive
dose (ie, the dose that will double the spontaneous mutation period of 10 days to 26 weeks, therapeutic abortion should be
rate) for humans is probably 100 cGy. Between 1% and 6% of considered to avoid radiation effects, including malformations,
spontaneous mutations in humans can be ascribed to back- microcephaly, and mental retardation.
ground radiation. With the use of image intensifiers, improved The peak incidence of gross malformations occurs during
radiographic film, and appropriate shielding to prevent scatter, early organogenesis (10–40 days of gestation in humans),
it is possible to attain satisfactory radiographic visualization of although cellular, tissue, and organ hypoplasia can be produced
internal structures with reduced exposure. The average dose of by radiation throughout the fetal and neonatal period with
irradiation to the gonads of some common diagnostic tech- sufficient dose. Diagnostic x-ray procedures should be avoided
niques is given in Table 23.7. The use of diagnostic radiographs in the pregnant woman unless there is overwhelming urgency.
and CT scans has increased and fueled concerns that toxic In women of childbearing age, possible damage to an early
radiation effects may emerge, especially among children exposed conceptus can be prevented by performing tests immediately
to increased diagnostic medical irradiation. Current recom- after the commencement of a menstrual period and obtain-
mendations stress the use of ionizing radiation only when ing a negative pregnancy test result. Compelling evidence that
necessary and substitution of alternate sources of imaging, such radiation may be a causative agent in childhood cancer after
as MRI, which relies on magnetic fields, when possible. prenatal exposure comes from several studies in Great Britain
In general, most mutations are harmful, and there is no and the United States.
known threshold dose for the genetic effect. Permanent sterility Some concrete information is available from the Japanese
in females is estimated to have a threshold of 250 to 600 cGy to survivors of the atom bomb attacks in 1945. Examination of
acute exposure and 0.2 Gy/year for protracted exposure. The children born to survivors demonstrates the primary effect
threshold dose for sterility varies based on the age of the patient, from in utero radiation was microcephaly and mental retarda-
with younger patients being more resistant to the deleterious tion. The most sensitive phase for mental retardation was from
effect. 8 to 15 weeks of gestation. In addition, permanent growth
restriction was also observed, especially in embryos exposed less
Fetal Effects than 1500 m from the center of the explosion. Hall reached the
The classic effects of radiation on the mammalian embryo are following conclusions:
as follows: (1) intrauterine and extrauterine growth restriction; 1. Moderately large doses of radiation (>200 cGy) delivered to
(2) embryonic, fetal, or neonatal death; and (3) gross congenital human embryos before 2 to 3 weeks of gestation are unlikely
malformations. Dose, gestational age, and dose rate are all to produce severe abnormalities in most children born,
important factors influencing radiation damage. The recom- although a considerable number of embryos may be reab-
mendation for fetal dose during the entire gestation is 0.5 rem sorbed or aborted (all-or-none phenomenon).
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 597
2. Significant irradiation between 4 and 11 weeks of gestation
leads to severe abnormalities in many organs.
3. Irradiation between 11 and 16 weeks of gestation may
produce some eye, skeletal, and genital organ abnormalities;
however, stunted growth, microcephaly, and mental retarda-
tion are often present.
4. Irradiation of fetuses between 16 and 20 weeks of gestation
may lead to a mild degree of microcephaly, mental retarda-
tion, and stunting of growth.
5. Irradiation after 30 weeks of gestation is unlikely to produce
gross structural abnormalities leading to a serious disability
but could cause functional disabilities.
PRINCIPLES OF CLINICAL
RADIATION THERAPY
The technical modalities used in modern radiation therapy may
be divided into two major categories:
1. External irradiation: This applies to irradiation from
sources at a distance from the body (eg, teletherapy with
60Co, linear accelerator, betatron, or orthovoltage radiograph
machines).
2. Local irradiation (brachytherapy): This applies to irradia-
tion from sources in direct proximity to the tissue or tumor.
Brachytherapy can be delivered with either an LDR system
or an HDR system. LDR systems require hospital admission
to a shielded room and dose delivery at roughly 50 to 100
cGy/h. HDR systems are commonly done on an outpatient
basis and deliver doses of 120 cGy/h.
a. Intracavitary irradiation is done with applicators loaded
with radioactive materials such as cesium or iridium  similar both for local control and survival, although there are
(eg, vaginal ovoids, vaginal cylinder, intrauterine tandem,
tandem and ring, or, historically, Heyman capsules).
b. Interstitial irradiation (endocurie therapy) is usually
delivered in the form of removable needles containing
cesium or iridium. The term also applies to permanent
isotope implants, such as 125I (iodine) seeds or 103Pd
(palladium).
c. Direct therapy was historically delivered by means of
cones from an orthovoltage machine (eg, transvaginal)
but is rarely available today.
d. Intraperitoneal or intrapleural instillation of radioactive
colloids, such as 32P, is yet another local therapy but is
infrequently used.
External-beam Radiation (Teletherapy)
External radiation is radiation therapy that is delivered from
outside the body. It is most commonly delivered with pho­
tons, electrons, or protons. Machinery to deliver the radiation
includes 60Co units, orthovoltage machines, and linear accelera-
tors, although linear accelerators are the overwhelming major-
ity. Except in the developing world, 60Co units are unusual.
Typically, a patient will need planning done before initiation of
radiation, called simulation. Marks or permanent tattoos are
applied to the skin to allow for daily setup and, commonly, a
planning CT is performed replacing the traditional fluoroscopic
simulation. The use of MRI, CT, or PET images to fuse with
treatment planning CT data is widely available to better delin-
eate tumor targets and normal tissue and in many centers is part
of the standard simulator machine. Three areas must be tar-
geted. The gross tumor volume requires the highest radiation
dose. Microscopic extensions into surrounding tissues must be
targeted but generally require a lesser dose for sterilization.
Subclinical disease presumed to be present in postoperative
beds or regional nodes must also be treated to prevent marginal
failures.
Local Radiation (Brachytherapy)
Local application of radiation (also known as brachytherapy)
permits very high doses to restricted tissue volumes. In this
situation, the physical principle (inverse square law) that the
intensity of irradiation rapidly decreases with distance from the
radiation source is used to advantage. Brachytherapy is well
suited to treat small tumors with well-defined limits and a
clinical situation in which it is desirable to restrict the volume
of tissue irradiated. Larger volumes of tissue that need radiation
therapy are best treated with external irradiation. Historically,
radium (226Ra) had been the most common isotope used for
local application, but because of storage, risk of leaks, and
extremely long half-life, it is rarely used in the United State.
Sources used today are often converted to mg-Ra-equivalents.
Brachytherapy sources such as 125I, 137Cs, 192Ir, and 103Pd are
more commonly used today (see Table 23.4).
Although conventional LDR intracavitary brachytherapy has
produced very good results in cervical cancer, remote afterload-
ing HDR intracavitary brachytherapy is becoming more wide-
spread. The treatment results of LDR and HDR appear to be
no large American randomized trials. Retrospective studies,
however, mirror the results of the randomized studies. There
remain concerns over potential differences in late complications
resulting from the different biologic mechanisms between the
continuous low dose rate of LDR and the intermittent high dose
rate of HDR. The increased interest in HDR arises from cost of
inpatient hospitalization, the risks of prolonged bed rest, and
radiation exposure to medical personnel with LDR systems. In
both LDR and HDR, it is very important to keep the doses to
normal tissues as low as possible by proper placement of radia-
tion carriers and the use of shielding and packing or retraction
techniques. HDR units use computer technology to “optimize”
the dwell time of a single source to give the required distribu-
tion. The American Brachytherapy Society has published con-
sensus guidelines on the administration of HDR for both
cervical and uterine carcinomas. Also in use as an alternative to
LDR or HDR is pulsed dose rate (PDR), although randomized
trials on this method are lacking, and published reports are few
but increasing.
The term dosimetry is applied to the measurement and cal-
culation of dose that the patient receives. In brachytherapy,
as radiation intensity rapidly decreases with increasing distance
from the source, tissue adjacent to the radiation source is treated
to a high dose while relatively sparing surrounding tissue. The
effectiveness of this distribution of irradiation depends on
meticulous application of these sources. Interstitial application
598 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy
of radioactive sources is more difficult than intracavitary appli-
cation. It is essential that the gynecologic oncologist be able to
critically assess the placement of tandem and ovoids, cylinder,
and ring to assess the optimal placement of brachytherapy
sources (Figs. 23.11 and 23.12). Increased use of computer
planning to optimize the dose to the tumor and minimize the
dose to the normal tissues is under active clinical investigation
and is likely to replace the current two-dimensional dosing
guidelines and restrictions based on calculated doses to points
(eg, points A, B, and bladder and rectal points) with three-
dimensional, volume-directed, image-guided brachytherapy
(IGBT). The European collaborative group Groupe Européen
de Curiethérapie and the European Society for Therapeutic
Radiology and Oncology (GEC-ESTRO) have published exten-
sive work on this subject and an international trial. EMBRACE
(Mri-guided BRachytherapy in CErvical cancer) is open to test
the utility and applicability of the new guidelines.
Normal Tissue Tolerance
The tolerance of any tissue (normal or tumor) to irradiation
therapy depends on several characteristics of radiation,
including (1) fractionation technique, (2) field arrangement,
(3) total dose, (4) dose rate, and (5) volume irradiated.
Fractionation is the number of treatments needed to deliver the
total dose. Pelvic radiation delivered to a patient for a total dose of
5000 cGy given in five daily fractions of 200 cGy each week for 5
weeks is well tolerated in most cases. However, if that same total
dose of 5000 cGy were given in five fractions of 1000 cGy every
Monday for 5 consecutive weeks, tolerance would be low.
In addition, multiple fields are used to minimize toxicity by
dividing the exposure of normal tissue into multiple different
regions. Three-dimensional conformal therapy (3DCF), IMRT,
and IGRT are areas of active investigation to further maximize
dose to tumor and minimize toxicity to the surrounding normal
tissues (Fig. 23.13). With external irradiation, the patient is
treated to all fields 5 days/week.
As is seen in LDR brachytherapy versus HDR brachytherapy,
dose rate affects tolerance. The final dose in HDR is necessarily
lower to compensate for normal tissue tolerance concerns with
the markedly higher dose rate in HDR. Conversion of doses to
a 2-Gy dose equivalent is recommended by the Groupe Euro-
Péen de Curiethérapie-European for Radiotherapy and Oncol-
ogy (GECT-ESTRO) guidelines and is becoming more common
(see later).
Finally, the volume of tissue irradiated is also an integral
factor in tolerance. For example, a 1-cm circular field of skin
would easily tolerate the fractionation and dose rate of 1000
cGy each Monday for 5 consecutive weeks. However, for a larger
volume, such as whole-pelvis radiation, such a treatment plan
is intolerable.
Patient factors also affect normal tissue tolerance. Previous
surgery affects the morbidity of radiation therapy. In both
cervical and uterine cancer, surgery identifies adverse surgical
pathologic findings that direct radiation therapy. In cervical
cancer, surgical evaluation of possible lymph node metastases,
particularly in advanced cancers, may be done, or a radical
hysterectomy may be aborted because on inspection, the tumor
is more advanced than originally indicated. Transperitoneal
lymph node dissection followed by pelvic and possibly para-
aortic radiation increases radiation-induced complications,
particularly to the bowel. Radiation complications can be severe,
including fistula formation, bowel obstruction, and perforation.
The retroperitoneal approach to lymph node dissection has a
decreased complication rate and is the preferred method of sur-
gically evaluating lymph node status in cervical cancer. Medical
conditions that affect blood flow such as diabetes, hypertension,
and peripheral vascular disease can also decrease normal tissue
tolerance.
Pelvic Organ Tolerance
Irradiation tolerance of the normal organs of the pelvis varies
from one patient to another and is subject to the factors previ-
ously mentioned, such as volume, fractionation, and total dose
of irradiation. As is illustrated in many areas of oncology, the
more advanced lesions require higher doses for tumor eradica-
tion, and hence the possibility of morbidity increases. This,
combined with the fact that advanced cancer often already
compromises the integrity of the bladder and rectum, means
that serious sequelae can develop in patients with advanced
cervical, vaginal, and corpus lesions when curative therapy is
sought. New advances in radiation delivery will, hopefully,
decrease these adverse effects.
The normal tissues of the cervix and the corpus of the uterus
can tolerate very high doses of radiation. In fact, they withstand
higher doses better than any other comparable volume of tissue
in the body; surface doses of 20,000 to 30,000 cGy in about 
2 weeks are tolerated. This remarkable tolerance level permits 
a large tumor dose and allows a very high percentage of central
control of cervical cancer. The unusual radiation tolerance of
the uterus and the vagina, stemming from an unusual ability
to recover from radiation injury, accounts for the success of
brachytherapy in the treatment of cervical lesions.
In contrast, the sigmoid, rectosigmoid, and rectum are more
susceptible to radiation injury than are other pelvic organs.
The frequency of injury to the large bowel often depends 
on the total dose administered by both the external beam and 
the intracavitary system. With external-beam radiation alone, the 
large bowel is the most sensitive of the pelvic structures. The 
bladder tolerates slightly more radiation than does the recto-
sigmoid, according to most authorities. Acceptable maximal
point doses are 75 Gy and 70 Gy to the bladder and rectum,
respectively. Fletcher proposed a rule that gives the upper
limits of pelvic irradiation and indirectly gives the tolerance
of the bladder and rectum. The guidelines limit the sum of
the central dose, stating that external-beam radiation dose plus
the number of milligram-hours of cesium administered by
brachytherapy should never exceed 10,000. There is a parallel
time guideline also critical to this limit. This is a necessary safety
to prevent compact systems from exceeding vaginal or cervical
tolerance. This guideline is valid only when the Fletcher-Suit
brachytherapy systems are used. Most of this is applicable
to therapy for the uterus, cervix, and vagina. In general, if a
large dose of intracavitary irradiation is applied centrally for
a small lesion, the amount of external beam applied centrally
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 599

A B

C
FIGURE 23.11  Assessing proper placement of tandem and ovoids. In both photos, small
interstitial silver seeds mark the cervix. Note that in A, the cervical stop, outlined in red, has
dropped away from the cervix, compromising the dose delivery to the tumor and increasing the
complications. In B, this has been corrected. Also note that the vaginal packing (delineated by
radiopaque string) lies below the ovoids and that the tandem is midline and bisects the ovoids.
In C, a lateral radiograph, the tandem again bisects the ovoids and lies beneath the bladder (the
Foley balloon is filled with contrast material) and does not lie too close to the sacrum.
600 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy
B A A B
75 150 150 75
30 50 100 200 200 100 50 30
FIGURE 23.12  Isodose curves surrounding a typical Fletcher-
Suit intracavitary application (tandem plus ovoids) for cervical
cancer. Note the location of points A and B and the relative
dose rates at distances from the system.
must be reduced. Conversely, if a lesion is large and the vaginal
geometry is poor, a smaller intracavitary dose can be given
and the dose administered by external beam may be raised  ment (eg, hydrogen peroxide douche, estrogen therapy) resolves
(6000–7000 cGy).
GEC-ESTRO dose/volume guidelines limit the bladder to
90 GyEQD2 and rectum/sigmoid to 70 to 75 GyEQD2 for a calcu-
lated 2-cc volume combining doses from both external-beam
irradiation and brachytherapy. In this system, doses from HDR
brachytherapy are converted by a formula to a 2-Gy equivalent
to allow the doses to be added (EQD2, or equivalent dose at
2 Gy). The formula for conversion is EQD2 = D X [(d + α/β)/2
+ α/β], where D is total dose, d is dose/fraction, and α/β is 3
for late-responding tissues and 10 for tumor/acute-responding
tissues. Certain assumptions are made in this model, such as the
same 2 cc of bladder, rectum, and sigmoid receive the maximal
amount of irradiation with each fraction of brachytherapy.
Especially in the mobile sigmoid colon, this assumption may be
erroneous but models the worst-case scenario. A recent paper
by Georg and colleagues demonstrated that the 5-year actuarial
rectal toxicity rate was 20% if the dose exceeded 75 GyEQD2 and
5% if the 2-cc dose remained below 75 GyEQD2. For the bladder,
the 5-year actuarial toxicity rate was 13% versus 9% if a value of
100 GyEQD2 was used. Insufficient events occurred in the sigmoid
colon in this study for definitive analysis, but recommendations
remain to keep the sigmoid less than 70 to 75 GyEQD2. It is hoped
that further study will refine these guidelines.
Pelvic radiation spares a significant portion of the small
bowel because bowel is normally in episodic motion. This tends
to prevent any one segment from receiving an excessive dose.
However, if loops of small bowel are immobilized as a result of
adhesions caused by previous surgery, they may be held directly
in the path of the radiation beam and thus injured (Fig. 23.14).
The result of such an injury is usually not manifested for at least
6 months or longer after completion of radiation. Studies
demonstrate that the use of IMRT in the postoperative setting
can decrease the acute effects of irradiation on the bladder and
bowel, but definitive randomized studies are not available to
date (see later).
Long-term Effects
Finally, it is important to understand the permanent nature
of radiation injury. When any area of the body is subjected to
tumoricidal doses of radiation, the normal tissues of that area
sustain an injury that is only partially repaired. The tumor
tissue disappears, but the normal tissue bed remains, and
residual radiation changes must be seriously considered if other
disease processes ensue. Radiobiologists estimate that in the
case of injury to normal tissues, only 5% to 20% of the damage
is repaired. If a second malignant neoplasm arises in that same
area many years later, additional tumoricidal radiation is fre-
quently impossible because of permanent radiation changes. In
addition, any surgical procedures performed within a previ-
ously irradiated field are at higher risk for poor healing, fistula
formation, and so forth.
Radiation-induced soft tissue necrosis can be a significant
complication. This is usually a result of a progressive oblitera-
tive endarteritis that leads to decreased blood flow and a
resultant hypoxic tissue bed. This causes increased fibrosis, poor
healing, and chronic ulceration. Local conservative manage-
the problem in many cases. A small group of patients has sig-
nificant tissue breakdown that may be painful and may lead to
fistula formation. The use of hyperbaric oxygen has been shown
to enhance healing in these radiation-induced injuries. Treat-
ment with hyperbaric oxygen requires entering a tank where
one breathes 100% oxygen at an increased atmospheric pres-
sure. This increases the oxygen concentration in all body tissues
up to 20 times normal. This treatment is done daily for 6 to 8
weeks. Side effects include nausea, claustrophobia, painful pres-
sure on the ears—similar to the changes experienced with
airline pressure changes—pneumothorax, and oxygen toxicity.
Permanent changes to the GU and GI tract can cause signs
and symptoms such as decreased bladder capacity, hematuria,
ureteral or urethral stricture, hematochezia, bowel obstruction,
chronic diarrhea, tenesmus, fecal incontinence, and fistula for-
mation. Gynecologic changes include dryness and shortening
of the vagina, dyspareunia, and decreased orgasm. All of these
long-term effects should be addressed by the oncology team to
maximize the patient’s quality of life.
NEW RADIATION MODALITIES
Protons
Protons result in an excellent physical dose distribution. The
dose increases slowly with depth and reaches a sharp maximum
near the end of the particle’s range called the Bragg peak. This
sharp dose peak allows for extremely precise, circumscribed
delivery. Other than the physical distribution advantage, protons
have biologic properties similar to x-rays. Protons are ideal for
specific clinical situations, such as spinal cord tumors and eye
melanomas, in which a sharp dose delivery is critical to avoid
normal tissue damage. Reports also describe the utility in more
common tumors, such as prostate cancer. Although useful in
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 601

FIGURE 23.13  Comparison of normal

tissue irradiated with four field box tech-
nique (A), three-dimensional conformal
therapy (B), and intensity-modulated
radiation therapy (C). The red represents
areas that receive 100% of the prescrip-
tion dose, yellow 90%, green 50%, and
blue 40%. Notice how the normal tissue
volume receives less dose as the treat-
ment is delivered more conformally.

C
602 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy
FIGURE 23.14  Small bowel in the pelvis demonstrated by
small bowel contrast.
several clinical situations, the cost of delivery from a cyclotron
or special linear accelerator makes it currently available in a few
cities, although interest is mounting and new centers are being
built or contemplated in other areas.
Electrons
Most modern linear accelerators can produce high-energy
electron beams. Electrons lose energy rapidly as they travel in
tissue and interact with tissue atoms, and ultimately their
kinetic energy is reduced to zero. Therefore, unlike photons,
electrons have a specific range dependent on energy and the
tissue traversed. Transvaginal electron irradiation can be used
for a copiously bleeding exophytic cervical lesion to induce
hemostasis. The dosimetry is such that most of the energy
delivered transvaginally is absorbed into the malignant lesions
itself. Lesions of the vulva and inguinofemoral lymph nodes are
also treated with electron beams in many institutions. The
limitations of electron therapy are related to the strengths.
Because it loses energy rapidly, it cannot be used for deep-seated
tumors, and the applicator must rest very close to the tumor
itself, so only fairly superficial, shallow lesions are appropriately
treated with electrons.
Fast Neutrons
Neutrons interact in tissue to produce recoil protons, α particles,
and other nuclear particles. Their potential usefulness stems
from a reduced OER (this translates into decreased hypoxic cell
resistance), reduced differential killing by cell cycle, reduced
ability for cells to repair sublethal damage, and higher effective-
ness for slowly cycling tumors.
Although randomized controlled trials demonstrated that
neutron therapy provided improved local control in some
tumors, its utility was limited by higher morbidity and cost.
Overall, use is limited by the cost of the cyclotron, limited depth
penetrations, high surface entrance dose, lack of sharp beam
boundaries, and variable intensity modulation.
Negative Pi Mesons and Other Heavy Ions
Negative pi mesons, or pions, are negatively charged particles
that have a mass 273 times that of an electron. These are pro-
duced in a cyclotron or linear accelerator using 400 to 800 MeV
protons that bombard a beryllium target. Pions exhibit a Bragg
peak produced by elicited protons, neutrons, and α particles.
Other heavy ions such as neon, argon, and carbon have been
studied, but equipment to produce these special particles is
expensive and not widely available. Use is limited to experimen-
tal therapy only. As with neutrons, these forms of radiation have
a high biologic effectiveness and a low dependence on oxygen.
NEW RADIATION DELIVERY TECHNOLOGY
Intraoperative Radiation
Several centers throughout the world are investigating the
utility of large-fraction intraoperative external irradiation.
Patients are subjected to operative procedures in which the area
of involvement is carefully defined, and radiation fractions of
1500 to 2500 cGy are delivered directly to the area identified.
Applications of this technique in gynecologic oncology have
been in the treatment of biopsy-proven positive paraaortic or
pelvic nodes and marginally resectable recurrences. Electron
beam radiation is delivered with one high-dose fraction with
the bowel and other sensitive normal tissues packed to the side,
thus minimizing the probability of visceral injuries. For best
results, external-beam radiation is often combined with intra-
operative therapy. Because the intraoperative accelerators only
deliver electrons, it is subject to the same limitations as all
electron beams (see previous discussion). Experience in both
primary and recurrent tumors has been reported. The results
are limited but have shown increased local control when used
selectively. The role of intraoperative radiation in gynecology is
not widespread and is limited to a few institutions that are
capable of providing this specialized therapy. New techniques
involving intraoperative low-energy radiation sources in the kV
range are being investigated in other sites such as breast, but
there are no reports of use in gynecologic cancers as yet.
Hyperthermia
As discussed previously, solid tumor masses often have hypo-
vascular centers, which are poorly penetrated by antineoplastic
drugs and have hypoxic, radioresistant cell fractions. Hyper-
thermia is another method used to overcome these relatively
radioresistant tumors. Although several anecdotal clinical observa-
tions have been made, current interest in hyperthermia is based
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 603
mainly on careful biologic studies on cells and transplantable
tumors performed in the 1980s. Although there is no evidence
that tumor cells are consistently more sensitive to heat than
normal cells, several factors may contribute to a therapeutic
gain. Tumor hypoxic cell populations have an acidic pH and are
nutritionally deprived. These factors increase sensitivity to heat.
Therapeutic gain is also derived from selective heat retention
in the tumor. The hypoxic core is maintained at a higher tem-
perature than the normal tissues, which more efficiently remove
heat secondary to better-organized vasculature. Ultimately, cell
death is dependent on the temperature achieved and is time
dependent. Hyperthermia is combined with radiation as each
modality preferentially kills a separate part of the tumor; in
addition, heat increases the cell kill of external radiation by
inhibiting sublethal and potentially lethal damage repair. Late
S phase is the most sensitive phase to hyperthermia but the
most resistant to low LET (photon) radiation, and thus the two
modalities complement one another. The first notable use of
hyperthermia in gynecologic oncology has been with interstitial
hyperthermia for deep tumors of the pelvis. Increased survival
has been demonstrated, although reports are mixed and the
therapy is not commonly available.
Three-dimensional Conformal Radiation Therapy
Three-dimensional conformal radiation therapy is linked to a
multiplicity of imaging modalities, especially CT. Beam place-
ment using a CT simulator replaces the conventional simulator
(fluoroscopic planning machine) for plan design to the extent
that the term “virtual simulation” is used to describe it. The
digitally reconstructed radiographs link the plan to the treat-
ment unit in a manner that is rapidly replacing the conventional
simulator. Three dimensional conformal therapy (3DCF) entails
shaping of the beam to conform to the target as seen by CT
imaging. The physician arranges the beams to maximize dose to
the tumor and minimize dose to normal tissues. Patient, tumor,
and normal target movement demand patient immobilization
and that adequate margin be placed around the targets to
prevent a “marginal miss.”
Intensity-modulated Radiation Therapy
Intensity-modulated radiation therapy, compared with 3DCF
therapy, uses the power of computers to perform hundreds to
thousands of iterations of planning to maximize and shape
tumor dose and minimize normal tissue dose (Fig. 23.15). This
form of planning, called forward planning, gives the computer
instructions on what dose to deliver to the targets and sets
limitations on normal structures. Both 3DCF therapy and
IMRT use small collimator “leaves” to finely shape the beam.
These “leaves” are mobile and block portions of the generated
x-rays. If the collimator “leaves” move while the radiation beam
is on and vary the beam intensity, areas of tumor and normal
tissue can receive a spectrum of doses, hence the term intensity
modulated. These collimator “leaves” also allow for irregular
shapes to be treated. This technology has demonstrated similar
local control with reduced complications in several sites such
as prostate and head and neck. In gynecologic cancer, decreased
radiation to normal tissues, including bowel, bladder, and bone
marrow, has been demonstrated, especially in the postoperative
setting. Papers have been published on the use of IMRT in post-
operative uterine and cervical carcinoma, vulvar carcinoma,
whole abdominal radiotherapy, vaginal carcinoma, and intact
cervical carcinoma. Because of the daily variation in bladder
and rectal filling, the mobility of the upper vagina and cervix,
and the change in cervical volume over the span of treatment
in intact cervical cancer, use of IMRT should be undertaken
with extreme caution and special attention should be given
to assure that the target is accurately delineated and treated
with each fraction. Randomized, prospective trials evaluating
IMRT are anticipated, and consensus guidelines for clinical
target volume delineation have been recently published by Lim
and colleagues. Introduction of new technology such as tomo-
therapy (a linear accelerator linked to an online CT scanner),
CyberKnife (a linear accelerator capable of fiducial imaging
to target radiation), and cone-beam CT (CT scan mounted to
the linear accelerator) for image-guided radiotherapy assists in
daily target and normal tissue localization but in gynecologic
cancer is still investigational. Other concerns regarding this
technology include the enormous physician and physics time
used for planning, increased cost, and the unknown long-term
consequences of lower dose but increased volume of tissue
exposed to radiation.
Stereotactic Radiotherapy
Stereotactic radiation and gamma knife radiation are similar to
IMRT and 3DCF radiation because they allow precise, high-
dose delivery of external radiation. It is commonly used for
both primary and metastatic brain tumors, small lung tumors,
and an increasing number of other sites. Whereas stereotactic
radiation uses a modification of the linear accelerator, gamma
knife is a separate machine with 201 separate 60Co sources used
to focus on the target.
Immune-tagged Radiation Therapy
Recently, several products that tag a radioisotope to a monoclo-
nal antibody have entered the market. This modality of radia-
tion allows delivery of the radioactive isotope to the unique
antibody target. It has been used successfully in lymphomas and
awaits the identification of a unique target before development
for a gynecologic use.
GLOSSARY
absorbed dose  The energy imparted to matter by ionizing radiation per unit
mass of irradiated material. The unit is the gray (Gy), defined to be an energy
absorption of 1 joule/kg. The old unit was the rad, which was defined as an
energy absorption of 100 ergs/g.
brachytherapy  Treatment of malignant tumors by radioactive sources that
are implanted close to (intracavitary) or within (interstitial) the tumor.
dosimetry  The term applied to the measurement and calculation of dose that
the patient receives.
electron volt (eV)  The energy of motion acquired by an electron accelerated
through a potential difference of 1 volt.
excitation  The moving of an electron to a more distant orbit within the same
atom.
gamma rays  Electromagnetic irradiation (originating inside the nucleus)
emitted by excited nuclei. The gamma rays from an isotope will have one or
several sharply defined energies.
604 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy

FIGURE 23.15  In A and B, note how little normal

tissue is treated to accomplish the sidewall nodal
boost. In C, note how the renal parenchyma and
spinal cord are relatively spared in treating the
paraaortic recurrence.

C
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 605
Gray (Gy)  The special name for the unit of absorbed dose and specific energy
impacted; 1 Gy = 1 joule/kg = 100 rads.
half-life  The time in which half the atoms of a radioactive species
disintegrate.
image-guided brachytherapy (IGBT)  The use of imaging for three-
dimensional, volume directed planning.
image-guided radiation therapy (IGRT)  The use of images taken before,
during, or after treatment while in the treatment room to allow visualization
of target, fiducial markers, or organs at risk.
intensity modulated radiation therapy (IMRT)  Computer technology
that allows variable fluence across the beam and increased conformance to
target relative to normal tissues.
inverse square law  The intensity of radiation from a point varies inversely as
the square of the distance from the source. Thus, the dose rate at 2 cm from a
source is one fourth that at 1 cm. At 3 cm, the dose rate is one-ninth that at 1 cm.
ionization  The removal of an electron from an atom, leaving a positively
charged ion.
ionizing radiation  Radiation capable of causing ionization.
isotope  Nuclides having an equal number of protons but a different number
of neutrons (excitable situation).
keV  1000 eV.
linear energy transfer (LET)  The energy lost by the particle or photon per
micron of path depth. High LET radiations are more effective against
hypoxic cells.
meV  1,000,000 eV.
oxygen enhancement ratio (OER)  The ratio of the dose required for a
given level of cell killing under hypoxic conditions compared with the dose
needed in air.
penumbra  The radiation outside the full beam, which is often caused by
scatter or incomplete collimation.
rad  A unit-absorbed dose of ionizing radiation equivalent to the absorption
of 100 erg per gram of irradiated material.
relative biologic effectiveness (RBE)  A ratio of the absorbed dose of a
reference radiation to the absorbed dose of a test radiation to produce the
same level of biologic effect, other conditions being equal.
rem  The old unit of dose equivalent. It is the product of the absorbed dose
in rads and modifying factor and is being replaced by the sievert.
roentgen (R)  An internationally accepted unit of radiation quantity: It is the
quantity of “x-ray or gamma irradiation such that the associated corpuscular
emission per 0.001293 g of air produces, in air, ions carrying 1 esu of
quantity of electricity of either sign.” X-rays originate outside the nucleus.
Sievert (SU):  The unit of dose equivalent in the SI system (1 Sv = 100 rem).
x-rays:  Rays emitted by a particular generator will emit a spectrum of
energies.
For the bibliography list, log onto www.expertconsult.com
〈http://www.expertconsult.com〉.
 CHAPTER 23  Basic Principles in Gynecologic Radiotherapy 605.e1
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