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Principles of Radiation Oncology

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Principles of Radiation Oncology
Arno J. Mundt, MD
John C. Roeske, PhD
Theodore D. Chung, MD, PhD
Ralph R. Weichselbaum, MD
Radiation Oncology is a field devoted to the
treatment of benign and malignant diseases with
ionizing radiation (IR). The field was born not
long after the discovery of x-rays by Wilhelm
Roentgen in 1895.1 Radiation therapy (RT) was
soon being used in the treatment of a wide vari-
ety of malignant tumors.2,3 It was also soon rec-
ognized, however, that radiation produced
adverse effects on normal tissues. In fact, due to
the significant cutaneous toxicity associated
with the available low-energy machines, RT had
limited applicability until the introduction of
high-energy (megavoltage) therapy in the 1950s.
Only then was it possible to treat deep-seated
tumors without excessive toxicity.
Over the past 20 years, tremendous advances
have been made in imaging and treatment deliv-
ery, allowing for improved targeting and
increased sparing of normal tissues. Increased
understanding of radiobiology has also provided
a means of further reducing the risk of treatment
sequelae while increasing the efficacy of treat-
ment. RT currently occupies an important role in
the management of benign and malignant dis-
eases throughout the body in both children and
adults and offers an effective means of palliation
when cure is not possible.
PHYSICAL BASIS OF
RADIATION THERAPY
TYPES OF RADIATION RT is delivered primarily
with high-energy photons (gamma rays and x-
rays) and charged particles (electrons). The dis-
tinction between gamma rays and x-rays lies in
their origin; gamma-rays originate from excited
and unstable nuclei, whereas x-rays are produced
by electron energy transitions within the atom or
RADIATION ONCOLOGY
through the deceleration of high-kinetic energy
electrons (bremstrahlung).4,5 Gamma rays are
typically produced by radioactive sources used in
brachytherapy (see below), whereas x-rays are
generated by linear accelerators and used in
external beam RT. Within a linear accelerator, a
narrow beam of electrons is accelerated to nearly
the speed of light before striking a tungsten tar-
get.5 As the electrons decelerate, they emit brem-
strahlung radiation (x-rays) with a spectrum rang-
ing from zero to their maximum kinetic energy.
Beam quality is expressed as their highest-energy
photons in terms of kVp (kilovolts peak) or MV
(megavolts). Therapeutic beam energies range
from 50 kVp to 25 MV or greater. In this energy
range, the relevant interactions of photons with
matter include the photoelectric effect, Compton
effect, and pair production.4,5 Compton effect is
the predominant interaction for therapeutic
beams, whereas for energies below 50 kVp, the
photoelectric effect is the most important interac-
tion, and pair production is the primary interac-
tion at energies above 25 MV. As a result of these
interactions electrons are set into motion, causing
ionization and excitation of other atoms in the
medium. As an x-ray beam passes through matter,
its intensity is reduced and can be expressed by
the following formula:
I (x) = Ioe-mx
where Io is the initial intensity of the photon
beam, I(x) is the intensity after traversing a depth
x and µ is the material’s linear attenuation coef-
ficient. High-energy beams are less attenuated
than low-energy beams and thus are used for the
irradiation of deep-seated tumors. Radiation
Section 9
39
intensity from a point source also decreases as
the inverse square of the distance from the
source, a dependence known as the inverse
square law.4,5
Unlike a photon beam, a charged particle trav-
els a known range in tissue proportional to its
energy. Tissues beyond the range of the charged
particle are thus not irradiated. Electrons are the
most common therapeutic charged particles and
are also produced by a linear accelerator. Instead
of striking a tungsten target, the beam passes
through a series of filters that broaden and shape
it. Charged particles interact with matter through
three primary processes: soft collisions (Coulomb
force interactions with outer shell electrons), hard
“knock on” collisions (direct interactions with
electrons), and nuclear field interactions.5 Typi-
cally, a 1 MeV electron will undergo 105 interac-
tions before losing its energy.4 Soft collisions
account for approximately half the energy trans-
ferred to matter. The remaining energy is trans-
ferred primarily by the relatively fewer, but more
energetic, hard collisions.
Other therapeutic modalities include neu-
trons6,7 and protons.8,9 Neutron beams are gen-
erated by bombarding a beryllium target with a
cyclotron-accelerated proton beam.5 Like pho-
tons, neutrons are exponentially attenuated.
Interactions with tissue include neutron–proton
collisions and neutron–nuclei reactions, which
set heavy charged particles in motion. Proton
beams are also generated by a cyclotron. Unlike
neutrons, protons primarily deposit their dose
near the end of their range, a phenomenon
known as a Bragg peak.4,5 The Bragg peak can
be modified to encompass the tumor without
delivering high doses to more distal tissues.8,9
586 SECTION 9 / Radiaton Oncology
RADIATION ABSORBED DOSE The quantifica-
tion of radiation has evolved over time. In the
early twentieth century, units of skin erythema
and the roentgen, a measure of ionization pro-
duced in air, were used. Today, the accepted unit
of measurement is “absorbed dose,” which is the
energy absorbed per unit mass. Physically,
absorbed dose represents the energy deposited
by secondary charged particles in the medium.
The unit of absorbed dose is the gray (Gy), which
is defined as the absorption of 1 joule per kilo-
gram (J/kg).4,5 One gray is equivalent to 100
centigray (cGy) or 100 rads.
TREATMENT PLANNING
AND DELIVERY
EXTERNAL BEAM THERAPY The goal of treat-
ment planning is to uniformly irradiate a speci-
fied target while minimizing the dose to sur-
rounding normal tissues.10 The spatial
distribution of radiation delivered depends on a
number of factors including patient anatomy, tis-
sue density, beam energy, and the configuration
of radiation portals. Because of the often com-
plex tumor geometry, image-based three-dimen-
sional (3D) planning is essential.11–14 Both the
concepts of treatment planning and the technical
considerations related to 3D planning are
described below.
Simulation and Target Delineation Simu-
lation involves patient positioning, fabrication of
treatment aids, including immobilization devices,
and the selection of treatment fields.15 Most
patients are simulated in the supine position.
However, specific positions are often indicated to
minimize the dose delivered to neighboring nor-
mal tissues. Breast and lung cancer patients, for
example, are simulated with their arms overhead
to allow for the use of angled (oblique) beams
which do not transverse the arms. Other special-
ized positions include the “frog leg” position (vul-
var cancer) and the “chin tuck” position (pituitary
tumors). Immobilization is accomplished with the
aid of thermoplastics, foam cradles, bite blocks
and other accessories. The goal of immobilization
is to minimize the day-to-day set-up variability
caused by patient movement. On a conventional
simulator, field borders are chosen under fluoro-
scopic guidance on the basis of patient anatomy
and knowledge of tumor spread. More recently,
computed tomography (CT) simulators allow for
direct acquisition of CT data with the patient in
the treatment position. Selection of beam orienta-
tions is performed virtually.
Imaging occupies a central role in RT plan-
ning, providing geometric information on exter-
nal patient contour and tumor size, shape, and
location relative to adjacent critical struc-
tures.16,17 For 3D planning, the process begins
with the acquisition of a CT scan with the patient
immobilized in the treatment position. Three vol-
umes are defined for planning:18 the gross tumor
volume (GTV), the clinical target volume
(CTV), and the planning target volume (PTV).
The GTV is the tumor visible on the treatment
planning images. Regions of microscopic spread
define the CTV. PTV encompasses both the
GTV and CTV with an added margin due to the
uncertainty in the treatment delivery process.
The PTV includes the effects of organ motion
and day-to-day setup uncertainty and typically
ranges from 3 to 10 mm.19,20 In addition, sur-
rounding normal tissues are delineated.
Although CT is the primary imaging modal-
ity for treatment planning, magnetic resonance
imaging (MRI) provides important complemen-
tary information,21–23 especially for intracranial
and head and neck tumors. Other modalities,
such as positron emission tomography (PET)
and single photon emission computed tomogra-
phy (SPECT), also provide complementary
information.24,25 Imaging data can be cross-cor-
related to transfer regions of interest from one
study to another.26–28
Treatment Planning Treatment planning is
performed interactively on a computer and is used
to generate a dose distribution superimposed on
CT images. Variables considered in planning
include beam energy and modality, number of
portals and beam angles, relative beam weights,
and beam-modifying devices (wedges, compen-
sators). Beam energy is chosen on the basis of
patient anatomy. High-energy photon beams are
used for deep-seated tumors; superficial tumors
may be treated with orthovoltage-energy photon
beams (100–250 kVp) or with electrons. Beam
number is determined by a variety of factors
including tumor size, shape, and location. Beam
modifying devices are used to compensate for
variations in external patient anatomy.
A number of tools have been developed that
aid in the design and evaluation of a treatment
plan.29–32 Beam’s eye view (BEV) allows the
visualization of the tumor geometry relative to
critical structures from the perspective of the
radiation beam.29 Beam orientations are chosen
that encompass the PTV but spare adjacent criti-
cal structures. In addition, BEV also permits the
design of customized shielding blocks. Quantita-
tive evaluation of treatment plans is performed
using dose volume histograms (DVH) and dose
surface histograms (DSH).31,32 DVH represents
the volume of a particular organ irradiated as a
function of dose. The surface area as a function
of dose is represented by DSH and is used in the
evaluation of hollow organs. Such quantitative
evaluation assists in the selection of the optimal
treatment plan. Other treatment planning tools
include digitally reconstructed radiographs30
and volume rendering.33,34
Treatment Delivery and Verification
Linear accelerators are used to administer
external beam RT (Figure 39-1). Most modern
accelerators have dual photon energies ranging
from 4 to 24 MV, and four to six electron ener-
gies (6–22 MeV). Accelerators are equipped
with a gantry which rotates through 360º allow-
ing treatment from any angle. Non–co-planar
beams may be delivered through a combination
of gantry and treatment table rotations. The
beam produced is rectangular in shape. Beam
shaping is accomplished with either cerrobend
blocks or a multi-leaf collimator (MLC). Cer-
robend is a low-melting-point alloy which
attenuates nearly all of the beam.5 Custom
blocks are designed for each field and are
placed manually. MLC, as the name implies,
consists of a series of leaves within the machine
head, which are typically 1 cm in width.35,36 An
MLC increases the efficiency of treatment
delivery by obviating the need for changing
blocks between fields and offers the capability
of delivering intensity modulated radiation
therapy (IMRT) (see below).
RT is delivered with the patient placed on the
treatment table in a customized immobilization
device. The patient is positioned so that the center
of the PTV is at the isocenter, the center of rotation
of all moving parts of the machine (gantry, colli-
mator, and table). On the first day of treatment, set-
up films are obtained and compared with those
taken at simulation. The position of anatomic land-
marks are evaluated, and patient moves are made
as needed. Films are also obtained at each treat-
ment angle, showing both the internal anatomy and
the field aperture. In recent years, electronic portal
imaging devices (EPIDs) have been intro-
duced.37,38 EPIDs offer the potential advantages of
online verification, as well as the ability to moni-
tor and compensate for patient motion during ther-
apy.39,40 Treatment delivery may be aided through
a record-and-verify system, a computer program
which monitors treatment parameters for each
patient.41,42 Such programs are becoming increas-
ingly integrated into comprehensive information
systems with links to the simulator and treatment
planning computers.
Intensity-Modulated Radiation Therapy
Conventional external beam RT is delivered with
beams of uniform intensity. Recent advances,
however, have made the use of beams of varying
intensity possible. This approach, known as
intensity-modulated RT (IMRT), allows the
high-dose region to be better conformed to the
shape of the PTV.43-46 Better conformality trans-
lates to increased sparing of surrounding tissues,
thereby allowing the delivery of higher radiation
doses to the tumor. The beam intensity patterns
used in IMRT are derived using an inverse pro-
cess45,46 and delivered using an MLC fitted on a
linear accelerator. Beam intensity is varied by
computer-controlled movement of the leaves of
the MLC into and out of the beam’s path. Deliv-
ery of IMRT requires accurate patient position-
ing and immobilization.15
IMRT has been shown to be a promising
approach in several disease sites. In prostate can-
cer, IMRT is used to minimize the volume of the
bladder and rectum irradiated, allowing higher
doses to be delivered to the prostate.47,48 IMRT has
also been used to decrease xerostomia (dry mouth)
in head and neck cancer patients by minimizing the
volume of parotid tissue irradiated.49-50 IMRT also
has shown promise in the treatment of pediatric
tumors51 and gynecologic malignancies.52,53
Examples of Treatment Plans Lung
Figure 39-2 illustrates an axial CT image, with
isodose lines superimposed in a patient with

Figure 39-1 A linear accelerator. (Four-color version of figure on CD-ROM)
locally advanced lung cancer. Anterior and
right-posterior oblique fields (18 MV photons)
are used to minimize the dose received by the
spinal cord and contralateral lung. DVHs of the
spinal cord and contralateral lung are shown
(Figure 39-3).
Prostate Figure 39-4 shows an axial slice
through the lower pelvis in a patient with early
stage prostate cancer. A six-field plan (18-MV
photons, opposed lateral and four oblique fields)
is used to minimize the dose delivered to the
bladder and rectum. For comparison a 9-field
IMRT plan (6 MV photons, equally spaced
beams) is shown in Figure 39-5. DSHs of the
bladder and rectum are illustrated with the dose
sparing achieved using intensity modulation
(Figure 39-6).
Gynecology At the University of Chicago,
IMRT is used as an alternative to traditional whole
pelvic RT in women with gynecologic malignan-
cies.52,53 Conventional whole pelvic RT results in
the irradiation of significant portions of the small
bowel. In contrast, the conformality achieved with
IMRT reduces the volume of normal tissues irra-
diated. Examples of traditional whole pelvic and
intensity-modulated plans in a patient with early
stage endometrial cancer are shown in Figures 39-
7 and 39-8. A comparison of the small bowel
DVHs is shown in Figure 39-9. Note the reduction
in the volume of small bowel receiving the pre-
scription dose (100%).
BRACHYTHERAPY Brachytherapy involves the
placement of radioactive sources either within an
existing body cavity (eg, the vagina) in close
proximity to the tumor (intracavitary) or directly
within a tumor (interstitial). Intracavitary
brachytherapy is accomplished with the aid of
specialized applicators; the best known and most
widely used is the Fletcher-Suit applicator for
carcinoma of the cervix. A tube-like tandem is
inserted into the uterus, and colpostats are posi-
tioned against the lateral fornices. Other applica-
tors include Heyman-Simon capsules (uterine
cancer) and vaginal cylinders (uterine and vagi-
nal tumors). Intracavitary brachytherapy may
also be performed by inserting radioactive
sources within a nasogastric tube (nasopharynx,
esophageal tumors), biliary stents (cholangiocar-
cinoma), or directly within the lumen of a
bronchus (lung cancer). Interstitial brachyther-
apy involves placing within a tumor hollow nee-
dles that can be replaced by flexible plastic
catheters. Interstitial brachytherapy in gyneco-
logic tumors uses a variety of treatment aids, for
example a Syed template.54 In head and neck
cancer, catheters are typically placed freehand
via a submental approach.
At most centers, brachytherapy is currently
performed with afterloading techniques which
minimize exposure to the staff. Radioactive
CHAPTER 39 / Principles of Radiation Oncology 587
sources are placed either temporarily or perma-
nently. Brachytherapy was initially instituted
with the use of naturally occurring isotopes, such
as radium or radon, but with the availability of
artificially produced isotopes, it has been prac-
ticed more frequently with cesium 137, iridium
198, and iodine 125.55 Plans are generated by
digitizing and reconstructing source positions
from plane radiographs. Three-dimensional dose
calculations are performed, and the dose is cal-
culated to a limited number of normal tissue
points. Recently, CT-guided brachytherapy has
been an area of research interest.56-58 Examples
of intracavitary and interstitial brachytherapy in
cervical and prostate cancer are shown in Figures
39-10 and 39-11.
Brachytherapy has been traditionally deliv-
ered over 3 to 4 days as an inpatient procedure at
a low dose rate (LDR), for example, 40 to 70
cGy/h. In recent years, high dose rate (HDR)
techniques have been introduced using high-
activity iridium sources with dose rates exceed-
ing 200 cGy/min. Unlike LDR, HDR is an out-
patient procedure requiring only minimal
anesthesia. It is particularly appealing to the
elderly and patients with multiple medical prob-
lems. Promising results have been reported in
many sites, including the head and neck,59
cervix,60 endometrium,61 and prostate.62 Con-
troversy exists regarding the increased potential
for late complications.63 Further follow-up and
randomized trials are needed to define the role of
HDR brachytherapy.
Stereotactic Radiosurgery and Radio-
therapy Stereotactic radiosurgery (SRS) is a
technique used to precisely deliver a single,
high-dose fraction of external beam radiation to
a small, intracranial volume.64 It was first devel-
oped by Leksell in the early 1950s as an alterna-
tive to surgery.65 The technique has since
evolved to include heavy charged particles,
gamma rays from Co-60 (gamma knife), and
megavoltage beams from linear accelerators.64
The delivery of multiple fractions using the
stereotactic process is known as stereotactic
radiotherapy (SRT).64,66 SRS and SRT have been
used to supplement conventional external beam
treatment in primary or metastatic brain
tumors.67 SRS is used to treat benign conditions,
such as arteriovenous malformations (AVMs),68
pituitary adenomas,69 and acoustic neuromas.70
Figure 39-2 Example of a treatment plan
in a patient with locally advanced lung can-
cer. Isodose lines are superimposed on an
axial CT image. (Four-color version of fig-
ure on CD-ROM)
588 SECTION 9 / Radiaton Oncology

100

90

80

70
Percent Volume

60
50

40

30

20
10 Figure 39-5 An intensity modulated radiation therapy
0
treatment plan in a patient with early-stage prostate cancer.
(Four-color version of figure on CD-ROM)
0 20 40 60 80 100
Percent Dose
varying relative biologic effectiveness (RBE).
100 Directly ionizing radiation (eg, neutrons) has a
greater RBE than indirectly ionizing radiation
90
(photons or electrons).75,76
80 Radiation damage is primarily manifested by
70 the loss of cellular reproductive capacity. Lethally
irradiated cells are, thus, said to undergo a repro-
Percent Volume

60
50
40
30
20
10
0 The concept that cell death following radia-
0 20
Figure 39-3 Dose volume histograms of the spinal cord and contralateral lung in the patient
shown in Figure 39-2.
Both SRS and SRT involve the localization of
a targeted lesion within a stereotactic frame. The
stereotactic frame is either fixed (screwed into
the cranium) (SRS) or relocatable (SRT). A
stereotactic frame allows positioning of a patient
with millimeter accuracy.64,71 The goal of
SRS/SRT is to conform the dose distribution to
the targeted lesion while minimizing the dose to
normal, surrounding brain parenchyma. In prac-
tice, this is accomplished with the use of multi-
40 60 80 100
Percent Dose
ple non–co-planar arcs. An example of a SRS
treatment plan in a patient with a solitary brain
metastasis from lung cancer is shown in Figure
39-12. This plan consists of five non–co-planar
arcs and was delivered with 6-MV photons on a
linear accelerator.
BIOLOGIC BASIS OF
RADIATION THERAPY
CELLULAR RESPONSE TO RADIATION Radiation
randomly interacts with molecules within the
cell. Although the critical target for cell killing is
the deoxyribonucleic acid (DNA),72 damage to
the cellular and nuclear membranes and other
ductive death. Consequently, most cell types do
not show morphologic evidence of radiation
damage until they attempt to divide. Alterna-
tively, some cell types are killed via the induction
of apoptosis.77 A cell that has sustained lethal
damage following radiation exposure may
undergo one or more divisions prior to metabolic
death and loss from the tumor population.
tion exposure may not be manifested until several
cell divisions later has clinical relevance, such
that tumors associated with very slowly prolifer-
ating cancers may persist for months and appear
histologically viable. The histologic appearance
may clear only after tumor cells have had the
opportunity to attempt to divide. Prostate carci-
noma, for example, may require up to 24 months
after RT prior to obtaining a normal biopsy.78
RADIATION SURVIVAL ANALYSIS Radiation sur-
vival can be studied both in vitro and in vivo. In
vitro experiments usually involve irradiating
exponentially growing cells to known doses of
radiation. Cells are plated, and after 2 to 3 weeks,
100
80
Percent volume

organelles may also be important. Radiation Conventional

Figure 39-4 Example of a treatment plan in a patient
with early stage prostate carcinoma. Isodose lines are
superimposed on an axial CT image. (Four-color version
of figure on CD-ROM)
deposition results in DNA damage manifested by 60
IMRT
single- and double-strand breaks (DSBs) in the
sugar-phosphate backbone of the DNA molecule. 40
Cross-links between DNA strands and chromoso-
mal proteins also occur. The mechanism of DNA 20
damage differs among the various radiation
types. For example, electromagnetic radiation is 0
indirectly ionizing via short-lived, hydroxyl free 0 25 50 75 100 125
radicals produced primarily by the ionization of Percent dose
cellular H2O.73 Protons and other heavy particles Figure 39-6 Rectum dose surface histograms (DSH)
are directly ionizing and damage DNA directly.74 comparing conventional and IMRT plans as shown in Fig-
Consequently, different types of radiation have ures 39-4 and 39-5.

Figure 39-7 A conventional whole pelvic radiation
therapy treatment plan in a patient with early-stage
endometrial carcinoma. (Four-color version of figure on
CD-ROM)
Figure 39-8 An intensity modulated whole pelvic radi-
ation therapy treatment plan in a patient with early-stage
endometrial carcinoma. (Four-color version of figure on
CD-ROM)
colonies are stained. The surviving fraction is
then calculated by dividing the number of
colonies by the plating efficiency of unirradiated
cells. A survival curve is then generated by
graphing the log of the surviving fraction versus
the absorbed dose (Figure 39-13). Typically, sur-
vival curves are characterized by an initial shoul-
der, followed by exponential decrease in the frac-
tion of surviving cells at higher doses.
In vivo models examine both the inherent
radiosensitivity of tumor cells and environmen-
tal influences, such as hypoxia and host immu-
nity. A model commonly used to study radiation
effects is the growth delay assay, which measures
100
80
Percent volume
60
40
IMRT
20
Conventional
0 response. IR also interacts directly with lipid
0 25 50 75 100 125
Percent dose
Figure 39-9 Small bowel dose volume histograms
(DVH) comparing conventional and IMRT treatment
plans as shown in Figures 39-7 and 39-8.
CHAPTER 39 / Principles of Radiation Oncology 589
the time interval required for a tumor exposed to
radiation to regrow to a specified volume (Figure
39-14).79 An assay that analyzes the dose
required to control 50% of tumors is the TCD50
assay, which has been widely employed to study
tumors in a variety of experimental systems.80
The radiobiologic use of transplantable solid
tumor systems in experimental animals has been
reviewed by Hall.75 Radiation survival parame-
ters can be assayed for normal tissues in vivo as
well as for tumors. For acutely responding tis-
sues, in vivo survival is measured by studying
clones of normal tissues regrowing in situ (eg,
skin, jejunal crypt cells) or cells transplanted to
another site (bone marrow stem cells). To study
radiation effects in late-responding tissues, such
as the nervous system, functional assays, such as
paralysis and death, may be employed.
Figure 39-10 Intracavitary brachy-therapy in a patient
MODELS OF RADIATION SURVIVAL CURVE with early-stage cervical cancer.
ANALYSIS Two empirically derived mathemati-
cal models have been used to analyze radiation
survival data (see Figure 39-13). In the multi-tar-
get model, the reciprocal of the slope of the sur-
vival curve is defined as D0, the radiosensitivity
of the cell population or tissue under investiga-
tion. D0 is the dose required to reduce the sur-
viving fraction to 37% in the exponential portion
of the survival curve. The width of the shoulder
region is represented by the quantities n or Dq.
Dq is the quasi-threshold dose, or the point at
which killing becomes exponential.
The linear quadratic model (surviving frac-
tion = eαD-βD2) fits radiation survival data to a Figure 39-11 Interstitial brachytherapy in a patient with
continuously bending curve, where D is dose and prostate carcinoma. (Four-color version of figure on CD-
α and β are constants. The linear component, a ROM)
measure of the initial slope, termed alpha, repre-
sents single-hit killing kinetics and dominates
the radiation response at low doses. The such as cell cycle regulation, DNA repair, apop-
quadratic component of cell killing, termed beta, tosis and tissue repopulation. Figure 39-15
represents multiple-hit killing and causes the illustrates the current perspective on the inter-
curve to bend at higher doses. The ratio of alpha actions between IR-induced DNA damage and
to beta is the dose at which the linear and cell signaling.
quadratic components of cell killing are equal.
The more linear the response to killing of cells at
low radiation dose, the higher is the value of
alpha, and the greater is the radiosensitivity of
the cells.81 Neither model has a firmly estab-
lished biologic basis, and, therefore, both should
be viewed as mathematical tools to describe the
cellular radiosensitivity.
Molecular Events Following Cellular
Exposure to Ionizing Radiation The ulti-
mate fate of the irradiated cell is not only a
function of the radiation dose but also influ-
enced by the cell’s natural defenses, including
the ability to detect the DNA lesions and to
repair them with high fidelity. Furthermore,
recent advances have revealed DNA is not the
only cellular target that influences the radiation
and protein signaling pathways and modulates
gene expression through a variety of mecha-
nisms including the direct activation of tran- Figure 39-12 Stereotactic radiosurgery treatment plan
scription factors. IR-induced activation of these in a patient with a solitary brain metastasis from a lung
signaling pathways can affect critical processes primary. (Four-color version of figure on CD-ROM)
590 SECTION 9 / Radiaton Oncology

n̄ Extrapolation number The P53 tumor suppressor gene plays a pivotal

role in the cellular response to IR. Through its C-
terminal domain, the P53 protein can bind directly
Dq to radiation-damaged DNA and to single-stranded
1 1
DNA ends, suggesting that P53 can act as a sensor

Surviving Fraction
of DNA damage. Exposing cells to DNA damag-
Surviving Fraction

Shoulder ing agents or to restriction endonucleases that

Region α Component induce DNA breaks results in the stabilization and
0.1 0.1
accumulation of P53 in the nucleus.93,99 This
( Slope= 1/D0) increase in P53 is associated with transcription of
.037 P21 and BAX, leading to the induction of G1
D0 0.01 arrest or apoptosis. ATM and CHK2, a mam-
0.01
β Component malian homolog of Cds1/Rad53 that is activated
by ATM, phosphorylates P53 and thereby pre-
vents its degradation. DNA-PK interacts with the
0.001 N-terminal region of P53 and contributes to its
0.001 sequence-specific DNA binding, transactivation
400 800 1200
200 400 600 function, and stability.100-102 Thus, P53 is an
effector as well as sensor of DNA damage. c-Abl,
A Dose (cGy)
B Dose (cGy)
a non-receptor tyrosine kinase, associates with
Figure 39-13 Models for survival curve analysis. Experimental data are typically shown as the fraction of cells sur-
P53103,104 to stabilize and induce its pro-apoptotic
viving a dose of radiation plotted on a logarithmic scale, whereas the dosage of radiation is plotted on a linear scale A. functions through a kinase-independent mecha-
When using the multitarget model, the shoulder region is quantified by extrapolation of the exponential portion of the nism.104 c-Abl also interacts with the P53-related
curve to the y-axis intercept. This point is referred to as n (extrapolation number), whereas a horizontal line drawn from protein P73 in the response to IR and other geno-
100% survival to the extrapolation line is referred to as Dq (or quasi-threshold dose). Slope of the terminal portion of the toxic agents.105-107 c-Abl has been implicated in
survival curve is quantified by the term Do, which is the inverse of the slope and designated as the radiosensitivity of the inhibiting the Mdm2 oncoprotein as well.108
cells or tissue under study. B. When using the linear-quadratic models for survival analysis, there are two components for Mdm2 binds the transcriptional activation domain
cell killing. The alpha component represents the initial slope, and the beta component represents the terminal slope of the of P53 and blocks its ability to regulate target
survival curve. The alpha component is proportional to the dose, whereas the beta component is proportional to the square
of the dose. The dose at which the alpha and beta components are equal is referred to as the alpha/beta ratio, which, for
genes and to exert antiproliferative effects. Mdm2
example, is 400 cGy in B. also promotes the degradation of P53 via the
ubiquitination/proteasome pathway. The role of
P53 in cell cycle regulation is discussed below.
Molecular Sensors and Effectors of Radia- sites of Ku/DNA complexes; and the question The Role of Growth and Stress-Signaling
tion-Induced DNA Damage As shown in Fig- mark denotes links between G2 arrest and P53 Pathways in the Radiation Response IR-
ure 39-15, components of the DNA-dependent mediated apoptosis currently under investigation. induced activation of signaling pathways can
protein kinase (DNA-PK) complex are involved
in sensing DSBs as well as the repair of these
breaks. DNA-PK consists of the 470 kDa cat- 10
1
Relative volume of R-1 Rhabdomyosarcoma's

alytic serine/threonine kinase (DNA-PKCs) and

the 70 and 80 kDa Ku heterodimer.82-84 Ku binds 2 3 4
directly to sites of DSBs,85,86 and DNA-PKCs is 5 6 7
recruited to sites of Ku/DNA complexes where it
is activated.84 The Ataxia Telangiectasia
Mutated (ATM) protein is also involved in sens-
ing DNA damage and is related to DNA-PKCs 1
and other members of the phosphatidylinositol
(PI) 3-kinase (PIK) family. ATM proteins are 1. controls
involved in cell cycle regulation, recombination, 2. 1000 rads Rö
telomere length control and the multiple steps in 3. 400 rads neutrons
the cellular response to DNA damage.87-89 AT 4. 2000 rads Rö
cells, like DNA-PKCs/Ku-deficient cells, are 10 -1 5. 800 rads neutrons
hypersensitive to IR.90-92 AT cells that are defi- 6. 3000 rads Rö
cient in ATM or express a nonfunctional mutant 7. 4000 rads Rö
protein also exhibit defects in IR-induced growth
arrest,93-95 radioresistant DNA synthesis and
chromosome instability.96–97
Because ATM is one of most widely studied 10 -2
components in the cellular response to DNA dam-
age, it has been placed in the center of this figure. -8 0 8 16 24 32 40 48 56 64 72 80
However, numerous other factors, such as the AT Time interval in days after irradiation
and Rad3-related (ATR) protein kinase, are essen-
Figure 39-14 Data points represent volume changes observed in tumors in animal models after irradiation. After an ini-
tial for cell-cycle modulation after the induction
tial decrease in the volume size, tumors grow back to the original volume over a time interval referred to as the growth
of other types of DNA damage.98 The red bars delay. Curve 1 is the growth of an unirradiated control tumor. Curves 2, 4, 6, and 7 represent the growth of tumors irra-
indicate three main cell-cycle checkpoints in late diated with 1,000, 2,000, 3,000, and 4,000 cGy of photons. Curves 3 and 5 represent the growth of tumors irradiated with
G1, late G2 and S; dashed lines show that the 400 and 800 cGy of 152 MeV neutrons. Growth delay is prolonged with increasing dosage and more densely ionizing
effect is of DSBs;85,86 DNA-PKCs is recruited to radiation, such as neutrons. Source: Barendsen and Broerse.7
 CHAPTER 39 / Principles of Radiation Oncology 591

Ionizing radiation to the nucleus.119 PKC inhibitors block IR-

M inhibitors such as calphostin C, PKC 412, and
G2 G1
Apoptosis
S activation of MAPK,124 indicating that EGFR,
P53
Ku70-KU80
Rad50 ATM
MRE11
NBS1 ATR
H2AX
c-Abl DNA-PKccs
Rad52 BRCA1 End alignment
Rad51 BRCA2
Rad54
Homology search XRCC4
DNA inversion DNA ligase
DNA synthesis
DNA ligase
DNA resolvases
End joining
[sometimes loss or gain
Homologous recombination of several nucleotides]
[error-free]
Figure 39-15 The presence of double-strand breaks (DSBs) leads to activation of the ataxia-telangiectasia-mutated
(ATM) protein kinase Targets of ATM phosphorylation include P53 and NBS1 and probably the phosphorylated histone
variant H2AX. In this way, ATM influences cell-cycle progression and DSB repair, and if the face of overwhelming dam-
age apoptosis. Preclinical studies have shown that delivery of an adenoviral vector expressing an anti-sense to ATM sen-
sitizes prostate cancer cells to IR treatment.97 AT patients exhibit pronounced toxicity to radiation, and therefore a can-
cer therapy strategy to block ATM expression/function requires localization to tumor tissue.
have a variety of consequences including opment of radioresistance.111,112 Ras and Raf
increased or decreased radiosensitivity, inducing thus represent potential targets for increasing
proliferation, differentiation or apoptosis or radiosensitization. For example, farnesyltrans-
affecting biologic behavior, eg, invasiveness or ferase inhibitors, which block cell membrane
metastases. Several of the key pathways that attachment and thereby activation of Ras,
have been explored are summarized. enhance IR-induced cell death.113 In addition,
Ras, Raf and MAPK Signaling The down-regulation of Raf expression with anti-
Ras/Raf signaling pathway mediates growth sig- sense oligonucleotides sensitizes tumor cells to
nals from receptors such as the epidermal growth the cytotoxic effects of radiation.114 IR-induced
factor receptor (EGFR), which is a member of Ras activation leads to upregulation of mitogen-
the ErbB family. Overexpression of EGFR has activated protein kinase (MAPK).115,116
been associated with uncontrolled proliferation, PKC signaling Protein kinase C (PKC)
anchorage-independent growth, autocrine was the first cytoplasmic serine/threonine kinase
growth regulation and increased radioresistance. found to be activated during the cellular response
IR activates the small G-protein Ras, which in to IR.117 IR-induced activation of PKC has been
turn activates c-Raf, a serine/threonine kinase attributed to the generation of phospholipase A2-
that interacts with Ras.109 Activating mutations mediated oxidation products.118 c-Abl also phos-
in the Ras oncogene has been associated with phorylates and activates cytoplasmic PKCδ in
radioresistance in certain cell lines.110 Activation irradiated cells.119 IR-induced activation of
of c-Raf-1 has also been implicated in the devel- PKCδ is associated with translocation of PKCδ
induced activation of the early growth response 1
gene (EGR-1) and c-Jun.117 In addition, PKC
chelyrithine chloride, exhibit greater than addi-
tive anti-tumor effects in animal models when
used in combination with IR.120-122 Radioprotec-
tion of b-FGF-treated endothelial cells is also
mediated by PKC activation.123 Selective modu-
lation of PKC could thus represent a strategy to
enhance tumor cell killing or normal tissue sur-
vival. Inhibitors of the EGFR block IR-induced
Ras, Raf, and MAPK all lie in the same IR
response pathway. A recent Phase II trial of a
blocking antibody to EGFR has shown substan-
tial improvement in the responses of head and
neck tumors to radiotherapy.125 Agents that tar-
get the intracellular tyrosine kinase region
include small molecule tyrosine kinase
inhibitors (TKIs), which act by interfering with
ATP binding to the receptor, and various other
compounds that act at substrate-binding regions
or downstream components of the signaling
pathway.124 This group of compounds offers sev-
eral advantages in cancer chemotherapy, includ-
ing the possibility of inhibiting specific deregu-
lated pathways in cancer cells while having
minimal effects on normal cell function. They
also have favorable pharmacokinetic and phar-
macodynamic properties and low toxicity. Some
TKIs, such as the reversible synthetic anilino-
quinazoline inhibitor ZD1839 (Iressa), are now
undergoing phase II to III clinical trials. A num-
ber of preclinical studies confirm Iressa’s activ-
ity in a broad spectrum of tumor types, both as
monotherapy and in combination with com-
monly used cytotoxic agents. A recent report
suggests that the relative expression of ErbB iso-
types may alter the potency of these agents. For
example, SU11925, a small molecule inhibitor
of the tyrosine kinase activity of both EGFR and
human EGF-receptor 2 (HER-2), exhibits simi-
lar potency against EGFR and HER-2 in vitro;
however, higher plasma concentrations of
SU11925 are required to inhibit EGFR phospho-
rylation in vivo in tumors that also express high
levels of HER-2 than in tumors that express
EGFR alone.125 This observation suggests that it
is more difficult to inhibit EGFR phosphoryla-
tion in cells that express high levels of HER-2.
Lyn/c-Abl/SAPK Lyn, a member of the c-
Src family of non-receptor protein tyrosine
kinases (PTKs), is activated in IR-treated
cells126,127 and is required for induction of the
stress-activated protein kinase (SAPK), a mem-
ber of the mitogen-activated protein kinase
(MAPK) family, which is involved in the apop-
totic response to genotoxic stress. Lyn inhibits
the cyclin-dependent kinase Cdc2 in irradiated
cells which is necessary for progression through
the premitotic checkpoint127 and inhibits DNA-
PKCs activity.128 c-Abl activates MEKK-1, and
thereby confers activation of the SEK1->SAPK
pathway. In this context, SAPK induces the acti-
vation of transcription factors including c-Jun,
592 SECTION 9 / Radiaton Oncology
0.10
Repair
Repopulation
Surviving Fraction
of SLD
0.01
G2-M G1-S
0 2 4 6 8 10 12 14
Hours Between Doses
Figure 39-16 The surviving fractions of Chinese hamster
cells exposed to two doses of x-rays separated by various
time intervals are shown. When the two doses are given
together (time between doses = 0 hours), the surviving frac-
tion is equal to that observed after the single larger dose of
radiation. As the two doses are separated by time, an
enhancement in survival occurs and is interpreted as the
repair of sublethal damage (dashed line). Subsequent radi-
ation doses result in a reduction in the surviving fraction.
This reduction in survival occurs because of more sensitive
phases of the cell cycle (G2 and M). Later time points
demonstrate increased surviving fractions due to radiation
synchronization of cells and their entry into resistant
phases of the cell cycle (G1 and S) Source: Elkind.38, 39
Elk-1 and ATF-2.129 In turn, binding of acti-
vated c-Jun to the AP-1 site in the c-Jun gene
promoter contributes to the activation of c-Jun
transcription in a positive feedback loop. IR-
induced activation of the c-Jun gene is blocked
by the antioxidant N-acetyl-L-cysteine
(NAC).130 IR also induces expression of the c-
fos and jun-B genes, which encode proteins that
associate with c-Jun.
Early response genes IR induces expres-
sion of the EGR-1 gene.131 Transcription of it is
conferred by IR-induced activation of serum
response (CARG) elements in the EGR-1 pro-
moter.131 As found for c-Jun, treatment with
NAC blocks induction of the EGR-1 gene in the
IR response.132 These findings showed that IR
activates the c-Jun and EGR-1 genes by ROS-
mediated signaling mechanisms. The finding
that IR activates gene transcription provided the
experimental basis for the design of gene therapy
strategies in which the spatial and temporal con-
trol of gene expression are regulated by high
energy x-rays. In this approach, a radio-inducible
promoter, such as that from the EGR-1 gene, is
inserted upstream to sequences encoding a ther-
apeutic protein. The CARG elements in the
EGR-1 promoter have been used to activate IR-
induced transcription of tumor necrosis factor
(TNF) or the HSV-1 thymidine kinase (TK).133-
135 The TNF protein functions as a radiosensi-
tizer and, in high local TNF concentrations,
selectively increases the sensitivity of the tumor
to IR treatment in the absence of systemic toxic-
ity.136 Several clinical trials are underway in
which the EGR-1/CARG promoter–TNF con-
struct is delivered to tumors in an adenoviral vec-
tor and activated by local radiotherapy.
CLASSIC ASPECTS OF DNA REPAIR IN RADIO-
THERAPY Irradiated cells that are not lethally
damaged may undergo repair of the damage to
their DNA. Sublethal damage repair (SLDR) is
operationally defined as the enhancement in
survival when a dose of radiation is separated
over a period of time. SLDR may be represented
by the extrapolation number (n) of the radiation
survival curve when a multi-target survival
model is employed.137-141
Sublethal damage has been studied in vitro
and in vivo. In general, SLDR experiments
divide a single dose into two relatively equal
doses spaced at variable time intervals. Elkind
and colleagues investigated this phenomenon in
great detail.137,142 Figure 39-16 shows results
representative of split-dose experiments. An
enhancement in survival, following two doses
separated in time, is observed in exponentially
growing Chinese hamster cells at 2 hours. This
enhancement in survival is due to the rapid repair
of SLD and is followed by a subsequent decline
in survival at 5 hours and then another increase
in survival at 8 hours. This variability in survival
is caused by synchronization of the exponen-
tially growing cell populations by the first radia-
tion dose and subsequent treatment with a sec-
ond dose during the radioresistant S-phase (t = 2
hours) or radiosensitive G2-M phase of the cell
cycle (t = 6 hours).138,140,141
The concept of SLDR is important during a
course of fractionated RT because the shoulder
region of the survival curve is recapitulated due
to SLDR.139 Fractionation magnifies the surviv-
ing fraction after each treatment to an exponent
equal to the number of treatments. Therefore,
small differences in survival after each dose may
have a great impact on treatment outcome. Most
human tumor cell lines studied in vitro have rel-
atively small shoulders;143-148 however, a large
capacity for SLDR has been reported for some
human tumor cell lines.79,144
The ability of tissues to undergo SLDR has
been demonstrated using a variety of normal tis-
sue clonogenic or functional assays.149-151 The
capacity of different cell populations to repair
SLD is reflected by the width of the shoulder (or
initial slope) of their survival curve. An increase
in the total dose required to give the same bio-
logic damage when a single dose (D1) is split into
two doses (total dose D2), with a time interval
between doses to obtain a single biologic end
point, is the capacity of a normal tissue to repair
SLD. The difference in the two doses, D2 - D1, is
the measure of SLDR by the tissue, provided that
the two doses are larger than those that generate
the shoulder region of the survival curve.81,150,152
(Figure 39-17), D2 - D1 = Dq. If the D0 is known,
then n can be calculated from the equation:
loge n = Dq/D0
Varying environmental conditions can influ-
ence cell survival after a dose of x-rays. Thus,
damage that is potentially lethal under a given set
of conditions may not be lethal if postirradiation
conditions are altered.153,154 The enhancement in
survival seen following manipulation of postirra-
diation conditions is referred to as the repair of
potentially lethal damage (PLD). PLD repair
(PLDR) has been demonstrated in vitro155,156
(Figure 39-18). PLDR has also been shown to
occur in vivo.155,157,158 PLDR is reported to be
more pronounced in large tumors, presumably
because a large proportion of cells are in G1 or
G0. PLDR has been described to occur principally
in the G1 phase of the cell cycle. Efficient PLDR
occurs in a variety of human tumor cell lines in
vitro.159-162 Weichselbaum and colleagues,161,
163,164 and Guichard and colleagues165 have sug-
gested that PLDR contributes to radiotherapy fail-
ure under certain circumstances.
PLDR and/or SLDR may not be expressed
under all conditions in vivo. For example, cells
must be genetically competent to repair these
types of damages, and the tumor environment
may affect the proliferative status of tumor
cells.154,164,166 Also, radiation (or chemother-
apy) may induce tumor proliferation, which
allows fixation of radiation damage before
PLDR or SLDR is complete.154,166 Therefore,
PLDR is likely to be most important in tumor
cells of intermediate or high radiosensitivity
when cells are quiescent between fractions. The
24-hour PLDR-surviving fraction, following
treatment of human tumor cells in plateau-phase
culture with a similar dose, is referred to as the
maximum recovery potential (MRP).80 Figure
34-18 shows that although two cell lines have
different amounts of initial lethal damage
induced by a constant radiation dose (a function
of D0 and n), the surviving fraction after a 24-
hour delay in subculture (a function of n, D0,
PLDR) may be similar.
Number of surviving cells per cm2 of Skin
104
Si
ng
103
le
Sp 24 h
Do
lit
(
se
Do s)
102
s
se
r
s
101
1
10-1
Dq=D2-D1
10-2 500 1000 1500 2000 2500
D1 D2
Dose in Rad
Figure 39-17 Single-dose and two-dose survival curves
for epithelial cells. The D0 is 135 cGy. The ordinate is not
the surviving fraction, as in survival curves for cells cul-
tured in vitro, but is the number of surviving cells per
square centimeter of skin (plating efficiency is obviously
not known in vivo). In the two-dose survival curve, the
interval between dose fractions is 24 hours. Although the
curves are parallel (similar D0), their graphic horizontal
separation number (n), may then be calculated from D0
and Dq. Source: Weners.194, 195

1.0 Maximum
Recovery
Potential
Radioresistant
Cell Line
Surviving Fraction
0.1
Surviving Fraction
After 24 Hours
Radiosensitive PLDR Time
Cell Line Function of n, D0
0.01 and PLDR
0.001
0 2 4 6 8 24
Hours Between Exposure
and Subculture
Figure 39-18 Maximum recovery potential (MRP) for
radioresistant and radiosensitive cells. Confluent cell
lines (noncycling) were irradiated and immediately sub-
cultured, which resulted in an initial surviving fraction
(0), which is generally equal or slightly less than the sur-
viving fraction of exponentially growing cells in tissue
culture. However, when these irradiated confluent cells
are not subcultured for the indicated time intervals, an
enhancement in survival, interpreted as STR repair of
potentially lethal damage (PLDR), occurs. The surviving
fractions of cells after a 24-hour delay in subculture
(MRP) of confluent cells is dependent on n, D0, and
PLDR. The initial surviving fraction of cells at 0 hours is
dependent on no and D0 but not on PLDR.
Molecular aspects of DNA repair in the
cellular response to ionizing radiation All
eukaryotes have evolved several mechanisms to
repair DSBs, which indicate the importance and
difficulty of repairing this type of DNA injury.
The two main pathways are homologous combi-
nation (HR) and non-homologous end-joining
(NHEJ). These two repair modes differ in their
requirement for a homologous template DNA
and in the fidelity of DSB repair. Whereas HR
ensures accurate DSB repair, NHEJ does not.
The contributions of these two DSBrepair path-
ways are likely to differ depending on the stage
of the cell cycle.98 However, the pathways are not
mutually exclusive because repair events that
involve both pathways can be detected. HR is
most efficient in the S and G2 phases of the cell
cycle because of the availability of sister chro-
matids as repair templates.167 In the absence of a
sister chromatid, DSB repair in G1 phase could
still efficiently occur through NHEJ.
HR can repair DSBs by using the undamaged
chromatid as a template, which results in the
accurate repair of the DSB. HR is mediated
through the RAD52 family of proteins.168 These
proteins include RAD50, RAD51, RAD52,
RAD54 and meiotic recombination 11
(MRE11). The initial cellular response to DSBs
is mediated through ATM and Nijmegen break-
age syndrome 1 (NBS1).169 Subsequent steps of
DSB repair through HR include DNA-end recog-
nition, possibly by RAD52, and nucleolytic pro-
cessing of the broken ends of DNA into 3'-end
single-stranded DNA. This single-stranded DNA
is bound by the RAD51 protein which mediates
crucial steps in the reaction—the search for a
homologous duplex template DNA and the for-
mation of joint molecules between the broken
DNA ends and the repair template. Other pro-
teins, including replication protein A (RPA),
RAD52, RAD5430 and several RAD51-related
proteins (eg, RAD51B, RAD51C, RAD51D,
XRCC2, XRCC3, and DMC1),170 are thought to
function as accessory proteins for RAD51 at var-
ious stages of HR. In mammalian cells, RAD51
forms nuclear foci in response to IR and
decreased expression of RAD51 confers sensi-
tivity to IR-induced DNA lesions.171 The later
steps of the process include polymerization of
nucleotides to restore degraded DNA strands and
resolution of the recombination intermediates.
Mice with targeted disruption of the RAD51
gene exhibit an embryonic lethal phenotype.172
Moreover, the failure to generate RAD51-/- stem
cells has indicated that RAD51 is essential for
cell viability. RAD51 interacts with P53173 and
BRCA1.174 Although the breast cancer suscepti-
bility proteins BRCA1 and BRCA2 are clearly
implicated in HR , their roles are not well under-
stood. Other studies have demonstrated that
RAD51 is phosphorylated by c-Abl in IR-treated
cells and that this response contributes to the
down-regulation of RAD51 activity in ATP-
dependent DNA strand exchange reactions.171
Treatment of cells with IR is also associated with
inactivation of RAD51 by caspase-3-mediated
proteolytic cleavage.175
In contrast to HR, NHEJ uses little or no
homology to couple DNA ends. This pathway is
not only used to repair DSBs generated by IR or
other exogenous DNA-damaging agents, but is
also required to process the DSB intermediates
that are generated during V(D)J recombina-
tion.176 Several proteins that are involved in
NHEJ have been identified. The Ku heterodimer,
which consists of Ku70 and Ku80, has a high
affinity for DNA ends, which indicates that it has
an early role in the NHEJ process. Ku bound to a
DNA end attracts the catalytic subunit of the
DNA-dependent protein kinase (DNA-PKCs), a
470-kDa polypeptide with a protein kinase
domain near its carboxyl terminus.177 DNA-
PKCs can subsequently phosphorylate several
cellular target proteins, including P53, the Ku
polypeptides and itself. At present, it is unclear
which phosphorylation targets of DNA-PKCs
are relevant in vivo. A complex that consists of
DNA ligase IV and XRCC4 (X-ray-repair-cross-
complementing defective repair in Chinese ham-
ster mutant 4) accomplishes the final ligation
step. Cell lines or animals that lack either of the
genes encoding these proteins do not carry out
V(D)J recombination and are sensitive to ioniz-
ing radiation.178 In addition to the involvement
of the RAD50–MRE11-containing complex in
HR, genetic experiments with yeast indicate that
this complex also has a role in NHEJ.179
Although cells deficient in components of
the NHEJ and HR pathways are more radiosensi-
tive than their wild-type counterparts, few
advances have been made in the development of
CHAPTER 39 / Principles of Radiation Oncology 593
inhibitors of IR-induced DSB repair. Initial
attempts at inhibiting DNA repair in irradiated
tumors were associated with increased normal
tissue toxicity. A more recent strategy using anti-
sense oligonucleotides to the RAD51 gene has
resulted in enhancement of the effects of radia-
tion on glioma cells in vitro and in animal mod-
els.180 With improvements in the selective deliv-
ery of radiotherapy, the spatial targeting of
IR-induced DSBs to tumors should theoretically
establish inhibition of DNA repair as an attrac-
tive therapeutic approach.
CELL CYCLE CHECKPOINTS, INTEGRATION OF
SIGNALLING, AND DNA REPAIR It is necessary
for one phase of the cell cycle to be completed
before initiating events associated with the fol-
lowing phase. Failure to achieve accurate com-
pletion of events may lead to genetic instability
and/or cell death. Cells have evolved mecha-
nisms to monitor genomic instability associated
with DNA damage. The surveillance mecha-
nisms and resulting inhibition of cell cycle pro-
gression are referred to as checkpoint controls.
For example, a DNA damage checkpoint control
communicates information between a DNA
lesion and the regulatory components of the cell
cycle. Radiation-induced single-strand breaks
(SSBs) and DSBs are associated with the initiat-
ing signal that activates checkpoint controls. In
general, the cell cycle is delayed at one or the
checkpoint by inhibiting cyclin-dependent
kinases (CDKs) until DNA repair is complete.
Following exposure to ionizing radiation, cells
arrest at the check points. Cell cycle regulation in
irradiated and nonirradiated cells has recently
been reviewed.181
DNA damage and its effect on cell cycle pro-
gression have been intensively studied in yeast
and Xenopus oocyte, as well as in mammalian
cells. Studies show that the kinase activity of
Cdc2-cyclin B complex is required for the G2-to-
M-phase (G2/M) transition in the normal cell
cycle and that tyrosine phosphorylation of Cdc2
inhibits its kinase activity.182 Both inhibition of
Cdc2 kinase activity and enhanced phosphoryla-
tion of Cdc2 have been observed following DNA
damage. The phosphorylation state of Cdc2 is
maintained by the kinases Wee1 and Myt1 and by
the phosphatase Cdc25. 119,121,123,183, Cdc2 is
inactivated by phosphorylation of Thr-14 and Tyr-
15 in the ATP-binding domain by the Wee1
kinase.184 Phosphorylation of Tyr-15 is also medi-
ated in part by IR-induced activation of the Lyn
tyrosine kinase.126,127 Although checkpoint regu-
lation of both sides exists, it is thought that regu-
lation of Cdc25 activity is an important factor in
the maintenance of G2 arrest after DNA damage.
In mammalian cells, two kinases, Chk1 and Cds1
(also known as Chk2), have been identi-
fied118,185,186 and shown to phosphorylate
Cdc25C and prevent it from dephosphorylating
(Ser-216) and activating Cdc2. 85,118,185,186,187,188,
Phosphorylation of Cdc25 facilitates association
with the 14-3-3 protein, resulting in its export
from the nucleus; however, the mechanism of
594 SECTION 9 / Radiaton Oncology
Chk1 and Cds1 activation following irradiation is
not clear. Studies in Chk1-deficient cells have also
shown that this kinase is required for initiating G2
arrest189,190 and is a downstream effector of ATM.
The response of Cds1 to DNA damage has been
shown to be dependent on the activity of ATM.
The ATM-dependent DNA damage checkpoint
pathway regulates both the G1-S and G2-M tran-
sitions in the response of mammalian cells to IR
treatment. The IR-induced arrest at the G1-S
DNA damage checkpoint is mediated predomi-
nately by P53-dependent induction of P21 expres-
sion and thereby inhibition of the Cdk2 kinase.191
P53 promotes arrest at the G0/G1 checkpoint.
Following radiation exposure, P53 protein levels
rise due to post-translational modifications that
increase the P53 half-life. This rise is transient
and is correlated with the presence of damaged
DNA. DNA strand breaks are the most potent
inducer of P53 following IR exposure.181 Cell
cycle arrest is induced by P53 when the protein
acts as a transcriptional activator. One of the most
important genes induced is P21waf-cip. The inter-
action of P21 with the cyclin E/CDK2 complex
inhibits the progression of cells into the S-phase.
P21 also binds directly to proliferating cell
nuclear antigen (PCNA). In addition, P53 inter-
acts with MDM2 and GADD45. As described
above, MDM2 negatively regulates P53 and
likely functions during the recovery phase in the
late G1-phase. GADD45 inhibits the progression
of cells into the S-phase. A second mechanism of
regulating the G1 checkpoint by P53 is mediated
by direct binding to proteins such RPA. Bristow
and colleagues192 showed that rat fibroblast
clones expressing increasing levels of transfected
mutant P53 showed loss of the G1/S checkpoint
and increasing levels of radioresistance. The
increased survival was not associated with loss of
apoptosis, but consistent with observations of
improved double strand break repair.193 This is
not consistent with a “more time for repair”
hypothesis for the G1/S checkpoint, because
checkpoint abrogation would then be expected to
sensitize and not protect. Interestingly, the
radiosensitivity of P53 null fibroblasts remained
unchanged, indicating a gain of function of
mutant P53, possibly due to improved damage
sensing via the carboxy terminus of the protein
which is known to bind to damaged DNA in a
nonsequence-dependent manner.
Pharmacological agents which override the
G2/M block often sensitize the cells to IR.194 The
classical inhibitor of the IR-induced G2 arrest
response is caffeine. The precise mechanism for
the effects of caffeine on G2 arrest is unresolved,
although ATM has been proposed as the tar-
get.195 Treatment of irradiated P53-deficient
cells with caffeine is associated with activation
of Cdc2 and hence mitotic cell death.196 These
findings are in concert with reports which
demonstrate that abrogation of the G2 check-
point results in differential radiosensitization of
G1 checkpoint defective cells.197 Caffeine and
its analogs, however, have not proven to be effec-
tive radiosensitizers in the clinic, in part because
of the toxicities associated with levels required
for inhibition of IR-induced G2 arrest. The
CHK1 inhibitors, UCN01 and SB-218078, block
DNA damage-induced G2 arrest in human
cells.198-200 These findings and the demonstra-
tion that UCN01 does not inhibit hCHK2198,199
have supported lack of involvement of CHK2 in
the G2 arrest response. Whereas UCN01 is
undergoing clinical evaluation as a radio- and
chemosensitizer, other inhibitors of CHK1/2,
such as debromohymenialdisine,201 are under
development. It is noteworthy that the concept of
caffeine-induced override of G2-M block has
been challenged by investigators who suggest
this cell cycle perturbation and enhancement of
the induced DNA damage associated with caf-
feine are attributed to inhibition of DNA repair
and or DNA synthesis.202-204
Both the initiation and elongation stages of
DNA replication (S-phase checkpoint) are inhib-
ited by IR. In budding yeast, the genes that regu-
late the S-phase checkpoint are RAD17, RAD24,
RAD53, and MEC3 and MEC1. The sequence of
gene interaction and function in mammalian
cells is under investigation. The ATM gene prod-
uct plays a role in replicon initiation and chain
elongation. Both MEC1 and ATM are members
of the PI3K gene family.
FRACTIONATION Early in the twentieth century,
it became apparent that RT was equally effica-
cious but better tolerated when administered in
divided doses,205 a concept known as fractiona-
tion. Fractionation spares normal tissues by
allowing time for repair and repopulation of nor-
mal cells. In addition, fractionation increases
tumor cell kill due to reoxygenation and reassort-
ment of tumor cells into sensitive phases of the
cell cycle.206 Conventional fractionation schemes
involve a daily fraction of 1.8 to 2 Gy 5 days a
week. Total treatment times depend on the total
dose prescribed and thus range from 3 to 7 weeks.
Various mathematical models have been pro-
posed to equate total dose, time, and fraction size
and achieve an isoeffective dose. However, clini-
cal utility of these models remains controversial.
Clinical interest in altered fractionation has
been resurrected due to recently reported
improved outcomes in patients with advanced
head and neck cancer. Hyperfractionation is
defined as the use of reduced size fractions given
twice or more per day such that a greater total
Capillary
O2
O2
Aerated Cell
Hypoxic Viable Cell
Anoxic Non-Viable Cell 150µ
dose is delivered by increasing the number of
treatments (50–60 vs. 30–35) in the same total
treatment time. Thus, relatively rapidly dividing
cell populations may have a higher proportion of
cells in the most sensitive phases of the cell cycle
at each treatment. Cells in late-responding nor-
mal tissues are slowly proliferating, and there-
fore, after a few fractions, many surviving cells
will be concentrated in the more resistant phases.
This strategy has been applied to a variety of
tumors, including primary brain tumors207 and
head and neck cancer.208
Accelerated fractionation decreases the over-
all treatment time to diminish clonogenic prolif-
eration between successive doses. Treatment is
given 2 to 4 times per day employing fraction
sizes of 1.5 to 2 Gy per treatment with 4 to 6 hour
interfraction intervals.81,209 The total daily dose
is thus 3 to 6 Gy and the total dosage is given in
3 to 4 weeks. Although treatment interruptions
are often necessary due to acute toxicity,210 the
total treatment time is substantially reduced.
Hypofractionation is the use of larger than stan-
dard daily fractions. This approach is typically
used when palliation is the goal. Treatment may
involve 4 to 10 Gy fractions delivered weekly or
several times a week as opposed to daily.
MODIFIERS OF THE RADIATION RESPONSE The
extent of DNA damage following radiation expo-
sure is dependent on several factors. One of the
most important is cellular oxygen.211 Hypoxic
cells are considerably less radiosensitive than aer-
ated cells. In fact, anoxic cells require 2 to 3 times
the radiation dose to produce an equivalent
amount of cell kill as do oxygenated cells. The dif-
ference in radiosensitivity between hypoxic and
aerated cells is known as the oxygen enhancement
ratio (OER). Oxygen is believed to prolong the
lifetime of the short-lived free radicals produced
by the interaction of x-rays and cellular H2O. Indi-
rectly ionizing radiation is consequently less effi-
cacious in tumors with significant areas of
hypoxia and necrosis. In contrast, damage follow-
ing exposure to directly ionizing radiation is inde-
pendent of cellular oxygen levels.212
Thomlinson and Gray observed that tumors
“outgrow” their vasculature resulting in necrotic
areas and suggested that tumor cells adjacent to
the anoxic region may be clonogenic but
hypoxic.213,214 As shown in Figure 39-19, the oxy-
gen tension within the tumor falls with the dis-
Figure 39-19 Oxygen diffusion through
tissue from a capillary resulting in hypoxic
cells. Oxygen diffuses an average of 150 Ci
from the capillary. Cells beyond this region
are anoxic and nonviable. Cells at the periph-
ery of this radius are hypoxic but viable.

tance from the capillary producing a hypoxic
region. In some experimental tumor systems,
reoxygenation of hypoxic tumor cells occurs
within 24 hours.215 A clinical observation which
supports the importance of oxygen levels in
patients undergoing RT is that severe anemia is
associated with worsened local control in a variety
of tumors. Several studies have demonstrated
improved survival in patients with locally
advanced cervical cancer treated with RT when
hemoglobin levels were above 11 g as compared
with patients with lower hemoglobin levels.216–218
Anemia has been associated with poorer survival
rates following RT in other tumors, including
endometrial, bladder, and pharyngeal can-
cers.219–221 The importance of cellular oxygen is
also demonstrated by improvements in outcome in
patients receiving hyperbaric oxygen.222,223
Numerous chemicals have been shown to
modify the effects of ionizing radiation. An
important class of compounds are the hypoxic
cell sensitizers, including metronidazole, mis-
onidazole, and etanidazole.224 These agents
mimic oxygen and have been shown in vitro to
increase cell kill of hypoxic cells.225 Clinical
experience, however, with these agents have
been mixed. Only two prospective trials have
demonstrated a benefit to their use in conjunc-
tion with RT.226,227 Toxicity is common, particu-
larly peripheral neuropathy. More promising
results with less toxicity have been noted with
the newest hypoxic sensitizer nimorazole.228
A second class of radiation sensitizers are the
thymidine analogues iododeoxyuridine (IUdR)
and bromodeoxyuridine (BudR).229 Both are
incorporated into DNA in the place of thymidine
and render DNA more suspectible to radiation
damage. Although several nonrandomized trials
have been promising,230,231 no prospective trial
has demonstrated a significant benefit to their
use. Of note, both are associated with consider-
able acute toxicity.
Multiple chemotherapeutic agents sensitize
cells to radiation including 5-fluorouracil, acti-
nomycin D, cisplatin, gemcitabine, fludarabine,
paclitaxel, doxorubicin, hydroxyurea, mitomycin
C, topotecan, and vinorelbine. The mechanism
of radiosensitization varies among the different
agents. Cisplatin inhibits both SLDR and
PLDR.232 Inhibition of repair may also help
explain the radiosensitizing properties of topote-
can.233 Doxorubicin increases cellular oxygen
levels by inhibiting mitochondrial and tumor cell
respiration.234 Hydroxyurea is toxic to cells in
the S-phase and inhibits entry of cells into the
G1- from the S-phase.235 Mitomycin C is prefer-
entially toxic to hypoxic cells.236 Paclitaxel syn-
chronizes cells into the G2- and M-phases.237
Other drugs act as radioprotectors by protect-
ing normal tissues from radiation damage while
reportedly not affecting tumor radiosensitivity. The
best known radioprotector is amifostine, a deriva-
tive of cysteamine which acts as a free radical scav-
enger. Following administration, amifostine
quickly penetrates into normal tissues, but only
slowly into tumors, and thereby results in a prefer-
ential protection of normal tissues. Promising
results have been reported in head and neck cancer
patients undergoing RT.238 Amifostine has also
been used to reduce chemotherapy-related seque-
lae.239 Various endogenous biologic response
modifiers also act as radio protectors, including
interleukin-1 and granulocyte macrophage colony-
stimulating factor (GM-CSF);240,241 neither are
classic radioprotectors, since they do not directly
scavenge free radicals but rather improve bone
marrow tolerance compartment.
GROWTH FACTOR AND CYTOKINE INDUCTION
FOLLOWING RADIATION EXPOSURE GROWTH
AND REGENERATION KINETICS The percentage
of cycling tumor cells is called the growth frac-
tion (GF). In human solid tumors, it is usually a
small proportion of the total number of cells. If
the GF remains constant with time, the growth
rate of the tumor is proportional to the GF. If the
GF decreases with time, the rate of the tumor
growth slows. Solid tumors usually grow at a
slower rate as they enlarge and so growth is
approximated by the Gompertz formula.81,242 In
circumstances of equilibrium in normal tissues,
each mitotic division results in the average of
only one new cell. Usually, one daughter cell is
lost by desquamation or metastasis. By defini-
tion, the cell loss factor (CLF) in a steady state is
1. Maximum growth occurs if the CLF is
reduced to 0. The only requirement for growth is
a reduction from 1.0 in the CLF, that is, an aver-
age of < 1 of two daughter cells of a division is
lost. A CLF of < 1 is characteristic of regenera-
tion of both normal tissue and malignant growth.
Tumor growth is usually characterized by CLFs
that are closer to 1 than 0.
An index for the potential regeneration of
tumors and normal tissue populations is the pro-
liferative activity of the cell population.81 One
common measurement of tumor growth is the
potential doubling time (PDT), which is defined
as the time required to double the number of
clonogenic cells if the CLF decreases to 0. In
this concept, the doubling time is equal to the
cell cycle time. Tumors with a high rate of both
cell production and loss have the potential for
early and rapid regeneration after irradiation or
other cytotoxic treatment. Thus, even though a
tumor may exhibit slow pretreatment growth, it
may regenerate rapidly. Excessive protraction in
the time of radiation fractionation or split-
course regimens may give inferior local control
results if accelerated proliferation occurs during
the period when radiation is not given. Clonal
proliferation during tumor regression after irra-
diation was demonstrated by Hermens and
Barendsen, who showed an exponential increase
in clonogen number in a rat rhabdomyosarcoma
during a time of tumor shrinkage (Figure 39-
20).243 Accelerated repopulation of irradiated
tumors and tissues may be associated with the
recruitment of quiescent cells into the cell cycle.
This effect is associated with radiation-medi-
ated induction of the immediate early genes
c-Jun and EGR1.244
CHAPTER 39 / Principles of Radiation Oncology 595
Although the induction of genes following
DNA damage was well known in bacteria, it was
only relative recently that induction of the tran-
scription of the proinflammatory cytokine TNFα
gene provided support for the theory that gene
activation mediates the mammalian cell response
to DNA damage.245 TNFα is transcriptionally
induced following irradiation of human tumor
cells in vitr,o246 and has paracrine and autocrine
effects on tumor cell killing and might account
for some of the systemic effects of localized RT.
bFGF is induced in endothelial cells and medi-
ates protection against apoptosis. The concept of
the induction and release of growth factors fol-
lowing IR was initially reported in tumor cells
and in normal endothelial cells.247 Subsequent
studies showed that IR induces expression of
genes encoding other growth factors, such as the
platelet-derived growth factor, interleukin-1187
and bFGF.183 IR-induction of TGFβ, which is
proposed to mediate fibrosis following IR and
thereby to mediate some of the late effects of RT
on normal tissues. Other cytokines have been
also reported to be induced following radia-
tion.248 Potential applications of these observa-
tions is the use of TNFα or other cytokines as
potential radioenhancing agents in gene therapy
combined with ionizing radiation (see below). It
has subsequently been discovered that b-FGF
protects some of the lung endothelium from radi-
ation-mediated apoptosis and has potential as a
radioprotector.249 Also, secretion of growth fac-
tors and cytokines may be an important step in
radiation carcinogenesis in normal cells. Inhibi-
tion of molecular mediators of deleterious late
radiation effects on normal tissues may increase
the therapeutic ratio and presents the possibility
of genetic manipulation in clinical radiotherapy.
The recent demonstration of EGFR activa-
tion by ionizing radiation makes this receptor
and other members of ErbB receptor tyrosine
kinase family important targets for radiosensi-
tizing therapeutic interventions.250 The radia-
tion-induced activation of EGFR results in cyto-
protective signaling dominantly involving
MAPK and PI3K. The inhibition of EGFR by
tyrphostin TK inhibitors or through over-expres-
sion of a dominant-negative (DN) EGFR inhibit
the radiation-induced cytoprotective response
and results in significant radiosensitization of
xenograft tumors in mice. The monoclonal anti-
body, IMC-C225, which blocks the binding of
EGF, exhibits antitumor activity in EGFR+
tumors and enhances radiation toxicity in cul-
tured human squamous cell carcinoma; it also
increases taxane-, platinum-induced cytotoxic-
ity in non-small cell lung carcinoma
xenografts.251 In A431 head and neck squamous
cell xenografts, IMC-C225 administered in con-
junction with irradiation yielded a radiation
enhancement factor of 3.62, attributable to both
tumor necrosis and anti-angiogenesis.252 In
phase I pharmacokinetic studies, IMC-C225 has
a long half-life, lending itself to convenient
weekly administration. The reported toxicity
profile of IMC-C225 is limited to allergic and
596 SECTION 9 / Radiaton Oncology

2000 rads of 300kV X-rays 1 and TNK.260 In this context, caspase-3 is inhib-
10
ited by P35 but not CRMA in vitro, and IR-
A induced activation of caspase-3, like the induc-
A tion of apoptosis, involves a P35-sensitive,
2 CRMA-insensitive pathway.260 Whereas cas-
pase-3 is activated by IR, as well as Fas ligand
1 and TNF, these findings are explained by
2 involvement of a CRMA-sensitive caspase in the
Fas- and TNF-induced, but not the IR-induced,
cascade. IR-induced activation of caspase-3 is
associated with the proteolytic cleavage of poly-
Relative tumor volume

1 2'
10 -1 (ADP-ribose) polymerase (PARP), 261 DNA-
PK,262 protein kinase Cδ,263,264 and protein
kinase C.265 The activation of caspase 3 and the
subsequent substrate cleavage in irradiated cells
are regulated by members of the Bc1-2/Bc1-x1
10 -2 1 family.266 Bc1-2 and Bc1-xL block the release
of cytochrome c from the mitochondria of cells

Fraction of clonogenic cells

exposed to IR and other agents.267-269 Whereas
B cytochrome c is not released from the mitochon-
dria of cells induced to undergo apoptosis with
Fas ligand,82 this event upstream to activation of
10 -3 10 -1
caspase-3 117 and the insensitivity of IR-induced
caspase-3 activity to CRMA260 support distinct
apoptotic signals in Fas- and IR-treated cells.
IR-induced apoptosis is mediated at least in
part by c-Abl dependent activation of P53 and its
10 -4 10 -2 homolog, P73.270 IR also induces translocation
of SAPK to mitochondria, interaction of SAPK
and Bcl-xL, and thereby release of cytochrome
c.271,272 In turn, cytochrome c activates caspase-
3 and the cleavage of diverse proteins that confer
10 -5 10 -3 the apoptotic response.273,274 Bcl-2 and Bcl-xL
-20 -16 -12 -8 -4 0 4 8 12 16 20 24 28 32 block IR-induced cytochrome c release and
Days after irradiation apoptosis.271,275,276 These findings have sup-
ported the transduction of DNA damage-induced
Figure 39-20 Growth curves of rat rhabdosarcoma tumors irradiated in vivo demonstrating accelerated repopulation. signals to mitochondria as a determinant of cell
A. Volume change in the tumor after a single dose of 2,000 cGy. Curve 1 is the growth of an unirradiated tumor. Curve
2 represents regression and regrowth of an irradiated tumor. B. Exponential increase in the fractions of clonogenic cells
fate in the IR response.
as a function of time after irradiation. Cells were obtained from the tumors irradiated in A, and the colony-forming assay
was used to determine clonogenic potential. This figure demonstrated that there is an exponential increase in the number DOSE RESPONSE AND THE THERAPEUTIC RATIO
of clonogenic cells within 6 to 10 days after irradiating a tumor in vivo and that clonogens can repopulate during tumor Various levels of radiation yield different tumor-
regression. Source: Hermens and Baredsen.76 control probabilities, depending on the size and
anatomic extent of the lesion. The total number
of surviving cells is proportional to the initial
dermatologic reactions. An ongoing phase III knowledge, the role of apoptosis in terms of end number and biologic characteristics of clono-
international multicenter randomized study in points important in radiation therapy are not genic cells and the total cell kill achieved with a
locally advanced squamous cell carcinoma of clear. The current model suggests that tumor specified dose of radiation. Dose-response rela-
the head and neck is evaluating therapeutic radi- cells with apoptotic propensity are more sensi- tionships for local control of homogeneous
ation therapy, either alone or in conjunction with tive to radiation. If this hypothesis is confirmed, tumor groups have been empirically determined.
IMC-C225. Preclinical studies have shown that strategies can be envisioned that may restore The higher the doses of radiation delivered, the
ZD1839, an oral anilinoquinazoline, inhibits the apoptotic propensity to radioresistant tumor cells more likely is tumor control (Table 39-1).
epidermal growth factor receptor-associated for therapeutic benefit. The dose of radiation that can be delivered to
TK, and has an additive to synergistic effect in Direct evidence for the activation of caspases a tumor is limited by the probability of serious
combination with radiation or chemotherapy in in the induction of apoptosis comes from studies normal tissue complications. Therefore, the
colon, head and neck, and non-small cell lung with peptide inhibitors,254 the cowpox virus pro- choice of a tumor dose is based on the relative
cancers. Phase I clinical trials have shown mod- tein CRMA,255 and the baculovirus protein probability of tumor control and normal tissue
est dose-related toxicity, and antitumor activity P35.256 Overexpression of CRMA inhibits the complications. The potential therapeutic gain
has been reported in a variety of malignancies induction of apoptosis in diverse settings, includ- can be estimated for an average group of patients
including lung cancer.253 ing activation of the Fas receptor and treatment on the basis of tumor size, histologic type, and
with TNFα.257,258 Similarly, the P35 protein the normal tissues that will be included in the
INDUCTION OF APOPTOSIS The response of functions as an inhibitor of caspases and blocks treatment fields. Figure 39-21 shows a theoretic
eukaryotic cells to IR and other DNA-damaging apoptosis in insect and mammalian cells.259 The dose-response relationship for tumor control and
agents includes the induction of apoptosis. For recent finding that IR-induced apoptosis normal tissue complications. The therapeutic
more than 40 years, radiobiologists have been involves activation of a CRMA-insensitive path- ratio is defined as the percentage of tumor cures
aware of cells in irradiated specimens that dis- way has supported the existence of apoptotic sig- obtained at a given level of toxicity for normal
play the features of apoptosis. Despite this nals that are distinct from those activated by Fas tissues. Hill suggests that the therapeutic ratio is
 CHAPTER 39 / Principles of Radiation Oncology 597

may supply up to 106 tumor cells with nutrients,

Table 39-1 Relationship of Tumor Diameter and Dose to Percent Local Control
% Control
Dose (5 x 200 cGy/wk) Squamous Cell Carcinoma Adenocarcinoma
5,000 > 90% microfoci > 90% subclinical
50% 2–3 cm nodes
6,000 80–90% T1 pharynx
and larynx
7,000 90% 1–3 cm nodes 90% axillary
80% T3–T4 tonsil
better defined in terms of a ratio of radiation fied to be less neurovirulent by one of two strate-
doses required to produce a given percentage of gies. Herpes genes that encode enzymes neces-
tumor control and complications.242 Figure 39- sary for viral DNA synthesis or the gamma1 34.5
21A depicts a favorable therapeutic ratio and gene are deleted. The 34.5 gene prevents host
Figure 39-21B depicts an unfavorable therapeu- protein syntheses shut-off, which has evolved to
tic ratio. The greater the displacement between defeat HSV proliferation. Advani and co-work-
the two curves (in the favorable situation), the ers employed a herpes virus (with gamma 34.5
more radiocurable is the tumor. deleted) combined with radiation and demon-
strated a superior antitumor effect when com-
GENE THERAPY AND RADIATION THERAPY pared with radiation or herpes virus alone in a
Experimental RT has been combined with gene flank model of human gliomas.278 These find-
therapy in a variety of different strategies. These ings were extended and confirmed by Bradley
include the use of a various different viral and and collegaues who employed IR and genetically
nonviral vectors to transduce tumor cells with engineered (GSE) herpes in an intracranial
enzymes that convert specific prodrugs to model of glioma and demonstrated a prolonga-
radiosensitizers, cytotoxins and/or immunomod- tion of survival in animals treated with the com-
ulatory cytokines and other molecules that dis- bination of herpes and ionizing radiation.279
rupt signaling pathways. Prodrug converting
enzymes include herpes simplex virus (HSV), ANTIANGIOGENIC THERAPY COMBINED WITH
thymidine kinase and bacterial cytosine deami- RADIATION THERAPY Ionizing radiation has
nase. In another approach, the tumor suppressor been reported to mediate vascular collapse and
gene P53 is employed to modulate radiation- thrombosis of very small tumor vessels. How-
mediated apoptosis in cells that lack P53. Limita- ever, ionizing radiation has not been considered
tions of gene therapy include the lack of trans- to target the tumor vessels. Tumor endothelial
duction of the entire tumor cell population as well cells arise from host endothelium and are genet-
as the lack of control of gene expression. In an ically stable, compared with tumor cells, and
attempt to compensate for lack of uniform tumor therefore are less likely to become resistant to
transduction and to achieve spatial and temporal DNA-damaging agents. Also one tumor vessel
control of gene therapy, Weichselbaum and co-
workers delineated a strategy whereby a radiation
inducible promotor is ligated to a therapeutic Favorable
gene of interest.277 Radiation-inducible DNA
sequences from the EGR-1 promoter were ligated Tumor
100
to a DNA encoding TNFα and cloned into a non- Control
replication competent adenoviral vector. Tumors
treated with ionizing radiation and EGR–TNFα 80
regressed more rapidly and to a greater extent
than tumors treated with EGR–TNFα or radia-
Percent
thus amplifying the cytotoxic antitumor effects
of IR. Teicher and colleagues conducted investi-
gations combining radiation and synthetic
antiangiogenesis compounds and demonstrated
an increase in tumor cure and tumor growth
delay.280 In spite of potential toxicities of the
antiangiogenesis drugs, these investigators vali-
dated the tumor vasculature as a potential target
for RT. In concert with these findings, the syn-
thetic angiogenesis inhibitor, TNP-470, has been
found to potentiate the effects of radiotherapy in
the treatment of human glioblastoma multiforme
xenografts in the nude mouse.281 Other studies
have demonstrated that the endogenous angio-
genesis inhibitor, angiostatin, enhances radia-
tion-mediated tumor regressions without an
increase in toxicity.282 The potentiation of radio-
therapy by angiostatin was observed in several
human tumor xenografts, including a human
glioma. A brief exposure to angiostatin enhances
tumor regression when delivered at the same
time as radiation.283 These findings also showed
that a prolonged course of angiostatin is not nec-
essary for optimal therapeutic effects. The
demonstration that endostatin similarly potenti-
ates the anti-tumor effects of radiotherapy indi-
cates that the interaction is broadly applicable to
angiogenesis inhibitors.284
Another strategy has been to potentiate the
effectiveness of radiotherapy with agents that
function by directly blocking positive regulators of
angiogenesis. For example, administration of anti-
bodies against the vascular endothelial growth fac-
tor (VEGF) potentiates radiotherapy of murine and
human tumor models, including that of a glioma
xenograft.283 These findings have been corrobo-
rated in other studies using anti-VEGF antibodies
or inhibitors (SU5416, SU6668, PTK787) of the
VEGF signaling pathway in combination with
radiotherapy.285-289 In addition, COX-2 inhibitors
Unfavorable
Tumor
Control
Normal Normal
tissue tissue
damage damage

tion alone. TNFα was induced seven-fold over 60

background levels in the tumor, but not in the
blood, thus achieving control over gene expres-
sion. This approach to gene therapy overcomes
some of the limitations of limited viral transduc-
tion by employing a diffusible cytokine. This
strategy has been recently evaluated for safety in
phase I clinical trials and is currently being tested
for efficacy in phase II trials in patients with pan-
creatic and esophageal cancer.
In another strategy which targets gene ther-
apy by IR, it has been demonstrated that geneti-
cally engineered herpes viruses can be induced
to proliferate in irradiated tumors. Herpes virus
can cause lethal encephalitis and has been modi-
40
20
0
Cumulative Dose Cumulative Dose
Figure 39-21 Dose control and complication curves in curable and noncurable tumors treated with radiotherapy. The
percentages of tumor control and normal tissue damage are sigmoidal. In a radiocurable tumor, such as Hodgkin’s dis-
ease, the dose required to control a tumor is less than the normal tissue tolerance. This results in a favorable therapeutic
ratio. The dosage required to control an unfavorable tumor, such as pancreatic carcinoma, is approximately that of the
normal tissue tolerance, resulting in an unfavorable therapeutic ratio. Source: Varian, Palo Alto, California.
598 SECTION 9 / Radiaton Oncology
have been reported to enhance the anti-tumor effi-
cacy of radiotherapy without increasing toxic-
ity.290-292 These findings collectively demonstrate
that inhibition of tumor angiogenesis potentiates
the efficacy of radiation therapy.
CLINICAL RADIATION ONCOLOGY RT alone is
used as curative therapy in a variety of tumor
types. Treatment may consist of external beam
alone, brachytherapy alone, or a combination of
the two. Although combined modality therapy is
more common today, definitive RT is still used in
early-stage head and neck as well as gynecologic
tumors. RT alone is associated with results com-
parable with that obtained with surgery for
tumors of the oral cavity,293 oropharynx,294
supraglottic larynx,295 and glottis.296 Moreover,
definitive RT is often associated with better long-
term functional outcome than surgery. Definitive
RT was recently compared in a large prospective
randomized trial with radical surgery in women
with early-stage operable cervical cancer. RT was
associated with identical tumor control rates with
less long-term sequelae.297 Another tumor type
commonly treated with RT alone is early stage
Hodgkin’s disease.298
RT alone is also the treatment of choice in
elderly patients. A common belief is that the
elderly are at higher risk for acute and chronic RT
sequelae. However, numerous investigators have
demonstrated that age per se is not associated with
increased toxicity.299,300 Instead, comorbidities
present in the elderly may increase their risk.301
Adjuvant Therapy A more common use
of RT is in combination with surgery and/or
chemotherapy. When combined with surgery, RT
may be given prior to (preoperative), following
(postoperative), or during (intraoperative)
surgery. Although common in the past, preoper-
ative RT is less used today except in large bor-
derline resectable tumors, for example, rectal
cancer302 and soft tissue sarcomas.303 In con-
trast, postoperative RT is used in many tumor
sites including tumors of the central nervous sys-
tem,304 head and neck,305 breast,306 lung,307 gen-
itourinary,308 and gastrointestinal tract.309 In
patients with resectable disease, postoperative
RT is preferred because it allows treatment to be
tailored to the pathology findings, and higher
doses are possible. Moreover, there is reduced
potential for interference in normal wound heal-
ing. Indications for postoperative RT include
close/positive margins, residual disease, and
lymph node involvement. Potential disadvan-
tages of postoperative RT include delaying ther-
apy until wound healing is complete and reduced
vascularity of tissues following surgery. Intraop-
erative RT is the delivery of a single large frac-
tion during surgery with either electrons or low
energy photons.310 This is accomplished with
either a dedicated treatment machine in the oper-
ating room or by transporting the patient to the
RT department during surgery. An important
benefit is that normal tissues, for example small
bowel, can be displaced out of the treatment
field. A disadvantage is that the total treatment is
delivered in a single fraction which obviates the
benefit of fractionation. Promising results have
been reported in retroperitoneal soft tissue sar-
coma.311 Brachytherapy has also been used at the
time of surgery. It is imperative, however, to
delay loading for several days to allow for ade-
quate wound healing.312
When combined with chemotherapy,
chemotherapy may be administered prior to
(neoadjuvant), during (concomitant) or following
RT (maintenance). Chemoradiotherapy approaches
have been shown to improve local control and erad-
icate micrometastatic disease. Neoadjuvant
chemotherapy has been used in a number of sites
including early stage non-Hodgkin’s lymphoma313
and small cell lung cancer.314 A potential advantage
is that bulky disease sites can be cytoreduced allow-
ing for smaller treatment volumes. However,
increasing evidence suggests that concomitant
chemoradiotherapy is preferable in a variety of dis-
ease sites. Concomitant chemoradiotherapy is used
in locally advanced cancer of the lung,315 head and
neck,316 esophagus,317 bladder,318 and cervix.319
Possible interactions between chemotherapeutic
drugs and radiation are summarized in Table 39-2.
In select sites, all three modalities are com-
bined. A variety of schedules have been used.
Examples include neoadjuvant chemotherapy,
surgery, and postoperative RT (locally advanced
breast cancer)320 and surgery followed by con-
comitant postoperative chemoradiotherapy (can-
cer of the pancreas and rectum).321,322
PROPHYLACTIC THERAPY The most common
example is the prophylactic treatment of
regional, clinically uninvolved lymph nodes.
Prophylactic cranial irradiation (PCI) is used in
patients with limited-stage small cell lung can-
cer323 and children with high-risk acute
leukemia.324 Other examples include breast irra-
diation in men with prostate cancer who receive
diethylstilbesterol (DES), whole lung RT in
patients with bulky mediastinal Hodgkin’s dis-
ease, and liver RT in advanced Hodgkin’s disease
and pancreatic cancer.325-327
PALLIATIVE THERAPY RT is an important
means of providing rapid and effective palliation
due to local and/or metastatic disease. Osseous
metastases secondary to breast, prostate, and
other cancers are treated with localized fields and
short-course regimens, for example, 30 Gy in 10
fractions. Pain relief is achieved in more than
70% of patients.328 The optimal fractionation
schedule, however, remains unclear. Rapid large
fractions, for example, 20 Gy over 5 days, are
equivalent to more protracted regimens using
smaller daily doses.329 Such approaches are indi-
cated in patients with symptomatic long-bone
sites that are not in close proximity to critical
organs. More rapid schedules may be possible.
The Radiation Therapy Oncology Group (RTOG)
is currently comparing 8 Gy in 1 fraction to 30 Gy
in 10 fractions in a randomized trial. Large-field
(hemibody) irradiation has been used in patients
with widespread bone metastases.330 Promising
results have also been reported with intravenous
144Sr331 and samarium.332***
Whole brain RT is indicated in patients with
cerebral metastases. Treatment is typically deliv-
ered over 10 days to total dose of 30 Gy. As with
osseous metastases, controversy exists over the
optimal treatment regimen in these patients.
Borgelt and colleagues reviewed various regimens
ranging from 20 Gy in 5 fractions to 40 Gy in 20
fractions on two randomized trials. No differences
were seen in terms of frequency or duration of
response. Overall, 50% of patients had significant
improvement in neurologic symptoms. However,
the less protracted regimens resulted in more rapid
overall response rates.333 Protracted regimens are
indicated, however, in patients with controlled pri-
maries and solitary metastases.
Other indications for palliative RT include
spinal cord compression,334 liver metastases,335
orbital metastases,336 and carcinomatous menin-
gitis.337 Palliative RT is also used in symp-
tomatic locally advanced lung338 and ovarian
cancer.339 Brachytherapy can be used in pallia-
tive treatment as well, for example, bronchial,340
biliary,341 and esophageal342 obstructions.
Therapy for Benign Disease RT is used in
a wide variety of benign tumors and conditions,
such as keloids,343 hemangiomas,344 des-
moids,345 and pterygium.346 Other indications
include renal347 and cardiac348 transplant rejec-
tion, macular degeneration,349 and heterotopic
bone prophylaxis following arthroplasty.350
Promising results have recently been reported in
the prevention of re-stenosis in patients undergo-
ing coronary angioplasty.351
RADIATION SEQUELAE Acute Sequelae
Acute radiation sequelae, such as skin desquama-
tion, mucositis, and diarrhea, occur during or
immediately following treatment. Such sequelae
are believed to be due to the interruption of repop-
ulation of rapidly proliferating tissues.352 The type
Table 39-2 Interaction of Radiotherapy and
Chemotherapy
Chemotherapy drug and radiation active against
different tumor cell subpopulations based on
hypoxia, cell cycle specificity, and pH
Decreased tumor cell repopulation following frac-
tionated radiation due to effects of chemotherapy
Increased tumor cell recruitment from G0 into a
therapy-responsive cell cycle phase
Increased tumor cell oxygenation following radiation
with improved drug or radiation activity
Improved drug delivery with shrinkage of tumor
Early eradication of tumor cells preventing emergence
of drug and/or radiation resistance
Eradication of cells resistant to one treatment modal-
ity by the other treatment
Cell cycle synchronization
Inhibition of repair of sublethal radiation damage or
inhibition of recovery frompotentially lethal radia-
tion damage

of reaction is dependent on the site irradiated. The
one exception is fatigue, which occurs in almost
all patients. Most acute sequelae are self-limited
and respond to pharmacologic management, such
as diphenoxylate hydrochloride with atropine sul-
fate (diarrhea) and viscous lidocaine (esophagi-
tis). It is imperative to control symptoms and
avoid prolonged treatment breaks, since treatment
protraction has been correlated with worse tumor
control in several disease sites.353,354 Prophylactic
medication may also be helpful. Promising results
have been reported using sulcralfate in patients
undergoing thoracic irradiation to decrease the
severity of esophagitis.355
The severity of acute sequelae is dependent
on a variety of factors. Two major factors are
fraction size and treatment volume. Whenever
large treatment volumes are used, it is thus
imperative to reduce the daily fraction size to
minimize acute sequelae. A commonly held
belief is that older patients are at higher risk for
acute sequelae. However, recent reports have dis-
puted this belief.299,300
Chronic Sequelae Chronic reactions, such
as fibrosis, fistulae, and necrosis, occur months
to years following treatment and are due, in part,
to damage to slowly proliferating tissues. Other
factors including vascular damage may also play
a part in their development. Chronic reactions,
like acute reactions, are dependent upon the irra-
diated site. Chronic reactions, however, are often
permanent. Sequelae vary widely in severity
ranging from mild fibrosis to small bowel
obstruction, fistulae, and second malignancies.
Overall, the risk of a second malignancy follow-
ing RT is low. The notable exception is osteosar-
coma arising in irradiated bones in children
treated for retinoblastoma, particularly the
hereditary type.356
Select chronic radiation sequelae are respon-
sive to medical management, for example, pneu-
monitis is managed with bronchodilators and, if
necessary, a course of corticosteroids. Recent
evidence supports the role of angiotensin II
receptor antagonist in the treatment and preven-
tion of radiation nephritis.357 Prophylactic medi-
cations may also decrease the risk of select late
sequelae. Promising results have been reported
with pilocarpine in head and neck cancer to
decrease the incidence of xerostomia.358
Recently, zinc sulfate has been found to reduce
the risk of significant taste alterations in patients
with head and neck cancer.359 The most impor-
tant means of reducing the risk of chronic seque-
lae, however, is prevention. Strict attention to
optimal technique is imperative. Soft tissue sar-
coma patients, for example, should never receive
treatment to the entire circumference of the
extremity, in order to reduce the risk of chronic
edema. The risk of late sequelae is also reduced
by avoiding the use of large daily fractions, since
fraction size is a major determinant of late
effects.360 As noted earlier, new approaches
including 3D CRT, IMRT, and inverse treatment
planning should further aid in reducing the risk
of late sequelae.
FUTURE DIRECTIONS
Since its first use a century ago, the role of RT
in the treatment of cancer has undergone
tremendous changes. Its role will continue to
change in the coming years. Definitive wide-
field irradiation approaches will be replaced
with small-volume treatment delivered in con-
junction with chemotherapy. In general, com-
bined modality approaches will become more
common, particularly organ preservation tech-
niques.361 RT will be increasingly integrated
into high-dose chemotherapy and stem cell pro-
grams, providing improved control of bulky and
refractory disease sites.362,363
The twenty-first century will see increased
understanding and application of radiobiologic
concepts to clinical radiation oncology. Potential
strategies include induction of apoptosis, modifi-
cation of cellular resistance, modulation of cell
cycle regulation, and predictive assays for tumor
control.364,181 Radiogenetic therapy will be intro-
duced into the clinic. Selected genes linked to
radioinducible promoters whose expression can
be regulated by ionizing radiation may improve
the therapeutic ratio of RT. These and other
approaches will continue to concretize the impor-
tance of RT in the treatment of the cancer patient.
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