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RADIATION ONCOLOGY
39
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 through the deceleration of high-kinetic energy intensity from a point source also decreases as
treatment of benign and malignant diseases with electrons (bremstrahlung).4,5 Gamma rays are the inverse square of the distance from the
ionizing radiation (IR). The field was born not typically produced by radioactive sources used in source, a dependence known as the inverse
long after the discovery of x-rays by Wilhelm brachytherapy (see below), whereas x-rays are square law.4,5
Roentgen in 1895.1 Radiation therapy (RT) was generated by linear accelerators and used in Unlike a photon beam, a charged particle trav-
soon being used in the treatment of a wide vari- external beam RT. Within a linear accelerator, a els a known range in tissue proportional to its
ety of malignant tumors.2,3 It was also soon rec- narrow beam of electrons is accelerated to nearly energy. Tissues beyond the range of the charged
ognized, however, that radiation produced the speed of light before striking a tungsten tar- particle are thus not irradiated. Electrons are the
adverse effects on normal tissues. In fact, due to get.5 As the electrons decelerate, they emit brem- most common therapeutic charged particles and
the significant cutaneous toxicity associated strahlung radiation (x-rays) with a spectrum rang- are also produced by a linear accelerator. Instead
with the available low-energy machines, RT had ing from zero to their maximum kinetic energy. of striking a tungsten target, the beam passes
limited applicability until the introduction of Beam quality is expressed as their highest-energy through a series of filters that broaden and shape
high-energy (megavoltage) therapy in the 1950s. photons in terms of kVp (kilovolts peak) or MV it. Charged particles interact with matter through
Only then was it possible to treat deep-seated (megavolts). Therapeutic beam energies range three primary processes: soft collisions (Coulomb
tumors without excessive toxicity. from 50 kVp to 25 MV or greater. In this energy force interactions with outer shell electrons), hard
Over the past 20 years, tremendous advances range, the relevant interactions of photons with “knock on” collisions (direct interactions with
have been made in imaging and treatment deliv- matter include the photoelectric effect, Compton electrons), and nuclear field interactions.5 Typi-
ery, allowing for improved targeting and effect, and pair production.4,5 Compton effect is cally, a 1 MeV electron will undergo 105 interac-
increased sparing of normal tissues. Increased the predominant interaction for therapeutic tions before losing its energy.4 Soft collisions
understanding of radiobiology has also provided beams, whereas for energies below 50 kVp, the account for approximately half the energy trans-
a means of further reducing the risk of treatment photoelectric effect is the most important interac- ferred to matter. The remaining energy is trans-
sequelae while increasing the efficacy of treat- tion, and pair production is the primary interac- ferred primarily by the relatively fewer, but more
ment. RT currently occupies an important role in tion at energies above 25 MV. As a result of these energetic, hard collisions.
the management of benign and malignant dis- interactions electrons are set into motion, causing Other therapeutic modalities include neu-
eases throughout the body in both children and ionization and excitation of other atoms in the trons6,7 and protons.8,9 Neutron beams are gen-
adults and offers an effective means of palliation medium. As an x-ray beam passes through matter, erated by bombarding a beryllium target with a
when cure is not possible. its intensity is reduced and can be expressed by cyclotron-accelerated proton beam.5 Like pho-
the following formula: tons, neutrons are exponentially attenuated.
PHYSICAL BASIS OF Interactions with tissue include neutron–proton
RADIATION THERAPY I (x) = Ioe-mx collisions and neutron–nuclei reactions, which
TYPES OF RADIATION RT is delivered primarily set heavy charged particles in motion. Proton
with high-energy photons (gamma rays and x- where Io is the initial intensity of the photon beams are also generated by a cyclotron. Unlike
rays) and charged particles (electrons). The dis- beam, I(x) is the intensity after traversing a depth neutrons, protons primarily deposit their dose
tinction between gamma rays and x-rays lies in x and µ is the material’s linear attenuation coef- near the end of their range, a phenomenon
their origin; gamma-rays originate from excited ficient. High-energy beams are less attenuated known as a Bragg peak.4,5 The Bragg peak can
and unstable nuclei, whereas x-rays are produced than low-energy beams and thus are used for the be modified to encompass the tumor without
by electron energy transitions within the atom or irradiation of deep-seated tumors. Radiation delivering high doses to more distal tissues.8,9
586 SECTION 9 / Radiaton Oncology
RADIATION ABSORBED DOSE The quantifica- define the CTV. PTV encompasses both the blocks or a multi-leaf collimator (MLC). Cer-
tion of radiation has evolved over time. In the GTV and CTV with an added margin due to the robend is a low-melting-point alloy which
early twentieth century, units of skin erythema uncertainty in the treatment delivery process. attenuates nearly all of the beam.5 Custom
and the roentgen, a measure of ionization pro- The PTV includes the effects of organ motion blocks are designed for each field and are
duced in air, were used. Today, the accepted unit and day-to-day setup uncertainty and typically placed manually. MLC, as the name implies,
of measurement is “absorbed dose,” which is the ranges from 3 to 10 mm.19,20 In addition, sur- consists of a series of leaves within the machine
energy absorbed per unit mass. Physically, rounding normal tissues are delineated. head, which are typically 1 cm in width.35,36 An
absorbed dose represents the energy deposited Although CT is the primary imaging modal- MLC increases the efficiency of treatment
by secondary charged particles in the medium. ity for treatment planning, magnetic resonance delivery by obviating the need for changing
The unit of absorbed dose is the gray (Gy), which imaging (MRI) provides important complemen- blocks between fields and offers the capability
is defined as the absorption of 1 joule per kilo- tary information,21–23 especially for intracranial of delivering intensity modulated radiation
gram (J/kg).4,5 One gray is equivalent to 100 and head and neck tumors. Other modalities, therapy (IMRT) (see below).
centigray (cGy) or 100 rads. such as positron emission tomography (PET) RT is delivered with the patient placed on the
and single photon emission computed tomogra- treatment table in a customized immobilization
TREATMENT PLANNING phy (SPECT), also provide complementary device. The patient is positioned so that the center
AND DELIVERY information.24,25 Imaging data can be cross-cor- of the PTV is at the isocenter, the center of rotation
EXTERNAL BEAM THERAPY The goal of treat- related to transfer regions of interest from one of all moving parts of the machine (gantry, colli-
ment planning is to uniformly irradiate a speci- study to another.26–28 mator, and table). On the first day of treatment, set-
fied target while minimizing the dose to sur- Treatment Planning Treatment planning is up films are obtained and compared with those
rounding normal tissues.10 The spatial performed interactively on a computer and is used taken at simulation. The position of anatomic land-
distribution of radiation delivered depends on a to generate a dose distribution superimposed on marks are evaluated, and patient moves are made
number of factors including patient anatomy, tis- CT images. Variables considered in planning as needed. Films are also obtained at each treat-
sue density, beam energy, and the configuration include beam energy and modality, number of ment angle, showing both the internal anatomy and
of radiation portals. Because of the often com- portals and beam angles, relative beam weights, the field aperture. In recent years, electronic portal
plex tumor geometry, image-based three-dimen- and beam-modifying devices (wedges, compen- imaging devices (EPIDs) have been intro-
sional (3D) planning is essential.11–14 Both the sators). Beam energy is chosen on the basis of duced.37,38 EPIDs offer the potential advantages of
concepts of treatment planning and the technical patient anatomy. High-energy photon beams are online verification, as well as the ability to moni-
considerations related to 3D planning are used for deep-seated tumors; superficial tumors tor and compensate for patient motion during ther-
described below. may be treated with orthovoltage-energy photon apy.39,40 Treatment delivery may be aided through
Simulation and Target Delineation Simu- beams (100–250 kVp) or with electrons. Beam a record-and-verify system, a computer program
lation involves patient positioning, fabrication of number is determined by a variety of factors which monitors treatment parameters for each
treatment aids, including immobilization devices, including tumor size, shape, and location. Beam patient.41,42 Such programs are becoming increas-
and the selection of treatment fields.15 Most modifying devices are used to compensate for ingly integrated into comprehensive information
patients are simulated in the supine position. variations in external patient anatomy. systems with links to the simulator and treatment
However, specific positions are often indicated to A number of tools have been developed that planning computers.
minimize the dose delivered to neighboring nor- aid in the design and evaluation of a treatment Intensity-Modulated Radiation Therapy
mal tissues. Breast and lung cancer patients, for plan.29–32 Beam’s eye view (BEV) allows the Conventional external beam RT is delivered with
example, are simulated with their arms overhead visualization of the tumor geometry relative to beams of uniform intensity. Recent advances,
to allow for the use of angled (oblique) beams critical structures from the perspective of the however, have made the use of beams of varying
which do not transverse the arms. Other special- radiation beam.29 Beam orientations are chosen intensity possible. This approach, known as
ized positions include the “frog leg” position (vul- that encompass the PTV but spare adjacent criti- intensity-modulated RT (IMRT), allows the
var cancer) and the “chin tuck” position (pituitary cal structures. In addition, BEV also permits the high-dose region to be better conformed to the
tumors). Immobilization is accomplished with the design of customized shielding blocks. Quantita- shape of the PTV.43-46 Better conformality trans-
aid of thermoplastics, foam cradles, bite blocks tive evaluation of treatment plans is performed lates to increased sparing of surrounding tissues,
and other accessories. The goal of immobilization using dose volume histograms (DVH) and dose thereby allowing the delivery of higher radiation
is to minimize the day-to-day set-up variability surface histograms (DSH).31,32 DVH represents doses to the tumor. The beam intensity patterns
caused by patient movement. On a conventional the volume of a particular organ irradiated as a used in IMRT are derived using an inverse pro-
simulator, field borders are chosen under fluoro- function of dose. The surface area as a function cess45,46 and delivered using an MLC fitted on a
scopic guidance on the basis of patient anatomy of dose is represented by DSH and is used in the linear accelerator. Beam intensity is varied by
and knowledge of tumor spread. More recently, evaluation of hollow organs. Such quantitative computer-controlled movement of the leaves of
computed tomography (CT) simulators allow for evaluation assists in the selection of the optimal the MLC into and out of the beam’s path. Deliv-
direct acquisition of CT data with the patient in treatment plan. Other treatment planning tools ery of IMRT requires accurate patient position-
the treatment position. Selection of beam orienta- include digitally reconstructed radiographs30 ing and immobilization.15
tions is performed virtually. and volume rendering.33,34 IMRT has been shown to be a promising
Imaging occupies a central role in RT plan- Treatment Delivery and Verification approach in several disease sites. In prostate can-
ning, providing geometric information on exter- Linear accelerators are used to administer cer, IMRT is used to minimize the volume of the
nal patient contour and tumor size, shape, and external beam RT (Figure 39-1). Most modern bladder and rectum irradiated, allowing higher
location relative to adjacent critical struc- accelerators have dual photon energies ranging doses to be delivered to the prostate.47,48 IMRT has
tures.16,17 For 3D planning, the process begins from 4 to 24 MV, and four to six electron ener- also been used to decrease xerostomia (dry mouth)
with the acquisition of a CT scan with the patient gies (6–22 MeV). Accelerators are equipped in head and neck cancer patients by minimizing the
immobilized in the treatment position. Three vol- with a gantry which rotates through 360º allow- volume of parotid tissue irradiated.49-50 IMRT also
umes are defined for planning:18 the gross tumor ing treatment from any angle. Non–co-planar has shown promise in the treatment of pediatric
volume (GTV), the clinical target volume beams may be delivered through a combination tumors51 and gynecologic malignancies.52,53
(CTV), and the planning target volume (PTV). of gantry and treatment table rotations. The Examples of Treatment Plans Lung
The GTV is the tumor visible on the treatment beam produced is rectangular in shape. Beam Figure 39-2 illustrates an axial CT image, with
planning images. Regions of microscopic spread shaping is accomplished with either cerrobend isodose lines superimposed in a patient with
CHAPTER 39 / Principles of Radiation Oncology 587
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
ductive death. Consequently, most cell types do
50 not show morphologic evidence of radiation
40 damage until they attempt to divide. Alterna-
tively, some cell types are killed via the induction
30
of apoptosis.77 A cell that has sustained lethal
20 damage following radiation exposure may
10
undergo one or more divisions prior to metabolic
death and loss from the tumor population.
0 The concept that cell death following radia-
0 20 40 60 80 100 tion exposure may not be manifested until several
Percent Dose cell divisions later has clinical relevance, such
that tumors associated with very slowly prolifer-
Figure 39-3 Dose volume histograms of the spinal cord and contralateral lung in the patient ating cancers may persist for months and appear
shown in Figure 39-2.
histologically viable. The histologic appearance
may clear only after tumor cells have had the
Both SRS and SRT involve the localization of ple non–co-planar arcs. An example of a SRS opportunity to attempt to divide. Prostate carci-
a targeted lesion within a stereotactic frame. The treatment plan in a patient with a solitary brain noma, for example, may require up to 24 months
stereotactic frame is either fixed (screwed into metastasis from lung cancer is shown in Figure after RT prior to obtaining a normal biopsy.78
the cranium) (SRS) or relocatable (SRT). A 39-12. This plan consists of five non–co-planar
stereotactic frame allows positioning of a patient arcs and was delivered with 6-MV photons on a RADIATION SURVIVAL ANALYSIS Radiation sur-
with millimeter accuracy.64,71 The goal of linear accelerator. vival can be studied both in vitro and in vivo. In
SRS/SRT is to conform the dose distribution to vitro experiments usually involve irradiating
the targeted lesion while minimizing the dose to BIOLOGIC BASIS OF exponentially growing cells to known doses of
normal, surrounding brain parenchyma. In prac- RADIATION THERAPY radiation. Cells are plated, and after 2 to 3 weeks,
tice, this is accomplished with the use of multi- CELLULAR RESPONSE TO RADIATION Radiation
randomly interacts with molecules within the
cell. Although the critical target for cell killing is 100
the deoxyribonucleic acid (DNA),72 damage to
the cellular and nuclear membranes and other 80
Percent volume
Surviving Fraction
of DNA damage. Exposing cells to DNA damag-
Surviving Fraction
0.10 CLASSIC ASPECTS OF DNA REPAIR IN RADIO- conditions are altered.153,154 The enhancement in
THERAPY Irradiated cells that are not lethally survival seen following manipulation of postirra-
Repair
Repopulation damaged may undergo repair of the damage to diation conditions is referred to as the repair of
Surviving Fraction
of SLD
their DNA. Sublethal damage repair (SLDR) is potentially lethal damage (PLD). PLD repair
operationally defined as the enhancement in (PLDR) has been demonstrated in vitro155,156
survival when a dose of radiation is separated (Figure 39-18). PLDR has also been shown to
over a period of time. SLDR may be represented occur in vivo.155,157,158 PLDR is reported to be
0.01
by the extrapolation number (n) of the radiation more pronounced in large tumors, presumably
survival curve when a multi-target survival because a large proportion of cells are in G1 or
G2-M G1-S model is employed.137-141 G0. PLDR has been described to occur principally
Sublethal damage has been studied in vitro in the G1 phase of the cell cycle. Efficient PLDR
0 2 4 6 8 10 12 14 and in vivo. In general, SLDR experiments occurs in a variety of human tumor cell lines in
Hours Between Doses divide a single dose into two relatively equal vitro.159-162 Weichselbaum and colleagues,161,
doses spaced at variable time intervals. Elkind 163,164 and Guichard and colleagues165 have sug-
Figure 39-16 The surviving fractions of Chinese hamster
cells exposed to two doses of x-rays separated by various and colleagues investigated this phenomenon in gested that PLDR contributes to radiotherapy fail-
time intervals are shown. When the two doses are given great detail.137,142 Figure 39-16 shows results ure under certain circumstances.
together (time between doses = 0 hours), the surviving frac- representative of split-dose experiments. An PLDR and/or SLDR may not be expressed
tion is equal to that observed after the single larger dose of enhancement in survival, following two doses under all conditions in vivo. For example, cells
radiation. As the two doses are separated by time, an separated in time, is observed in exponentially must be genetically competent to repair these
enhancement in survival occurs and is interpreted as the growing Chinese hamster cells at 2 hours. This types of damages, and the tumor environment
repair of sublethal damage (dashed line). Subsequent radi- enhancement in survival is due to the rapid repair may affect the proliferative status of tumor
ation doses result in a reduction in the surviving fraction.
This reduction in survival occurs because of more sensitive
of SLD and is followed by a subsequent decline cells.154,164,166 Also, radiation (or chemother-
phases of the cell cycle (G2 and M). Later time points in survival at 5 hours and then another increase apy) may induce tumor proliferation, which
demonstrate increased surviving fractions due to radiation in survival at 8 hours. This variability in survival allows fixation of radiation damage before
synchronization of cells and their entry into resistant is caused by synchronization of the exponen- PLDR or SLDR is complete.154,166 Therefore,
phases of the cell cycle (G1 and S) Source: Elkind.38, 39 tially growing cell populations by the first radia- PLDR is likely to be most important in tumor
tion dose and subsequent treatment with a sec- cells of intermediate or high radiosensitivity
ond dose during the radioresistant S-phase (t = 2 when cells are quiescent between fractions. The
hours) or radiosensitive G2-M phase of the cell 24-hour PLDR-surviving fraction, following
Elk-1 and ATF-2.129 In turn, binding of acti- cycle (t = 6 hours).138,140,141 treatment of human tumor cells in plateau-phase
vated c-Jun to the AP-1 site in the c-Jun gene The concept of SLDR is important during a culture with a similar dose, is referred to as the
promoter contributes to the activation of c-Jun course of fractionated RT because the shoulder maximum recovery potential (MRP).80 Figure
transcription in a positive feedback loop. IR- region of the survival curve is recapitulated due 34-18 shows that although two cell lines have
induced activation of the c-Jun gene is blocked to SLDR.139 Fractionation magnifies the surviv- different amounts of initial lethal damage
by the antioxidant N-acetyl-L-cysteine ing fraction after each treatment to an exponent induced by a constant radiation dose (a function
(NAC).130 IR also induces expression of the c- equal to the number of treatments. Therefore, of D0 and n), the surviving fraction after a 24-
fos and jun-B genes, which encode proteins that small differences in survival after each dose may hour delay in subculture (a function of n, D0,
associate with c-Jun. have a great impact on treatment outcome. Most PLDR) may be similar.
Early response genes IR induces expres- human tumor cell lines studied in vitro have rel-
sion of the EGR-1 gene.131 Transcription of it is atively small shoulders;143-148 however, a large
conferred by IR-induced activation of serum capacity for SLDR has been reported for some
Number of surviving cells per cm2 of Skin
104
response (CARG) elements in the EGR-1 pro- human tumor cell lines.79,144
moter.131 As found for c-Jun, treatment with The ability of tissues to undergo SLDR has Si
ng
NAC blocks induction of the EGR-1 gene in the been demonstrated using a variety of normal tis- 103
le
Sp 24 h
IR response.132 These findings showed that IR sue clonogenic or functional assays.149-151 The
Do
lit
(
se
Do s)
activates the c-Jun and EGR-1 genes by ROS- capacity of different cell populations to repair 102
s
se
r
mediated signaling mechanisms. The finding SLD is reflected by the width of the shoulder (or
s
that IR activates gene transcription provided the initial slope) of their survival curve. An increase 101
experimental basis for the design of gene therapy in the total dose required to give the same bio-
strategies in which the spatial and temporal con- logic damage when a single dose (D1) is split into
1
trol of gene expression are regulated by high two doses (total dose D2), with a time interval
energy x-rays. In this approach, a radio-inducible between doses to obtain a single biologic end
promoter, such as that from the EGR-1 gene, is point, is the capacity of a normal tissue to repair 10-1
inserted upstream to sequences encoding a ther- SLD. The difference in the two doses, D2 - D1, is Dq=D2-D1
apeutic protein. The CARG elements in the the measure of SLDR by the tissue, provided that 10-2 500 1000 1500 2000 2500
EGR-1 promoter have been used to activate IR- the two doses are larger than those that generate D1 D2
Dose in Rad
induced transcription of tumor necrosis factor the shoulder region of the survival curve.81,150,152
(TNF) or the HSV-1 thymidine kinase (TK).133- (Figure 39-17), D2 - D1 = Dq. If the D0 is known, Figure 39-17 Single-dose and two-dose survival curves
135 The TNF protein functions as a radiosensi- then n can be calculated from the equation: for epithelial cells. The D0 is 135 cGy. The ordinate is not
tizer and, in high local TNF concentrations, the surviving fraction, as in survival curves for cells cul-
selectively increases the sensitivity of the tumor loge n = Dq/D0 tured in vitro, but is the number of surviving cells per
square centimeter of skin (plating efficiency is obviously
to IR treatment in the absence of systemic toxic-
not known in vivo). In the two-dose survival curve, the
ity.136 Several clinical trials are underway in Varying environmental conditions can influ- interval between dose fractions is 24 hours. Although the
which the EGR-1/CARG promoter–TNF con- ence cell survival after a dose of x-rays. Thus, curves are parallel (similar D0), their graphic horizontal
struct is delivered to tumors in an adenoviral vec- damage that is potentially lethal under a given set separation number (n), may then be calculated from D0
tor and activated by local radiotherapy. of conditions may not be lethal if postirradiation and Dq. Source: Weners.194, 195
CHAPTER 39 / Principles of Radiation Oncology 593
1.0 Maximum crucial steps in the reaction—the search for a inhibitors of IR-induced DSB repair. Initial
Recovery homologous duplex template DNA and the for- attempts at inhibiting DNA repair in irradiated
Potential mation of joint molecules between the broken tumors were associated with increased normal
Radioresistant
Cell Line
DNA ends and the repair template. Other pro- tissue toxicity. A more recent strategy using anti-
Surviving Fraction
0.1
teins, including replication protein A (RPA), sense oligonucleotides to the RAD51 gene has
Surviving Fraction
RAD52, RAD5430 and several RAD51-related resulted in enhancement of the effects of radia-
After 24 Hours proteins (eg, RAD51B, RAD51C, RAD51D, tion on glioma cells in vitro and in animal mod-
Radiosensitive PLDR Time XRCC2, XRCC3, and DMC1),170 are thought to els.180 With improvements in the selective deliv-
Cell Line Function of n, D0 function as accessory proteins for RAD51 at var- ery of radiotherapy, the spatial targeting of
0.01 and PLDR
ious stages of HR. In mammalian cells, RAD51 IR-induced DSBs to tumors should theoretically
forms nuclear foci in response to IR and establish inhibition of DNA repair as an attrac-
decreased expression of RAD51 confers sensi- tive therapeutic approach.
tivity to IR-induced DNA lesions.171 The later
0.001 steps of the process include polymerization of CELL CYCLE CHECKPOINTS, INTEGRATION OF
0 2 4 6 8 24
nucleotides to restore degraded DNA strands and SIGNALLING, AND DNA REPAIR It is necessary
Hours Between Exposure
resolution of the recombination intermediates. for one phase of the cell cycle to be completed
and Subculture
Mice with targeted disruption of the RAD51 before initiating events associated with the fol-
Figure 39-18 Maximum recovery potential (MRP) for gene exhibit an embryonic lethal phenotype.172 lowing phase. Failure to achieve accurate com-
radioresistant and radiosensitive cells. Confluent cell Moreover, the failure to generate RAD51-/- stem pletion of events may lead to genetic instability
lines (noncycling) were irradiated and immediately sub- cells has indicated that RAD51 is essential for and/or cell death. Cells have evolved mecha-
cultured, which resulted in an initial surviving fraction cell viability. RAD51 interacts with P53173 and nisms to monitor genomic instability associated
(0), which is generally equal or slightly less than the sur-
viving fraction of exponentially growing cells in tissue
BRCA1.174 Although the breast cancer suscepti- with DNA damage. The surveillance mecha-
culture. However, when these irradiated confluent cells bility proteins BRCA1 and BRCA2 are clearly nisms and resulting inhibition of cell cycle pro-
are not subcultured for the indicated time intervals, an implicated in HR , their roles are not well under- gression are referred to as checkpoint controls.
enhancement in survival, interpreted as STR repair of stood. Other studies have demonstrated that For example, a DNA damage checkpoint control
potentially lethal damage (PLDR), occurs. The surviving RAD51 is phosphorylated by c-Abl in IR-treated communicates information between a DNA
fractions of cells after a 24-hour delay in subculture cells and that this response contributes to the lesion and the regulatory components of the cell
(MRP) of confluent cells is dependent on n, D0, and down-regulation of RAD51 activity in ATP- cycle. Radiation-induced single-strand breaks
PLDR. The initial surviving fraction of cells at 0 hours is dependent DNA strand exchange reactions.171 (SSBs) and DSBs are associated with the initiat-
dependent on no and D0 but not on PLDR.
Treatment of cells with IR is also associated with ing signal that activates checkpoint controls. In
inactivation of RAD51 by caspase-3-mediated general, the cell cycle is delayed at one or the
Molecular aspects of DNA repair in the proteolytic cleavage.175 checkpoint by inhibiting cyclin-dependent
cellular response to ionizing radiation All In contrast to HR, NHEJ uses little or no kinases (CDKs) until DNA repair is complete.
eukaryotes have evolved several mechanisms to homology to couple DNA ends. This pathway is Following exposure to ionizing radiation, cells
repair DSBs, which indicate the importance and not only used to repair DSBs generated by IR or arrest at the check points. Cell cycle regulation in
difficulty of repairing this type of DNA injury. other exogenous DNA-damaging agents, but is irradiated and nonirradiated cells has recently
The two main pathways are homologous combi- also required to process the DSB intermediates been reviewed.181
nation (HR) and non-homologous end-joining that are generated during V(D)J recombina- DNA damage and its effect on cell cycle pro-
(NHEJ). These two repair modes differ in their tion.176 Several proteins that are involved in gression have been intensively studied in yeast
requirement for a homologous template DNA NHEJ have been identified. The Ku heterodimer, and Xenopus oocyte, as well as in mammalian
and in the fidelity of DSB repair. Whereas HR which consists of Ku70 and Ku80, has a high cells. Studies show that the kinase activity of
ensures accurate DSB repair, NHEJ does not. affinity for DNA ends, which indicates that it has Cdc2-cyclin B complex is required for the G2-to-
The contributions of these two DSBrepair path- an early role in the NHEJ process. Ku bound to a M-phase (G2/M) transition in the normal cell
ways are likely to differ depending on the stage DNA end attracts the catalytic subunit of the cycle and that tyrosine phosphorylation of Cdc2
of the cell cycle.98 However, the pathways are not DNA-dependent protein kinase (DNA-PKCs), a inhibits its kinase activity.182 Both inhibition of
mutually exclusive because repair events that 470-kDa polypeptide with a protein kinase Cdc2 kinase activity and enhanced phosphoryla-
involve both pathways can be detected. HR is domain near its carboxyl terminus.177 DNA- tion of Cdc2 have been observed following DNA
most efficient in the S and G2 phases of the cell PKCs can subsequently phosphorylate several damage. The phosphorylation state of Cdc2 is
cycle because of the availability of sister chro- cellular target proteins, including P53, the Ku maintained by the kinases Wee1 and Myt1 and by
matids as repair templates.167 In the absence of a polypeptides and itself. At present, it is unclear the phosphatase Cdc25. 119,121,123,183, Cdc2 is
sister chromatid, DSB repair in G1 phase could which phosphorylation targets of DNA-PKCs inactivated by phosphorylation of Thr-14 and Tyr-
still efficiently occur through NHEJ. are relevant in vivo. A complex that consists of 15 in the ATP-binding domain by the Wee1
HR can repair DSBs by using the undamaged DNA ligase IV and XRCC4 (X-ray-repair-cross- kinase.184 Phosphorylation of Tyr-15 is also medi-
chromatid as a template, which results in the complementing defective repair in Chinese ham- ated in part by IR-induced activation of the Lyn
accurate repair of the DSB. HR is mediated ster mutant 4) accomplishes the final ligation tyrosine kinase.126,127 Although checkpoint regu-
through the RAD52 family of proteins.168 These step. Cell lines or animals that lack either of the lation of both sides exists, it is thought that regu-
proteins include RAD50, RAD51, RAD52, genes encoding these proteins do not carry out lation of Cdc25 activity is an important factor in
RAD54 and meiotic recombination 11 V(D)J recombination and are sensitive to ioniz- the maintenance of G2 arrest after DNA damage.
(MRE11). The initial cellular response to DSBs ing radiation.178 In addition to the involvement In mammalian cells, two kinases, Chk1 and Cds1
is mediated through ATM and Nijmegen break- of the RAD50–MRE11-containing complex in (also known as Chk2), have been identi-
age syndrome 1 (NBS1).169 Subsequent steps of HR, genetic experiments with yeast indicate that fied118,185,186 and shown to phosphorylate
DSB repair through HR include DNA-end recog- this complex also has a role in NHEJ.179 Cdc25C and prevent it from dephosphorylating
nition, possibly by RAD52, and nucleolytic pro- Although cells deficient in components of (Ser-216) and activating Cdc2. 85,118,185,186,187,188,
cessing of the broken ends of DNA into 3'-end the NHEJ and HR pathways are more radiosensi- Phosphorylation of Cdc25 facilitates association
single-stranded DNA. This single-stranded DNA tive than their wild-type counterparts, few with the 14-3-3 protein, resulting in its export
is bound by the RAD51 protein which mediates advances have been made in the development of from the nucleus; however, the mechanism of
594 SECTION 9 / Radiaton Oncology
Chk1 and Cds1 activation following irradiation is of the toxicities associated with levels required dose is delivered by increasing the number of
not clear. Studies in Chk1-deficient cells have also for inhibition of IR-induced G2 arrest. The treatments (50–60 vs. 30–35) in the same total
shown that this kinase is required for initiating G2 CHK1 inhibitors, UCN01 and SB-218078, block treatment time. Thus, relatively rapidly dividing
arrest189,190 and is a downstream effector of ATM. DNA damage-induced G2 arrest in human cell populations may have a higher proportion of
The response of Cds1 to DNA damage has been cells.198-200 These findings and the demonstra- cells in the most sensitive phases of the cell cycle
shown to be dependent on the activity of ATM. tion that UCN01 does not inhibit hCHK2198,199 at each treatment. Cells in late-responding nor-
The ATM-dependent DNA damage checkpoint have supported lack of involvement of CHK2 in mal tissues are slowly proliferating, and there-
pathway regulates both the G1-S and G2-M tran- the G2 arrest response. Whereas UCN01 is fore, after a few fractions, many surviving cells
sitions in the response of mammalian cells to IR undergoing clinical evaluation as a radio- and will be concentrated in the more resistant phases.
treatment. The IR-induced arrest at the G1-S chemosensitizer, other inhibitors of CHK1/2, This strategy has been applied to a variety of
DNA damage checkpoint is mediated predomi- such as debromohymenialdisine,201 are under tumors, including primary brain tumors207 and
nately by P53-dependent induction of P21 expres- development. It is noteworthy that the concept of head and neck cancer.208
sion and thereby inhibition of the Cdk2 kinase.191 caffeine-induced override of G2-M block has Accelerated fractionation decreases the over-
P53 promotes arrest at the G0/G1 checkpoint. been challenged by investigators who suggest all treatment time to diminish clonogenic prolif-
Following radiation exposure, P53 protein levels this cell cycle perturbation and enhancement of eration between successive doses. Treatment is
rise due to post-translational modifications that the induced DNA damage associated with caf- given 2 to 4 times per day employing fraction
increase the P53 half-life. This rise is transient feine are attributed to inhibition of DNA repair sizes of 1.5 to 2 Gy per treatment with 4 to 6 hour
and is correlated with the presence of damaged and or DNA synthesis.202-204 interfraction intervals.81,209 The total daily dose
DNA. DNA strand breaks are the most potent Both the initiation and elongation stages of is thus 3 to 6 Gy and the total dosage is given in
inducer of P53 following IR exposure.181 Cell DNA replication (S-phase checkpoint) are inhib- 3 to 4 weeks. Although treatment interruptions
cycle arrest is induced by P53 when the protein ited by IR. In budding yeast, the genes that regu- are often necessary due to acute toxicity,210 the
acts as a transcriptional activator. One of the most late the S-phase checkpoint are RAD17, RAD24, total treatment time is substantially reduced.
important genes induced is P21waf-cip. The inter- RAD53, and MEC3 and MEC1. The sequence of Hypofractionation is the use of larger than stan-
action of P21 with the cyclin E/CDK2 complex gene interaction and function in mammalian dard daily fractions. This approach is typically
inhibits the progression of cells into the S-phase. cells is under investigation. The ATM gene prod- used when palliation is the goal. Treatment may
P21 also binds directly to proliferating cell uct plays a role in replicon initiation and chain involve 4 to 10 Gy fractions delivered weekly or
nuclear antigen (PCNA). In addition, P53 inter- elongation. Both MEC1 and ATM are members several times a week as opposed to daily.
acts with MDM2 and GADD45. As described of the PI3K gene family.
above, MDM2 negatively regulates P53 and MODIFIERS OF THE RADIATION RESPONSE The
likely functions during the recovery phase in the FRACTIONATION Early in the twentieth century, extent of DNA damage following radiation expo-
late G1-phase. GADD45 inhibits the progression it became apparent that RT was equally effica- sure is dependent on several factors. One of the
of cells into the S-phase. A second mechanism of cious but better tolerated when administered in most important is cellular oxygen.211 Hypoxic
regulating the G1 checkpoint by P53 is mediated divided doses,205 a concept known as fractiona- cells are considerably less radiosensitive than aer-
by direct binding to proteins such RPA. Bristow tion. Fractionation spares normal tissues by ated cells. In fact, anoxic cells require 2 to 3 times
and colleagues192 showed that rat fibroblast allowing time for repair and repopulation of nor- the radiation dose to produce an equivalent
clones expressing increasing levels of transfected mal cells. In addition, fractionation increases amount of cell kill as do oxygenated cells. The dif-
mutant P53 showed loss of the G1/S checkpoint tumor cell kill due to reoxygenation and reassort- ference in radiosensitivity between hypoxic and
and increasing levels of radioresistance. The ment of tumor cells into sensitive phases of the aerated cells is known as the oxygen enhancement
increased survival was not associated with loss of cell cycle.206 Conventional fractionation schemes ratio (OER). Oxygen is believed to prolong the
apoptosis, but consistent with observations of involve a daily fraction of 1.8 to 2 Gy 5 days a lifetime of the short-lived free radicals produced
improved double strand break repair.193 This is week. Total treatment times depend on the total by the interaction of x-rays and cellular H2O. Indi-
not consistent with a “more time for repair” dose prescribed and thus range from 3 to 7 weeks. rectly ionizing radiation is consequently less effi-
hypothesis for the G1/S checkpoint, because Various mathematical models have been pro- cacious in tumors with significant areas of
checkpoint abrogation would then be expected to posed to equate total dose, time, and fraction size hypoxia and necrosis. In contrast, damage follow-
sensitize and not protect. Interestingly, the and achieve an isoeffective dose. However, clini- ing exposure to directly ionizing radiation is inde-
radiosensitivity of P53 null fibroblasts remained cal utility of these models remains controversial. pendent of cellular oxygen levels.212
unchanged, indicating a gain of function of Clinical interest in altered fractionation has Thomlinson and Gray observed that tumors
mutant P53, possibly due to improved damage been resurrected due to recently reported “outgrow” their vasculature resulting in necrotic
sensing via the carboxy terminus of the protein improved outcomes in patients with advanced areas and suggested that tumor cells adjacent to
which is known to bind to damaged DNA in a head and neck cancer. Hyperfractionation is the anoxic region may be clonogenic but
nonsequence-dependent manner. defined as the use of reduced size fractions given hypoxic.213,214 As shown in Figure 39-19, the oxy-
Pharmacological agents which override the twice or more per day such that a greater total gen tension within the tumor falls with the dis-
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 Figure 39-19 Oxygen diffusion through
the effects of caffeine on G2 arrest is unresolved, tissue from a capillary resulting in hypoxic
although ATM has been proposed as the tar- Capillary cells. Oxygen diffuses an average of 150 Ci
get.195 Treatment of irradiated P53-deficient from the capillary. Cells beyond this region
cells with caffeine is associated with activation O2 are anoxic and nonviable. Cells at the periph-
ery of this radius are hypoxic but viable.
of Cdc2 and hence mitotic cell death.196 These
findings are in concert with reports which
demonstrate that abrogation of the G2 check- O2
tance from the capillary producing a hypoxic ential protection of normal tissues. Promising Although the induction of genes following
region. In some experimental tumor systems, results have been reported in head and neck cancer DNA damage was well known in bacteria, it was
reoxygenation of hypoxic tumor cells occurs patients undergoing RT.238 Amifostine has also only relative recently that induction of the tran-
within 24 hours.215 A clinical observation which been used to reduce chemotherapy-related seque- scription of the proinflammatory cytokine TNFα
supports the importance of oxygen levels in lae.239 Various endogenous biologic response gene provided support for the theory that gene
patients undergoing RT is that severe anemia is modifiers also act as radio protectors, including activation mediates the mammalian cell response
associated with worsened local control in a variety interleukin-1 and granulocyte macrophage colony- to DNA damage.245 TNFα is transcriptionally
of tumors. Several studies have demonstrated stimulating factor (GM-CSF);240,241 neither are induced following irradiation of human tumor
improved survival in patients with locally classic radioprotectors, since they do not directly cells in vitr,o246 and has paracrine and autocrine
advanced cervical cancer treated with RT when scavenge free radicals but rather improve bone effects on tumor cell killing and might account
hemoglobin levels were above 11 g as compared marrow tolerance compartment. for some of the systemic effects of localized RT.
with patients with lower hemoglobin levels.216–218 bFGF is induced in endothelial cells and medi-
Anemia has been associated with poorer survival GROWTH FACTOR AND CYTOKINE INDUCTION ates protection against apoptosis. The concept of
rates following RT in other tumors, including FOLLOWING RADIATION EXPOSURE GROWTH the induction and release of growth factors fol-
endometrial, bladder, and pharyngeal can- AND REGENERATION KINETICS The percentage lowing IR was initially reported in tumor cells
cers.219–221 The importance of cellular oxygen is of cycling tumor cells is called the growth frac- and in normal endothelial cells.247 Subsequent
also demonstrated by improvements in outcome in tion (GF). In human solid tumors, it is usually a studies showed that IR induces expression of
patients receiving hyperbaric oxygen.222,223 small proportion of the total number of cells. If genes encoding other growth factors, such as the
Numerous chemicals have been shown to the GF remains constant with time, the growth platelet-derived growth factor, interleukin-1187
modify the effects of ionizing radiation. An rate of the tumor is proportional to the GF. If the and bFGF.183 IR-induction of TGFβ, which is
important class of compounds are the hypoxic GF decreases with time, the rate of the tumor proposed to mediate fibrosis following IR and
cell sensitizers, including metronidazole, mis- growth slows. Solid tumors usually grow at a thereby to mediate some of the late effects of RT
onidazole, and etanidazole.224 These agents slower rate as they enlarge and so growth is on normal tissues. Other cytokines have been
mimic oxygen and have been shown in vitro to approximated by the Gompertz formula.81,242 In also reported to be induced following radia-
increase cell kill of hypoxic cells.225 Clinical circumstances of equilibrium in normal tissues, tion.248 Potential applications of these observa-
experience, however, with these agents have each mitotic division results in the average of tions is the use of TNFα or other cytokines as
been mixed. Only two prospective trials have only one new cell. Usually, one daughter cell is potential radioenhancing agents in gene therapy
demonstrated a benefit to their use in conjunc- lost by desquamation or metastasis. By defini- combined with ionizing radiation (see below). It
tion with RT.226,227 Toxicity is common, particu- tion, the cell loss factor (CLF) in a steady state is has subsequently been discovered that b-FGF
larly peripheral neuropathy. More promising 1. Maximum growth occurs if the CLF is protects some of the lung endothelium from radi-
results with less toxicity have been noted with reduced to 0. The only requirement for growth is ation-mediated apoptosis and has potential as a
the newest hypoxic sensitizer nimorazole.228 a reduction from 1.0 in the CLF, that is, an aver- radioprotector.249 Also, secretion of growth fac-
A second class of radiation sensitizers are the age of < 1 of two daughter cells of a division is tors and cytokines may be an important step in
thymidine analogues iododeoxyuridine (IUdR) lost. A CLF of < 1 is characteristic of regenera- radiation carcinogenesis in normal cells. Inhibi-
and bromodeoxyuridine (BudR).229 Both are tion of both normal tissue and malignant growth. tion of molecular mediators of deleterious late
incorporated into DNA in the place of thymidine Tumor growth is usually characterized by CLFs radiation effects on normal tissues may increase
and render DNA more suspectible to radiation that are closer to 1 than 0. the therapeutic ratio and presents the possibility
damage. Although several nonrandomized trials An index for the potential regeneration of of genetic manipulation in clinical radiotherapy.
have been promising,230,231 no prospective trial tumors and normal tissue populations is the pro- The recent demonstration of EGFR activa-
has demonstrated a significant benefit to their liferative activity of the cell population.81 One tion by ionizing radiation makes this receptor
use. Of note, both are associated with consider- common measurement of tumor growth is the and other members of ErbB receptor tyrosine
able acute toxicity. potential doubling time (PDT), which is defined kinase family important targets for radiosensi-
Multiple chemotherapeutic agents sensitize as the time required to double the number of tizing therapeutic interventions.250 The radia-
cells to radiation including 5-fluorouracil, acti- clonogenic cells if the CLF decreases to 0. In tion-induced activation of EGFR results in cyto-
nomycin D, cisplatin, gemcitabine, fludarabine, this concept, the doubling time is equal to the protective signaling dominantly involving
paclitaxel, doxorubicin, hydroxyurea, mitomycin cell cycle time. Tumors with a high rate of both MAPK and PI3K. The inhibition of EGFR by
C, topotecan, and vinorelbine. The mechanism cell production and loss have the potential for tyrphostin TK inhibitors or through over-expres-
of radiosensitization varies among the different early and rapid regeneration after irradiation or sion of a dominant-negative (DN) EGFR inhibit
agents. Cisplatin inhibits both SLDR and other cytotoxic treatment. Thus, even though a the radiation-induced cytoprotective response
PLDR.232 Inhibition of repair may also help tumor may exhibit slow pretreatment growth, it and results in significant radiosensitization of
explain the radiosensitizing properties of topote- may regenerate rapidly. Excessive protraction in xenograft tumors in mice. The monoclonal anti-
can.233 Doxorubicin increases cellular oxygen the time of radiation fractionation or split- body, IMC-C225, which blocks the binding of
levels by inhibiting mitochondrial and tumor cell course regimens may give inferior local control EGF, exhibits antitumor activity in EGFR+
respiration.234 Hydroxyurea is toxic to cells in results if accelerated proliferation occurs during tumors and enhances radiation toxicity in cul-
the S-phase and inhibits entry of cells into the the period when radiation is not given. Clonal tured human squamous cell carcinoma; it also
G1- from the S-phase.235 Mitomycin C is prefer- proliferation during tumor regression after irra- increases taxane-, platinum-induced cytotoxic-
entially toxic to hypoxic cells.236 Paclitaxel syn- diation was demonstrated by Hermens and ity in non-small cell lung carcinoma
chronizes cells into the G2- and M-phases.237 Barendsen, who showed an exponential increase xenografts.251 In A431 head and neck squamous
Other drugs act as radioprotectors by protect- in clonogen number in a rat rhabdomyosarcoma cell xenografts, IMC-C225 administered in con-
ing normal tissues from radiation damage while during a time of tumor shrinkage (Figure 39- junction with irradiation yielded a radiation
reportedly not affecting tumor radiosensitivity. The 20).243 Accelerated repopulation of irradiated enhancement factor of 3.62, attributable to both
best known radioprotector is amifostine, a deriva- tumors and tissues may be associated with the tumor necrosis and anti-angiogenesis.252 In
tive of cysteamine which acts as a free radical scav- recruitment of quiescent cells into the cell cycle. phase I pharmacokinetic studies, IMC-C225 has
enger. Following administration, amifostine This effect is associated with radiation-medi- a long half-life, lending itself to convenient
quickly penetrates into normal tissues, but only ated induction of the immediate early genes weekly administration. The reported toxicity
slowly into tumors, and thereby results in a prefer- c-Jun and EGR1.244 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
have been reported to enhance the anti-tumor effi- delivered in a single fraction which obviates the results have also been reported with intravenous
cacy of radiotherapy without increasing toxic- benefit of fractionation. Promising results have 144Sr331 and samarium.332***
ity.290-292 These findings collectively demonstrate been reported in retroperitoneal soft tissue sar- Whole brain RT is indicated in patients with
that inhibition of tumor angiogenesis potentiates coma.311 Brachytherapy has also been used at the cerebral metastases. Treatment is typically deliv-
the efficacy of radiation therapy. time of surgery. It is imperative, however, to ered over 10 days to total dose of 30 Gy. As with
delay loading for several days to allow for ade- osseous metastases, controversy exists over the
CLINICAL RADIATION ONCOLOGY RT alone is quate wound healing.312 optimal treatment regimen in these patients.
used as curative therapy in a variety of tumor When combined with chemotherapy, Borgelt and colleagues reviewed various regimens
types. Treatment may consist of external beam chemotherapy may be administered prior to ranging from 20 Gy in 5 fractions to 40 Gy in 20
alone, brachytherapy alone, or a combination of (neoadjuvant), during (concomitant) or following fractions on two randomized trials. No differences
the two. Although combined modality therapy is RT (maintenance). Chemoradiotherapy approaches were seen in terms of frequency or duration of
more common today, definitive RT is still used in have been shown to improve local control and erad- response. Overall, 50% of patients had significant
early-stage head and neck as well as gynecologic icate micrometastatic disease. Neoadjuvant improvement in neurologic symptoms. However,
tumors. RT alone is associated with results com- chemotherapy has been used in a number of sites the less protracted regimens resulted in more rapid
parable with that obtained with surgery for including early stage non-Hodgkin’s lymphoma313 overall response rates.333 Protracted regimens are
tumors of the oral cavity,293 oropharynx,294 and small cell lung cancer.314 A potential advantage indicated, however, in patients with controlled pri-
supraglottic larynx,295 and glottis.296 Moreover, is that bulky disease sites can be cytoreduced allow- maries and solitary metastases.
definitive RT is often associated with better long- ing for smaller treatment volumes. However, Other indications for palliative RT include
term functional outcome than surgery. Definitive increasing evidence suggests that concomitant spinal cord compression,334 liver metastases,335
RT was recently compared in a large prospective chemoradiotherapy is preferable in a variety of dis- orbital metastases,336 and carcinomatous menin-
randomized trial with radical surgery in women ease sites. Concomitant chemoradiotherapy is used gitis.337 Palliative RT is also used in symp-
with early-stage operable cervical cancer. RT was in locally advanced cancer of the lung,315 head and tomatic locally advanced lung338 and ovarian
associated with identical tumor control rates with neck,316 esophagus,317 bladder,318 and cervix.319 cancer.339 Brachytherapy can be used in pallia-
less long-term sequelae.297 Another tumor type Possible interactions between chemotherapeutic tive treatment as well, for example, bronchial,340
commonly treated with RT alone is early stage drugs and radiation are summarized in Table 39-2. biliary,341 and esophageal342 obstructions.
Hodgkin’s disease.298 In select sites, all three modalities are com- Therapy for Benign Disease RT is used in
RT alone is also the treatment of choice in bined. A variety of schedules have been used. a wide variety of benign tumors and conditions,
elderly patients. A common belief is that the Examples include neoadjuvant chemotherapy, such as keloids,343 hemangiomas,344 des-
elderly are at higher risk for acute and chronic RT surgery, and postoperative RT (locally advanced moids,345 and pterygium.346 Other indications
sequelae. However, numerous investigators have breast cancer)320 and surgery followed by con- include renal347 and cardiac348 transplant rejec-
demonstrated that age per se is not associated with comitant postoperative chemoradiotherapy (can- tion, macular degeneration,349 and heterotopic
increased toxicity.299,300 Instead, comorbidities cer of the pancreas and rectum).321,322 bone prophylaxis following arthroplasty.350
present in the elderly may increase their risk.301 Promising results have recently been reported in
Adjuvant Therapy A more common use PROPHYLACTIC THERAPY The most common the prevention of re-stenosis in patients undergo-
of RT is in combination with surgery and/or example is the prophylactic treatment of ing coronary angioplasty.351
chemotherapy. When combined with surgery, RT regional, clinically uninvolved lymph nodes.
may be given prior to (preoperative), following Prophylactic cranial irradiation (PCI) is used in RADIATION SEQUELAE Acute Sequelae
(postoperative), or during (intraoperative) patients with limited-stage small cell lung can- Acute radiation sequelae, such as skin desquama-
surgery. Although common in the past, preoper- cer323 and children with high-risk acute tion, mucositis, and diarrhea, occur during or
ative RT is less used today except in large bor- leukemia.324 Other examples include breast irra- immediately following treatment. Such sequelae
derline resectable tumors, for example, rectal diation in men with prostate cancer who receive are believed to be due to the interruption of repop-
cancer302 and soft tissue sarcomas.303 In con- diethylstilbesterol (DES), whole lung RT in ulation of rapidly proliferating tissues.352 The type
trast, postoperative RT is used in many tumor patients with bulky mediastinal Hodgkin’s dis-
sites including tumors of the central nervous sys- ease, and liver RT in advanced Hodgkin’s disease
tem,304 head and neck,305 breast,306 lung,307 gen- and pancreatic cancer.325-327
Table 39-2 Interaction of Radiotherapy and
itourinary,308 and gastrointestinal tract.309 In
Chemotherapy
patients with resectable disease, postoperative PALLIATIVE THERAPY RT is an important
RT is preferred because it allows treatment to be means of providing rapid and effective palliation Chemotherapy drug and radiation active against
tailored to the pathology findings, and higher due to local and/or metastatic disease. Osseous different tumor cell subpopulations based on
doses are possible. Moreover, there is reduced metastases secondary to breast, prostate, and hypoxia, cell cycle specificity, and pH
potential for interference in normal wound heal- other cancers are treated with localized fields and Decreased tumor cell repopulation following frac-
ing. Indications for postoperative RT include short-course regimens, for example, 30 Gy in 10 tionated radiation due to effects of chemotherapy
close/positive margins, residual disease, and fractions. Pain relief is achieved in more than Increased tumor cell recruitment from G0 into a
lymph node involvement. Potential disadvan- 70% of patients.328 The optimal fractionation therapy-responsive cell cycle phase
tages of postoperative RT include delaying ther- schedule, however, remains unclear. Rapid large Increased tumor cell oxygenation following radiation
apy until wound healing is complete and reduced fractions, for example, 20 Gy over 5 days, are with improved drug or radiation activity
vascularity of tissues following surgery. Intraop- equivalent to more protracted regimens using Improved drug delivery with shrinkage of tumor
erative RT is the delivery of a single large frac- smaller daily doses.329 Such approaches are indi- Early eradication of tumor cells preventing emergence
tion during surgery with either electrons or low cated in patients with symptomatic long-bone of drug and/or radiation resistance
energy photons.310 This is accomplished with sites that are not in close proximity to critical Eradication of cells resistant to one treatment modal-
either a dedicated treatment machine in the oper- organs. More rapid schedules may be possible. ity by the other treatment
ating room or by transporting the patient to the The Radiation Therapy Oncology Group (RTOG) Cell cycle synchronization
RT department during surgery. An important is currently comparing 8 Gy in 1 fraction to 30 Gy Inhibition of repair of sublethal radiation damage or
benefit is that normal tissues, for example small in 10 fractions in a randomized trial. Large-field inhibition of recovery frompotentially lethal radia-
bowel, can be displaced out of the treatment (hemibody) irradiation has been used in patients tion damage
field. A disadvantage is that the total treatment is with widespread bone metastases.330 Promising
CHAPTER 39 / Principles of Radiation Oncology 599
of reaction is dependent on the site irradiated. The FUTURE DIRECTIONS 17. Kuszyk BS, Ney DR, Fishman EK. The current state of the
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