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5
RadiationTherapy
PatriciaJ.Eifel
LaurenE.Colbert
Radiation therapy plays a major role in the treatment of patients with gynecologic
malignancies.Forwomenwithcervicalcancer,radiationtherapyistheprimarytreatmentfor
patientswithadvanceddisease,yieldscureratesequaltothoseseenafterradicalsurgeryfor
patients with early tumors (1,2), and reduces the risk of local recurrence after surgery for
patientswithhigh-riskfeatures(3,4).Forwomenwithendometrialcancer,radiationtherapy
reduces the risk of local recurrence after hysterectomy for patients with high-risk features
(5–8)andisapotentiallycurativeprimarytreatmentforpatientswithrecurrentdiseaseand
for those who are unfit for primary surgery (9–13). Radiation therapy is an effective
treatment for selected patients with ovarian cancer (14,15) and is the primary curative
treatmentfor most patientswith invasive vaginalcancer(16,17). It hasalsohad a steadily
expandingroleinthemanagementofpatientswithcarcinomasofthevulva(18–20).
Computer technology and information systems have transformed many aspects of
radiationtherapypracticeinthepasttwodecades,makingpossiblethree-dimensional
treatment planning based on computed tomography (CT) and magnetic resonance
imaging (MRI), and optimized inverse planning, computer-controlled treatment
delivery,andimage-based remoteafterloading brachytherapy.Thesetechniquesenable
radiation oncologists to restrict radiation-dose distributions to specified target volumes,
therebydelivering themaximal doseto thetumor whilesparingnormaltissuesas muchas
possible. However, the planning and delivery of these advanced techniques are laborintensive, costly, and potentially more prone to error than was the case with traditional,
generallysimplertechniques.
Radiationbiologists and clinicianscontinue to advance theunderstanding of themolecular
mechanisms involved in radiation-induced cell death, the nature of drug–radiation
interactions,theimportanceofradiationdose,thetimeoverwhichthedoseisgiven,andthe
dose per fraction. In 1999 and 2000, the results of randomized clinical trials
demonstrated a significant improvement in pelvic disease control and survival when
concurrent chemotherapy was added to radiation therapy for patients with locally
advancedcervicalcancer(21–23).Theseresultsledtooneofthemostsignificantchanges
in the standard treatment of gynecologic cancers in decades. In this chapter, the basic
principlesofradiationtherapy,radiationbiology,andradiationphysicsarereviewed.
RadiationBiology
RadiationDamageandRepair
Celldeathcanbedefinedasthelossofclonogeniccapacity(i.e.,theabilityofthecellto
reproduce). Most cell death caused by ionizing radiation is mitotic cell death. Ionizing
radiationmayalsocauseprogrammedcelldeath(apoptosis).
The critical target formost radiation-induced cell death is the DNA within the cell’s
nucleus. Photons or charged particles interact with intracellular water to produce highly
reactivefree radicalsthat inturn interactwith DNAtoproducestrandbreaks thatinterfere
withthecell’sabilitytoreproduce.Althoughthisinteractionmaycauseacell’s“reproductive
death,”thecellmaycontinuetobemetabolicallyactiveforsometime.Radiation-induced
damagemaynotbeexpressedmorphologicallyuntildaysorevenmonthslaterwhenthe
cellattemptstodivide(mitoticcelldeath).Insomecases,adamagedcellmayundergoa
limitednumberofdivisionsbeforeitdies,havinglosttheabilitytoreproduceindefinitely.
Apoptosis (programmed cell death) may play an important role in radiation-induced
celldeath(24).Incontrasttomitoticcelldeath,apoptosismayoccurbeforecelldivisionor
afterthecell hascompletedmitosis.TheplasmamembraneandnuclearDNAmaybothbe
importanttargetsforthistypeofcelldeath.Apoptosisappearstobeaparticularlyimportant
mechanism of radiation-induced cell death in certain postmitotic normal tissues, including
humansalivaryglandsandlymphocytes.Radiation-inducedapoptosishasbeenobservedin
someproliferatingnormaltissuesandtumors.Biologistsareactivelystudyingthepathways
that regulate the expression of radiation-induced apoptosis, in the hope that they can be
exploitedtoimprovelocaltumorcontrol(25).Investigatorsarecurrentlyexploringtargeted
agents that may stimulate proapoptotic molecules or inhibit antiapoptotic molecules in the
radiation-inducedapoptoticcascade(e.g.,BCL2)(26).
CellSurvivalCurves
Theeffectsofionizingradiationonthesurvivalofmammaliancellpopulationsinvitro
aretypicallyexpressedgraphicallyasdose–responseor“cellsurvival”curves(27).The
survivingfraction ofcells isplotted (onan exponentialscale)againstthedose ofradiation
(ona linear scale).Experimentaldata using single doses of sparsely ionizing radiation
(e.g.,x-rays, gammarays, electrons,orprotons)typicallyproducecell survivalcurves
withtwocomponents(Fig.5.1):ashoulderregionandanexponentialregion.
Several mathematical models, based on different hypothetical mechanisms of cell killing,
have been devised to describe radiation dose–response relationships. These include the
following:
1. Themultitargetmodel(alsoreferredtoastheN-D0model)
2. Thelinear–quadraticmodel(alsoreferredtoastheα⁄βmodel)
Themultitargetmodel(Fig.5.1A)isdescribedbytheexpressionlogeN=Dq/D0,where
NandDqmeasurethewidthoftheshoulderandD0istheslopeofthefinalexponential
portion of the survival curve. This model derives from the classic target theory, which
holdsthateachcellcontainsmultiplesensitivetargets,allofwhichmustbehittokillthecell.
Thepresenceofashoulderregionisbelievedtoreflectaccumulationofsublethalinjuryin
someoftheirradiatedcells(27,28).Althoughthemultitargetmodelaccuratelydescribesthe
exponentialportion of the dose–response curve, itisa poor fit to experimentaldatain the
shoulderregion. In particular,it fails to predict the approximately linear slope (D1) of the
initialportionoftheshoulder(Fig.5.1B).
Thelinear–quadraticmodeldescribes thedose–responserelationshipaccordingto the
equation S = exp − (αD + βD2), where S is the surviving fraction, D is the dose of
radiation,andαandβareconstants(Fig.5.1B).Thismodelpresupposestwocomponents
of cell death: one that is proportional to the dose (αD) and one that is proportional to the
squareofthedose(βD2).Thedoseatwhichthelinearandquadraticcomponentsareequalis
α/β(Fig.5.1A).Thismodelfitsexperimentaldataparticularlywellforthefirstfewlogsof
celldeath,whicharemostrelevanttofractionatedandlow–dose-rate(LDR)irradiation,butit
iscontinuouslybendingonalog–linearplot.Thisbendisinconsistentwithexperimentaldata
thatdemonstrateastraightlineonalog–linearplotforthedistalportionofthecellsurvival
curve.Forthisreason,thelinear–quadraticmodelmaynotaccuratelypredicttheeffect
oftreatmentschedulesthatinvolveverylargedosesperradiationfraction.
Fractionation
Conventional radiation therapy is usually given in a fractionated course with daily
doses of 180 to 200 cGy (centiGray) per fraction. Hypothetical cell survival curves for
normaltissueandtumorcellsillustratetheadvantageoffractionation(Fig.5.2).Whenadose
ofradiationisdividedintomultiplesmallerdosesseparatedbyanintervalsufficienttoallow
maximum repair of sublethal injury,a relatively shallow dose–response curve is achieved,
reflectingarepetitionoftheshoulderofthesingle-dosecellsurvivalcurve.Theslopeofthe
fractionated-dosecellsurvivalcurvedependsonthecharacteroftheshoulder(NandDq).
The sparing effect of fractionation is greatest for cells with a response to radiation
characterizedbyarelativelybroadshoulder,reflectingthecells’greaterabilitytoaccumulate
andrepairsublethaldamageduringtheinterfractioninterval.Manynormaltissuesandsome
poorlyresponsivetumorsexhibitthistypeofresponsetofractionatedirradiationinvivoand
in vitro. In contrast, most tumors and some acutely responding normal tissues (e.g., bone
marrow and intestinal crypt cells) have a dose–response curve with a relatively narrow
shoulder,implyingrelativelylittlesparingeffectoffractionation.
Thebiologic effects of various fractionation schemes can be estimated and compared
usingthelinear–quadraticformula.Foratotalradiationdoseddividedinnwell-separated
fractions,thebiologiceffectisgivenbyE=n(αd+βd2).Somerearrangementoftheequation
gives:
E/α=nd×(1+d/(α/β))
ThequantityE/αistermedthebiologicallyeffectivedose(BED)andisthevalueusedto
compare various fractionation schedules. The value of α/β provides an estimate of the
fractionation sensitivity of a tissue. Tissues that are greatly spared by fractionation (most
normal tissues) generally have a low α/β value (e.g., 2 to 3), while tumors and acutely
respondingtissuestendtohavearelativelyhighvalue(e.g.,8to10).
Thedifferencebetweenthefractionation sensitivityoftumorsandnormaltissuesis an
important determinant of the therapeutic ratio (the differencebetween tumor control
andnormaltissuecomplications)offractionatedirradiation.
Dose-RateEffect
Sofar,thisdiscussionofcellsurvivalcurvesandfractionationhasreferredtoradiationgiven
inacuteexposures—thatis,atarateof100cGyperminuteorgreater.Atthesedoserates,
theshoulderofthesurvivalcurveispronounced.Asthedoserateisdecreased,cellshavea
greateropportunity to repairsublethalinjuryduring the exposure.Thisis called the
dose-rate effect. The slope of the survival curve becomes increasingly shallow and the
shoulderlessapparent(Fig.5.3)untila doserateis reachedatwhich allsublethalinjury is
repaired. In experimental systems, the dose-rate effect appears to be much more
pronounced for normal cells than for tumor cells. This differential effect implies a
favorable therapeutic ratio that is exploited with LDR intracavitary and interstitial
brachytherapy.
Figure 5.1 Parameters commonly used to characterize the relationship between
radiationdoseandcellsurvivalinmammalian culture. In the multitarget,orN-D0, model
(A), N is the extrapolation number, N and Dq measure the width of the shoulder, and D
0
represents the slope of the final exponential portion of the survival curve. The multitarget
modelprovidesan accuratedescriptionofexperimentaldata intheexponentialportionof the
survival curve. The linear–quadratic model (B) more accurately describes the shape of the
initialshoulderportionofthecurve.Becausetheshoulder hasmoreinfluenceonfractionated
radiation therapy, the linear–quadratic model is more often used to predict the results of
fractionatedclinicalradiationtherapy.(ModifiedwithpermissionfromHallEJ.Radiobiologyfor
theRadiologist.5thed.Philadelphia,PA:LippincottWilliams&Wilkins;2000.)
Figure5.2 Relationshipbetweenradiationdoseandsurvivingfractionofcellstreatedin
vitro with radiation delivered in a single dose or in fractions. Top: Most tumors and
acutelyrespondingnormaltissues.Bottom:Late-respondingnormaltissues.Formosttumors
and acutely responding normal tissues, the cellular response to single doses of radiation is
described by a curve with a relatively shallow initial shoulder (Top, yellow line). Cellular