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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
survival curves for late-responding normal tissues (Bottom, yellow line) have a more
pronouncedshoulder, suggesting that these cells have a greater capacity to accumulate and
repairsublethalradiationinjury.Whenthetotaldoseofradiationisdeliveredinseveralsmaller
fractions(DoseA[dose/fraction] = blueline, ora larger fraction Dose B[dose/fraction]=red
line),the response to eachfraction is similar and the overall radiation survivalcurve reflects
multiple repetitions of the initial portion of the single-dose survival curve. Note that the total
dose required to kill a specific proportion of the cells decreases as the dose per fraction
increases (red line). Arrows indicate the differential effects of relatively large versus small
fractions of radiation. The greater differential effects of fractionated irradiation on normal
tissues (Bottom) than on tumor (Top)reflect the greater capacity of late-responding normal
tissues to accumulate and repair sublethal radiation injury. (Reprinted with permission from
KarcherKH,KogelnikHD,ReinartzG,eds.ProgressinRadio-OncologyII.NewYork:Raven
Press;1982:287–296.)
Figure5.3Responseof mousejejunalcryptcells todifferentdoseratesofγrays.The
mice were subjected to total-body irradiation,and the proportionof surviving crypt cells was
determined by counting regenerating microcolonies in the crypts 3.5 days after irradiation.
Therewasadramaticdifferenceincellkillingbecauseofrepairofsublethalinjuryatlow-dose
rates.In thissystem,the lowest-doserate(0.54cGyperminute)causeslittlereductioninthe
numberofsurvivingcellsevenafterhighdosesbecauserepopulationduringthelongexposure
balancesthecellkillingfromradiation.(FromFuKK,PhillipsTL,KaneLJ,etal.Tumorand
normaltissueresponseto irradiation invivo:variationwith decreasing dose rates. Radiology
1975;114:709–716,withpermission.)
TheFourRs
Thebiologiceffectof a given dose of radiation is influenced by the dose, fraction size,
interfraction interval, and time over which the dose is given. Four factors, classically
referredto as “the four Rs of radiobiology,” govern the influence of dose, time, and
fractionationonthecellularresponsetoradiation.ThefourRsareasfollows:
1. Repair
2. Repopulation
3. Redistribution
4. Reoxygenation
Repair
Because fractionated irradiation permits greater recovery of sublethal injury during
treatment,ahighertotaldoseofradiationisrequiredtoachieveagivenbiologiceffect
whenthe totaldoseis dividedintosmallerfractions.The broaderthe shoulderofthe
survivalcurve,thegreatertheincreaseindoserequiredtoachievethesamelevelofcell
death as achieved by a single dose. Two-dose experiments with varying interfraction
intervalshaveindicatedthataspaceofatleast4hours,andprobablymorethan6hours,is
necessarytocompleterepairofaccumulatedsublethalinjury.Clinicalstudiestendtoconfirm
these findings; for this reason, altered fractionation (“hyperfractionated”) protocols
usuallyrequireaminimumintervalof4to6hoursbetweentreatments.
Repopulation
Repopulationreferstothecellproliferationthatoccurs duringdelivery ofacourse of
radiationtreatment. The magnitude of the effect of repopulation on the dose required to
produceagivenlevelof celldeathdependsonthe doublingtimeofthecellsinvolved.For
cellswitharelativelyshortdoublingtime,asignificantincreaseindosemayberequiredto
compensate for a protraction in the overall delivery time. This phenomenon may be of
considerablepracticalimportance.Thespeedofrepopulationofnormaltissuesthatmanifest
radiation injury soon after exposure (skin, mucosal surfaces, etc.) limits contraction of a
courseoffractionatedirradiation.Unnecessaryprotractionprobablyreducestheeffectiveness
of a dose of radiation by permitting time for repopulation of malignant clonogens during
treatment (29–31). Cytotoxic treatments—including chemotherapy, radiation therapy,
and possibly surgical resection—may trigger an increase in the proliferation rate of
survivingclonogens.Thisaccelerated repopulationmay increasethedetrimentaleffect
of treatment delays and may influence the effectiveness of sequential multimodality
treatments(32,33).
Redistribution
Studiesofsynchronizedcellpopulationsshowsignificantdifferencesintheradiosensitivity
of cells in different phases of the cell cycle (34). Cells are usually most sensitive to
radiationinthelateG2phaseandduringmitosisandaremostresistantinthemid-to
lateSandearlyG1phases.Whenasynchronousdividingcellsreceiveafractionateddoseof
radiation, the first fraction tends to synchronize the cells by killing off those in sensitive
phasesofthecellcycle.CellsremainingintheSphasebegintoprogresstoamoresensitive
phaseofthecellcycleduringtheintervalbeforethenextfractionisgiven.Thisredistribution
ofcellstoamoresensitivephase of the cell cycle tends to increase the overall cell death
achieved from a fractionated dose of ionizing radiation, particularly if the cells have a
relativelyshortcellcycletime.
Reoxygenation
Thesensitivityoffullyoxygenatedcellstosparselyionizingradiationisapproximately
threetimesthatofcellsirradiatedunderanoxicconditions.Thismakesoxygenthemost
effectiveknown radiationsensitizer. Themolecular interactions responsibleforthe oxygen
effectarenotcompletelyunderstood,butitisbelievedthatoxygenstabilizesthereactivefree
radicalsproducedbytheionizingevents.Theratiobetweenthedoseneededtoachievea
givenlevelofcelldeathunderoxygenatedversushypoxicconditionsisreferredtoasthe
oxygenenhancementratio(Fig.5.4).
Most normal tissues are fully oxygenated, but significant hypoxia occurs in at least some
solid tumors, rendering the tumor cells relatively resistant to the effects of radiation. The
clinicalimportanceoftumorhypoxiaisuncertain,becausehypoxiccellsinitiallytendto
become better oxygenated during a course of fractionated irradiation (35). This
phenomenon,calledreoxygenation,tends to increase the response of tumors to a dose of
fractionatedradiation.
TreatmentStrategiesforOvercomingRadioresistanceof
HypoxicCells
Many treatment strategies have been explored to overcome the relative radioresistance of
hypoxiccellsinhumansolidtumors.Theseincludethefollowing:
1. Hyperbaricoxygenorcarbogenbreathing
2. Redcelltransfusionoruseofredcellgrowthfactors
3. Pharmacologic agents that act as hypoxic cell sensitizers (e.g., misonidazole) or that
selectivelykillpotentiallyradioresistanthypoxiccells(e.g.,tirapazamine)
4. High-linear-energy-transferradiation
None of these approaches have clearly demonstrated an improvement in outcome;
however,manyoftherelevantstudieswereseverelycompromisedbytechnicalorlogistical
problems.
Studiesofintratumoraloxygentensionhavesuggestedthatpatientswithhypoxictumorstend
tohave apoor prognosis;however,this correlationalso appearsto bepresentinsurgically
treatedpatients,andmayinpartreflectatendencyforbiologicallyaggressivetumorstobe
hypoxic(36).
An early randomized study of transfusion in anemic patients with locally advanced
cervical cancer hinted at improved local control when oxygen-carrying capacity was
increased(37).Thefindingsofthissmallstudyhavenotyetbeenconfirmedinalarger
prospective trial, and the results remain inconclusive. One group of investigators (38)
suggested that allogeneic transfusion may be harmful, although their results conflict with
thoseofmostotherstudies.
Inthelate1990s,thecommercialavailabilityofrecombinanterythropoietinledinvestigators
to explore the impact of growth factor–induced increases in the hemoglobin level on the
outcome of patients treated with radiation therapy. Initial enthusiasm was tempered by
negative results of a randomized trial in patients with head and neck cancer and by
reports of increased thromboembolic events in patients receiving erythropoietin (39).
TheGynecologicOncologyGroupprematurelyclosedarandomizedtrialofchemoradiation,
withorwithouterythropoietin,inpatientswithlocallyadvancedcervicalcancerbecauseof
concernsabouttheriskofthromboembolism(40).Inthatstudy,thromboticeventsoccurred
in 11 of 57 patients (19%) who received erythropoietin versus 4 of 52 (8%) treated with
chemoradiationalone(p=NS);the impact of erythropoietinonoutcome was inconclusive
becauseofthesmallnumberofpatientsinthestudy.
Figure 5.4 Survival curves for mammalian cells irradiated under aerated and hypoxic
conditions. The dose required to produce a given level of damage is approximately three
timesgreaterunder hypoxicoranoxicconditions thanunderfullyoxygenated conditions.The
ratio of doses is the oxygen enhancement ratio (OER). Sometimes the shoulder also is
reduced under hypoxic conditions. (Modified with permission from Hall EJ. Radiobiology for
theRadiologist.5thed.Philadelphia,PA:LippincottWilliams&Wilkins;2000.)
Mostretrospective studiesofpatients withcervical cancer havedemonstrated a correlation
betweentheminimumhemoglobinlevelduringtreatmentandoutcome,butallofthemwere
compromised by confounding risk factors (41–43). Even with multivariate analysis,
investigatorshavebeenunabletosortoutwhetheranemicpatientshavepoorerresponsesto
radiation because of their low hemoglobin levels or have low hemoglobin levels because
poorlyresponsivetumorsaremorelikelytobleed.In2015,Bishopetal.(44)publishedan
analysisof2,359patientswithstageI–IIIcervicalcancerstreatedwithradiationalone
orwith definitivechemoradiotherapy. In this study of well-characterized patients, no
independentcorrelationwasfoundbetweenminimumhemoglobinduringradiationand
therateofcentraldiseaserecurrence.Inparticular,whenpatientsweregroupedaccording
totumordiameter,therewasnodifferenceinthelocalcontrolrateforpatientswithminimum
hemoglobinvalues<10or≥10;thiswastrueevenforlargetumorsmeasuring5–6–9cmor
>7cmindiameter.
Because the results of studies in patients with cervical cancer have repeatedly failed to
confirmtheimportanceofhemoglobinintheeffectivenessoffractionatedradiationtherapy,
cliniciansare less enthusiasticthan they oncewereabout aggressive transfusionif patients
are otherwise hemodynamically stable. In general, hemoglobin levels should at least be
maintainedatalevelof8to9g/dL;patientswhosehemoglobinlevelsfallbelow10g/dL
should generally be transfused if they are just beginning treatment or are actively
bleeding because of the muted bone marrow response to anemia during
chemoradiation.
Linear-EnergyTransferandRelativeBiologicEffectiveness
Therateofdepositionofenergyalongthepathofaradiationbeamisreferredtoasits
linear-energy transfer (45). Photons, high-energy electrons, and protons produce sparsely
ionizingradiationbeams (low–linear-energytransfer),whereaslargeratomicparticles(e.g.,
neutrons,alphaparticles,carbonions)producemuchmoredenselyionizingradiationbeams
(high–linear-energytransfer).
The biologic effects of densely ionizing radiation beams differ in several important ways
from those of more sparsely ionizing radiation beams. With high–linear-energytransfer
radiationbeams:
1. There is little or no repairable injury and therefore no shoulder on the tumor cell
survivalcurve.
2. Themagnitudeofcelldeathfromagivendoseisgreater,increasingtheterminalslope
ofthesurvivalcurve.
3. Theoxygenenhancementratioisdiminished.
The unit of relative biologic effectiveness is used to compare the effects of different
radiation beams. Relative biologic effectiveness is defined as the ratio between a test
radiation dose and the dose of 250-kV x-rays needed to produce a specific biologic
effect.The relativebiologic effectivenessmaydiffersomewhataccording tothe tissueand
biologicendpointbeingstudied.
Inpractice,fewfacilitiesexistfor theproductionofhigh–linear-energytransferbeams,and
theirusehashadnomajorimpactontheresultsoftreatmentforgynecologicmalignancies.
Hyperthermia
Temperature is another factor that can modify the effect of ionizing radiation (27).
Supraphysiologictemperaturesalonecanbetoxictocellsbecauseheatispreferentiallytoxic
tocellsinalow-pHenvironment(frequentinareasofhypoxia)andtocellsintherelatively
radioresistantSphaseofthecellcycle.Temperaturesintherangeof42°to43°Csensitize
cellstoradiationbyreducingtheshoulderandincreasingtheslopeofthecellsurvival
curve.Becauseofthedifferentvascularsuppliesoftumorsandnormaltissues,hyperthermia
may produce greater temperature elevations in tumors, increasing the possible therapeutic
advantagewhenheatiscombinedwithirradiation.
Biologistsand clinicians have tried to find ways to exploit this effectformanyyears, but
havebeenhamperedbytechnologiclimitationsontheabilitytoselectivelyheatdeep-seated
tumors (46). A trial from Amsterdam (47) reported that survival was improved when
hyperthermiawasusedwithirradiationinpatientswithlocallyadvancedcervicalcancer.The
patientsin this study receivedrelatively low doses ofradiation, did not receiveconcurrent
chemotherapy,andhadpoorerthanexpectedpelvicdiseasecontrolinthecontrolarm,butthe
findingssuggestthattheapproachmaydeservefurtherstudy.
InteractionsbetweenRadiationandDrugs
Drugs and radiation interact in a number of ways to modify cellular responses. Steel and
Peckham (48) categorized these interactions into four groups: spatial cooperation
(independentaction),additivity,supra-additivity,andsubadditivity.
SpatialCooperation—IndependentAction
Spatialcooperationisthesituationinwhichdrugsandradiationactindependentlywith
differenttargetsandmechanismsofactionsothatthetotaleffectofthecombinationis
equal to that of each agent separately. For example, a site that is protected from
chemotherapy (e.g., the brain) may be treated with radiation to prevent recurrence.
Alternatively,adrug maybeusedtodestroymicroscopicdistantdisease,whileradiationis
usedtosterilizelocaltumorthatmaynotbecurablewithchemotherapyalone.
Additivity
Additivityisthesituationinwhichtwoagentsactonthesametargettocausedamage
thatisequaltothesumoftheirindividualtoxiceffects.
Supra-additivity
When there is supra-additivity, a drug potentiates the effect of radiation, causing a
greaterresponsethanwouldbeexpectedfromsimpleadditivity.
Subadditivity
Withsubadditivity,theamountofcelldeaththatresultsfromtheuseofthetwoagents
is less than that expected from simple additivity (the amount may still be greater than
expectedfromeithertreatmentalone).
Clinically,itisdifficulttodeterminewhichmodeofinteractionoccurswhentwoagentsare
usedconcurrently. When a greater response is observed than would be expected from
radiation alone, the interaction is often described as synergistic, but may be only
additiveorevensubadditive.
ClinicalEvidenceofBenefitFromCombinationsofRadiationand
Chemotherapy
In 1999 and 2000, the first strong evidence of a benefit from the use of concurrent
cisplatin-based chemotherapy with radiation was reported in a series of studies
involving patients with locoregionally advanced cervical cancer and with high-risk
cervicalcancerafterhysterectomy(21–23).Theseresultswereconfirmedinasubsequent
meta-analysis(49)andinalargepopulation-basedstudythatcomparedoutcomesbeforeand
after chemoradiation was designated as standard treatment in Canada (50). Although
randomizedstudieshavenotbeenperformedforothergynecologicdiseasesites,populationbased studies have suggested that there may be similar benefits from administration of
concurrentchemotherapyforpatientswithvaginalorvulvarcancers.
Trials of neoadjuvant chemotherapy before radiation have provided less evidence of
benefit(51). Several studies published by Sardi et al. in the 1990s (51) suggested benefit
whenashort,intensivecourseofchemotherapywasgivenbeforeradiationtherapy,butthis
wasnotcomparedwiththelaterstandardofchemoradiation.Otherstudiesdemonstratedno
improvementorevenpooreroverallsurvivalrateswhencisplatin-based chemotherapywas
givenbeforedefinitiveradiationtherapy(51).Meta-analysesinothertumorsites,e.g.,head
and neck (52) and anal cancers (53), have also demonstrated the benefit of concurrent
chemoradiationbuthavefailedtodemonstratebenefitfromneoadjuvantchemotherapygiven
beforedefinitiveradiotherapyorchemoradiation.
RadiationTherapyandtheImmuneSystem
In the modern era of immunotherapy and immune-targeted agents, it is worth noting that
radiationtherapyhasbothlocalandsystemicimmunemodulatoryeffects(54).Theseeffects
cansimultaneouslybeimmunestimulatoryandimmunosuppressive;themagnitudeofthese
effectsmayvarydependingonthedoseandscheduleofradiationtherapy.
As discussed previously, ionizing radiation initiates double-stranded DNA breaks,
activation of apoptotic cascades, release of DNA and RNA from the nucleus to the
cytoplasm,andeventuallycelldeath(55,56).Theresultingcellulardebrisstimulatesa
widevariety ofproinflammatorycytokines, suchascalreticulin, whichinturn activate
and recruit immune-stimulatory cells, including macrophages, cytotoxic T cells, and
dendriticcells(57).Dendriticcellsinthetumormicroenvironmentmayalsoactasantigenpresenting cells, potentially leading to increased tumor antigen presentation to major
histocompatibilitycomplex(MHC)molecules.
However, immune cells tend to be exquisitely sensitive to radiation. Radiation,
particularlytolargevolumes,causesapromptdeclineincirculatinglymphocytesandcauses
a decline in bone marrow stem cells within the treated volume. The magnitude of these
effectsiscorrelatedwiththevolumeoftissue,particularlybonemarrow,irradiated.Thereis
somevariabilityinthesensitivityofvariousimmunecellpopulations.
Regulatory T cells are relatively radioresistant and regenerate quickly,leading to an
imbalancebetweentheirregulatoryfunctionsandthenonregulatoryfunctionsofother
Tcells, such as CD8+ cytotoxic T cells and CD4+ helper T cells. There is evidence that
radiation can cause these regulatory T cells to migrate to adjacent lymph nodes,
increasingthesystemicexpressionofimmunosuppressivecytokinessuchasTGFβand
CTLA-4.Myeloid-derivedsuppressorcells,thatplayakeyroleintumorvascularizationand
animmunosuppressive rolein the tumormicroenvironment (56),areextremely resistantto
radiation and are even recruited to tumor stroma for protection following local radiation.
Because CTLA-4 drives regulatory T-cell migration into draining lymph nodes and
MDSC migration into the tumor microenvironment, a combination CTLA-4 therapy
andradiationmayhelpovercomesomeoftheimmunosuppressiveeffectsofradiation.
It has been suggested that invivo radiation of cancer cells may help to create an “in situ
vaccine”byincreasingtumorneoantigenpresentationbydendriticcellsleadingtoactivation
ofantitumorcytotoxicTcells(58).Thisvaccineeffectisthoughttocontributetotherare,but
sometimes impressive, “abscopal effect”—the response of unirradiated distant tumor
depositsthatissometimesseenwhenasinglesiteisirradiated,evenintheabsenceofany
other treatment. Mouse studies have shown that radiation in combination with
immunotherapy can induce an abscopal effect in immune-competent, but not in immunedeficientmice(54).Althoughmanycasereportsandsmallserieshavedescribedfindingsthat
suggest this enhanced abscopal effect of combined radiation therapy and immunotherapy
(59,60), clinical trials have as yet failed to demonstrate a clear improvement over either
treatmentalone(61).