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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
Luoetal.(62)havefound,usinganimalmodels,thatadministrationofconcurrentcisplatin
orotherchemotherapyinconjunctionwithimmune checkpoint blockade may enhance the
radiation-inducedabscopaleffect.Thisisonefactorthatmakesgynecologiccancers,which
arefrequentlytreatedwithconcurrentcisplatinchemotherapy,particularlyinterestingtargets
for combinations of radiation therapy and immunotherapy. Ongoing trials are currently
investigatingthesetreatmentsinanumberofdifferentsettings(63).
TherapeuticRatio
Ionizing radiation interacts with all the tissues in its path, not exclusively tumor tissue.
Radiation can be considered an effective cancer treatment only if there is a differential
biologic effecton tumor and normal tissues. The difference between tumor control and
normaltissuecomplicationsisreferredtoasthetherapeuticgainortherapeuticratio.
Ingeneral,therelationshipbetweentheprobabilityoftumorcureortheprobabilityof
normaltissueinjuryandthedoseofradiationcanbedescribedbyasigmoidcurve(Fig.
5.5).Atrelativelylowradiationdoses,thereisaninsufficientamountofcelldeathtoproduce
anylikelihoodoftumorcure.Asthedoseisincreased,athresholdisreachedatwhichsome
curesbegintobeobserved.Formosttumorsystems,the likelihoodofcurerisesrapidlyas
theradiationdoseincreasesbeyondthisthresholdandthenreachesaplateau.Theshapeand
slopeofthedose–responsecurvevaryaccordingtothetumortypeandsize(64–66).
A similar sigmoid relationship is seen when the likelihood of complications is plotted
againstthe radiation dose. Ifthesigmoid curve for normal tissuecomplications is to the
rightofthesigmoidcurvefortumorcontrol,thentreatmentwithdosesthatfallbetweenthe
two curves may achieve tumor control without causing complications. The difference
between these curves represents the therapeutic ratio. The primary goal of radiation
researchistoimprovethetherapeuticratiobyincreasingtheseparationbetweenthesedose–
responsecurves,maximizingtheprobabilityofcomplication-freetumorcontrol.
EffectsofRadiationonNormalTissues
Theextentofradiationdamagetonormaltissuesdependsonanumberoffactors,including
the radiation dose, the organ, the volume of tissue irradiated, and the division rate of the
irradiated cells. Tissues that have rapid cell turnover (i.e., tissues whose functional
activity requires constant cell renewal) tend to manifest radiation injury soon after
exposure, often during a fractionated course of radiation therapy. Examples of acutely
respondingtissuesincludemostepithelia(e.g.,skin,hair,gastrointestinalmucosa,bone
marrow, reproductive tissues). In contrast, tissues that have slower cell turnover (i.e.,
tissueswhosefunctionalactivitydoesnotrequireconstantcellrenewal)tendtomanifest
radiationinjurymonths, or years afterexposure.Examples of late-respondingtissues
aretheconnectivetissues,muscle,andneuraltissues.
Figure 5.5 Theoretical sigmoid dose–response curves for tumor control and severe
complications.Thetherapeuticratioisrelatedtothedistancebetweenthetwocurves.Dose
Acontrols tumorin80%ofcaseswitha5%incidenceof complications (bluecurve). Dose B
yields a 10–15% increase in the tumor control probability but a much greater risk of
complications,narrowingthetherapeuticratio(orangecurve).
Insomenormaltissues,celldeathmayoccurthroughthemechanismofapoptosis.Although
apoptosisisnottheprimarymechanismofdamageinmostcasesofnormaltissueinjury,itis
important in the response of lymphocytes, salivary gland cells, and a small proportion of
intestinalcryptcells(24).
AcuteReactions
Acutereactionstopelvicirradiation,suchasdiarrhea,areusuallyassociatedwithmucosal
denudation,whichinturnstimulatesanincreaseincellproliferation(67).Thisregenerative
responseisusuallysufficienttopreventserioussideeffectswithweeklydosesof900to
1,000cGygiveninfivefractions.Thisempiricallyderivedscheduleisthemostcommonly
usedforclinicalradiationtherapy.Iftreatmentisacceleratedtodeliverthedoseovermuch
shorter periods, the regenerative capacity of the epithelium may be overwhelmed and the
acute reaction so severe that a break in treatment is needed to allow for epithelial
regeneration.Theseverityofacutereactions depends on the volume of the normal tissues
irradiatedandthespecificnatureofthetissues.Superinfectionwithcandidaorbacteriamay
exacerbatetheeffectsofradiation,particularlytoskinormucosalsites(68).
LateReactions
Thepathogenesisoflateradiationcomplications(i.e.,thosethatoccurmonthstoyearsafter
radiationtherapy)differsfromthatofacutereactionsandisstillincompletelyunderstood.It
ishypothesizedthatlateeffectsofradiationresultfromthefollowing:
1. Damage to vascular stroma that causes an epithelial proliferation with decreased
bloodsupplyandsubsequentfibrosis.
2. Damage to slowly or infrequently proliferating parenchymal stem cells that
eventuallyresultsinlossoftissueororganfunction(67).
The likelihood of developing serious late effects from radiation depends on many factors,
including,butnotlimitedto,thedoseofradiation,theradiationdoseperfraction,thevolume
oftissueirradiated,theradiationdoserate,patientcharacteristics,othertreatments(suchas
surgeryorchemotherapy),andtheendpointbeingmeasured.
Because late-responding tissues are not proliferating rapidly, the duration of a course of
radiation treatment does not alter their tolerance. However,late-responding normal tissues
tendtobequitesensitivetochangesinthedoseperfraction,soforagivendoseofradiation
administeredovera given period of time, the risk of late effects will be greater with
larger fractions. This fractionation effect is responsible for the advantage of
hyperfractionated schedules in clinical settings in which late normal tissue reactions are
severely dose limiting (Fig. 5.2) (69–71). This fractionation effect has important
implications for treatments such as high–dose-rate (HDR) brachytherapy, intensitymodulatedradiationtherapy(IMRT),andstereotacticbodyradiationtherapy(SBRT),
whereaportionofthetarget(andpossiblyadjacentnormaltissue)frequentlyreceivesdoses
ofmorethan2Gyperfraction.
Some tissues—such as the liver,kidney, and lung—consist of functional subunits that are
arrangedmoreorlessinparallel.Thesetissuescantolerateahighdoseofradiationgiventoa
smallportionoftheorganwithoutseriouslate effects,buttendtoberelativelysensitiveto
moderatewhole-organdoses.Otherorgans,suchasbowelorureter,areorganizedinaserial
fashion,anddeliveryofadamagingdosetoevenasmallportionoftheorgancancausetotal
organfailure.Forallofthereasonsdiscussedpreviously,normaltissuetolerancescannotbe
describedintermsofsimpledoselimits,butsomegeneralizationscanbemadeaboutthe
toleranceofindividualtissues(dosesrefertoexternalradiationgivenindailyfractionsof
1.8to2GyorwithLDRbrachytherapy).
Uterus
Theuterusandcervixaretypicallydescribedasresistanttoradiation;however,whatis
reallymeantbythisisthatportionsoftheuteruscanbetreatedtoveryhighdoses(morethan
100 Gy in some cases) without the patient developing serious complications in adjacent
criticalstructures(e.g.,bowelandbladder).The uterus probably cannot sustain pregnancy
after such doses. Even moderate doses of 40 to 50 Gy probablycause enough smooth
muscleatrophytoprohibitasuccessfultermpregnancy,butthisisrarelytested.Women
whohavereceived20to30Gyormoretotheuterusduringtheperimenarchalperiodhave
subsequently become pregnant, but have tended to have spontaneous second trimester
abortions, probably because of underdevelopment of the uterus. Patches of endometrium
frequentlycontinuetofunctionafterdosesof50Gyormore.
Ovary
The radiation dose required to cause ovarian failure is highly dependent on the
patient’sage. Perimenarchal girls may continue to menstruate and can become pregnant
afterreceivingasmuchas30Gytotheovaries;however,theyusuallyexperiencepremature
menopause10to20yearslater.Mostadultwomenhaveovarianfailureafterreceiving20
Gyto the ovaries; as little as 5 to 10 Gy can induce menopause in older premenopausal
women.
Vagina
The radiation tolerance of the vagina depends on the region (upper, middle, lower,
anterior,posterior,orlateral),andlengthofvaginatreated,aswellastheradiationdose,
fraction size, dose rate, hormonal support, and other factors. Small portions of the
surface of the lateral apical vagina can be treatedto a very high dose (e.g., 140 Gy)
withoutcausingmajorcomplicationsinadjacentstructures.However,thesehighdoses
cause atrophy and shortening of the apical vagina. The vaginal tolerance dose is less if
treatmentincludesmorethantheapicalvagina,orifthedoseincludestheposterior,ordistal,
vagina.Evenmoderatedoses(e.g.,40to50Gy)maydecreasetheelasticityofthe vagina,
althoughitissometimesdifficulttodistinguishthedirecteffectsofradiationfromthoseof
thetumor,alteredhormonalenvironment,aging,andotherfactors.
SmallIntestine
Theriskofsmallintestinalsideeffectsishighlydependentontheradiationdoseandvolume
irradiatedand onthepatient’shistory. Inthe absence ofcomplicatingfactors, the entire
small intestine can tolerate doses up to 30 Gy without major late effects. Smaller
volumes can tolerate 45 to 50 Gy with a low risk of complications; the risk of chronic
diarrhea and bowel obstruction increases rapidly with doses greater than 50 to 60 Gy and
approaches100%ifasignificantvolumeofsmallbowelreceives70 Gyormore (72).The
riskofbowelobstructionissignificantlyincreasedinpatients whohave ahistory ofmajor
transperitonealsurgery,pelvicinfection,orheavysmoking(73).
Rectum
In most cases, the entire rectum can tolerate 45 to 50 Gy with a low risk of major
sequelae. Small portions of the anterior rectal wall can tolerate doses of up to 70 Gy.
However,the risk of seriouslateeffects(severe bleeding, obstruction, or fistula) increases
steeplyasthevolume ofrectumtreatedtoahighdoseisincreased(74).Intheprospective
EMBRACE study of image-guided brachytherapy, patients whose treatment delivered ≥75
Gyto2ccofrectumhadanunacceptable12.5%rateoffistulaat3yearsversus0–2.7%for
patientswho receivedlowerdoses (74).TheEMBRACE grouphas recommended limiting
the rectal D2cc dose to ≤65 Gy if this can be accomplished without compromising the
likelihoodoftumorcontrol(75).
Bladder
The entire bladder can be treated to 45 to 50 Gy with a very low rate of severe
morbidity.However,thisdosemayhavesubtleeffectsonbladder’scontractility,particularly
inpatientswhohavealsoundergoneradicalhysterectomy.Smallportionsofthebladdercan
tolerate doses of 80 Gy or more with a low risk of major morbidity (severe bleeding,
contracture, or fistula). The dose–response relationship is poorly defined in this range,
because traditional methods of bladder dose estimation have used reference points that
systematically underestimated the maximum dose. The most accurate dose–response
estimatesfor patientstreated withchemoradiation forintact cervicalcancerprobably come
fromtheEMBRACEIIstudyofimage-guidedbrachytherapy(75,76).Theseauthorsreported
a slight increase in the overall prevalence of bladder symptoms (including frequency,
urgency,andincontinence)from21%atbaselinetoabout25%at3years.Severesideeffects
wererarewitha0.7%rateof fistula formation for patients whose tumors did not initially
involvethebladder.Thisrateis similarto thatreported ina largeretrospectivestudy from
MDAndersonCancerCenter(77).
Ureter
Surgicallyundisturbeduretersappeartotolerate85to90Gyofcombinedexternalbeam
radiationandLDRintracavitarytreatmentwithalowriskofstricture.However,higherdoses
maycauseureteralstrictureandsecondaryhydronephrosis(76,78).
Kidney
Mostpatientscantolerateasmuchas18to22Gytobothkidneyswithverylittleriskof
long-termdamage.Higherdosescausepermanentdamagetorenalparenchyma.Ifthepatient
hasnormalrenalfunction,50%ormoreoftherenalparenchymacanbetreatedtoahigh
dosewithoutcausingrenalfailure;however,renalhypertensionmayoccurifanentirekidney
isobliteratedwithradiation.Underlyingrenaldiseaseorconcurrentuseofchemotherapy
candecreaserenaltolerance.
Liver
Inmostcases,thelivercantolerateasmuchas30Gy(at1.5Gyperfraction)totheentire
organ,althoughthisdosewillcausetransientelevationofalkalinephosphataselevelsandcan
causedysfunction in a small proportionofpatients. Higher doses cause seriousdamageto
liverparenchymabutcanbetoleratedifdeliveredtoonlyaportionoftheliver.Toleranceis
highly dependent on underlying hepatic function and can be markedly decreased with
concurrent delivery of some chemotherapeutic agents and during periods of hepatocyte
regeneration(e.g.,afterpartialhepatectomy).
SpinalCordandNerves
Transversemyelitis and paralysis can occur in a small proportion of patients who receive
doses as low as 50 Gy to the spinal cord, and the risk increases rapidly as the dose
approaches60Gyat2Gyperfraction.Peripheralnerves,includingthecaudaequina,are
rarelyaffectedafter 50 Gy and usually toleratedosesashighas 60 Gy without serious
sequelae.
Bone
Aslittleas10to15Gyofradiationcausestransientdepletionofbonemarrowelements.
Withdosesofmorethan30to40Gy,permanentdamageisdonetosupportingelements,and
bone marrow within the irradiated area will not repopulate normally.This damage can be
seenasfattyreplacementofthemarrowcavityonMRI.
Symptomatic fracture is rare after treatment with 40 to 45 Gy of pelvic radiation.
However, routine MRI sometimes detects small, usually asymptomatic, insufficiency
fracturesofthepelvisafterthisdose(79).Hipfracturemaybeseenafterdosesaslowas40
Gytotheentirefemoralheadandneck,andtheriskprobablyincreasesrapidlyasthedose
approaches60Gy.Patientswhoareelderly,verythinorwhohaveahistoryofosteoporosis
havean increasedrisk ofdevelopinginsufficiencyfractures (80). Therisk of fractureafter
radiationtherapy mayalso dependonthe boneirradiated,the volumeof boneinthe highdoseregion,concomitantsteroiduse,andotherfactors.
ScoringofLateComplicationsofRadiationTherapy
A numberof systemshavebeen usedto score latecomplications ofradiation therapy.The
Radiation Therapy Oncology Group/European Organization for Research and
TreatmentofCancerLateRadiationMorbidity(RTOG/EORTC)scheme(Table5.1)has
frequentlybeenusedtoscorelateradiation-relatedevents.However,increasingly,clinicians
areusingtheCommonTerminologyCriteriaforAdverseEvents(CTCAE)toscoreboth
radiation and chemotherapy related side effects (81). This unified system reflects the fact
that,withtoday’smultimodalitytreatment,severalfactorsmaycontributetoadverseevents.
InEurope,somegroupsusethe Franco-ItalianGlossary,ascoringsystemthatincorporates
earlyandlatesurgicalandradiation-relatedsideeffects(82).
TreatmentStrategiestoExploitDifferencesBetweenTumor
andNormalTissueintheResponsetoFractionatedRadiation
Therapy
A variety of altered fractionation schemes have been devised to exploit the different
sensitivitiesoftumorandnormaltissues to fractionation and the possible effects of tumor
cell repopulation. These include (i) hyperfractionation, in which the dose per fraction is
reduced,thenumberoffractionsandtotaldoseareincreased,andtheoveralltreatmenttime
is relatively unchanged; (ii) accelerated fractionation, in which the dose per fraction is
unchanged, the overall treatment duration is reduced, and the total dose is unchanged or
decreased; and (iii) hypofractionation, in which the dose per fraction is increased, the
numberoffractionsandtotaldosearereduced,andtheoveralltreatmenttimeisdecreased.
With hyperfractionation, treatment is usually given two or more times daily with at
least 4 to 6 hours between fractions to allow repair of sublethal injury. This scheme
should permit delivery of a higher dose of radiation without increasing the risk of late
complicationsortheoveralldurationoftreatment.Hyperfractionationschemesmayhavean
advantageiftheincreaseddosedeliveredperdaydoesnotcauseunacceptableacuteeffects
andifpatientsarewillingtoaccepttheaddedinconvenienceoftwoorthreetreatmentsdaily.
Accelerated fractionation schemes do not reduce the risk of late effects and tend to
increase the acute effects of treatment, but may be advantageous because treatment is
completedoverashortertime,reducingtumorcellrepopulationduringtreatment(70).Such
schemesare likely tobe of limitedvalue in themanagementof gynecologicmalignancies,
becauseacutesideeffectstendtolimittherateoftreatmentdelivery.
Hypofractionationschedules are usuallyavoidedwhen the treatment goal iscurativeand
dose-limitingcriticalstructuresareinorclosetothetargetvolume.Becausetheα/βoflaterespondingnormaltissuesislessthantheα/βofmosttumors,largefractionstendtohavea
therapeuticdisadvantage.Malignantmelanoma,whichappearstohavearelativelylowα/β,
maybearareexceptiontothispattern.
Table5.1RTOGandEORTCLateRadiationMorbidityScoringScheme
a
Hypofractionated schedules are frequently used for palliative treatmentbecause they
areconvenientandproducerapidsymptomrelief.However,inmostcases,thenecessary
reduction in total dose reduces the likelihood of complete eradication of tumor within the
treatmentfield.Hypofractionationmaybeparticularlybeneficialifthetumortargetissome
distancefromcriticalstructuresandiftheradiationtreatmentplanischaracterizedbyasteep
dosegradientsuchthatthetargetreceivesarelativelyhighdoseper fraction,whilenormal
tissue structures receive no more than approximately 2 Gy per fraction. Under ideal
circumstances, HDR brachytherapy plans and some highly conformal external beam plans
achievethisfavorablegeometry.
Stereotactic Body Radiotherapy (SBRT), sometimes referred to as stereotactic
radiosurgery, is an extreme form of hypofractionation in which a small number of large
dosesofradiation(usuallyfiveorfewer)areusedtoablatetumor.Becausethereisverylittle
recoverablesublethalinjurywiththeseschedules,tightgeometricalconformalityisneededto
obtain a favorable balance between tumor control and normal tissue preservation. During
SBRT, great care must be taken to avoid exposing vulnerable normal tissues to the target
dose.
Treatmentis usuallydeliveredusinghighly conformal treatment plans with precise patient
positioning and immobilization. These techniques are particularly useful for treatment of
tumors surrounded by normal tissues that have a parallel structure (e.g., lung or liver)
because ablation of a small volume of these normal tissues has little effect on the overall
organ function. SBRT may be more dangerous in situations where tumor is very close to
seriallystructuredorgans,whichcanbeseriouslycompromisedifevenasmallportionofthe
organisseverelydamaged(e.g.,bowel,ureter,orbladder).Forthisreason,SBRTshouldbe
used with extreme caution in the pelvis, where tumors are typically surrounded by
vulnerable structures and where very tightly conforming treatment plans may lead to
undertreatmentofaportionofthetumororofadjacentsitesofmicroscopicdisease.
CombinationsofSurgeryandRadiationTherapy
Becausesurgeryandradiationtherapyarebotheffectivetreatments,clinicianshavetriedto
improve locoregional control or reduce treatment morbidity by combining the two
modalities. Theoretically, surgery may remove bulky tumor that could be difficult to
control with tolerable doses of radiation, and radiation may sterilize microscopic
diseaseattheperipheryofthesurgicalbed.Thetwomodalitiesarecombinedinanumber
ofways:
1. Preoperativeirradiation
2. Diagnosticsurgery(surgicalstaging)followedbydefinitiveirradiation
3. Intraoperativeirradiation
4. Surgicalresectionfollowedbypostoperativeirradiation
5. Combinationsoftheseapproaches
PreoperativeIrradiation
Preoperativeirradiation is sometimes used to sterilize possible microscopic disease at
themarginsofaplannedoperativesite.Thisispotentiallymostusefulwhenthesurgeon
anticipatesclosemarginsadjacenttoacriticalstructure(e.g.,theurethraoranusinapatient
withlocallyadvancedvulvarcancer).
Inpatientswithuterinecancer,preoperativeirradiationhaslargelybeenabandonedin
favorof postoperative irradiation, which can be planned when information from the
surgical specimen is available and which avoids unnecessarily treating patients with
veryearly-stagedisease. Preoperative irradiation is sometimes used to treat patients with
stageIIendometrialcancerthatgrosslyinvolvesthecervixandisusedinsomepatientswith
bulky cervical cancers involving the uterine body. This is because the dose deliverable to
paracervicaltissues ismuch greaterwhen theuterus isstillinplaceto holdan intrauterine
applicator than after surgery, when only an intravaginal applicator can be used; however,
surgerytendstobeamoreeffectivewayofeliminatingdiseaseintheuterinefundus,which
maybedifficulttotreattohighdosewithintracavitarybrachytherapy.
Some studies have suggested that lower doses of radiation may be required to sterilize
microscopicdiseaseinatumorbedundisturbedbysurgerybecauseanintactvascularsupply
isbetterabletodeliveroxygen.Becausetheriskofoperativecomplicationsisincreasedafter
high-dose radiation therapy,doses given when surgical resection is anticipated are usually
lower than doses given when a tumor is irradiated definitively. The greatest risk of
preoperative radiation therapy is that if the tumor remains unresectable, the
effectivenessofadditionalirradiation willbe markedlydecreasedbythe longinterval
betweentreatments.
IntraoperativeIrradiation
In some cases, intraoperative irradiation can be delivered by the following means (i)
withapermanentimplant(using
125
Ior
198
Au);(ii) withafterloadingcathetersinthe
operativebed(using
192
Ir);or(iii)withaspecialelectronbeamororthovoltageunitin
theoperatingroom.Theseapproachesdeliverradiationdirectlytothesiteofmaximumrisk
whenthetargetcanbevisualizeddirectlyandnormaltissuesnearestthetreatmentareacan
beremovedfromthefield.Displacementofnormaltissues,particularlybowel,fromthe
treatment field is an important physical advantage of intraoperative external beam
techniques that may counterbalance the biologic disadvantage to any normal tissues
remaininginthefieldwhenanentiredoseisdeliveredinasinglelargefraction.
PostoperativeIrradiation