Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
4
Chemotherapy
GottfriedE.Konecny
MichaelL.Friedlander
GeneralPrinciples
TumorGrowthandChemotherapy
A wide variety of chemotherapeutic agents and a growing number of targeted agents are
available to treat women with gynecologic cancers. The selection of a treatment regimen
should be based on the results of randomized phase III trials, but this may not always be
possible. When treating patients with uncommon cancers, treatment decisions can usually
onlybeinformedbyphase2studies.
Treatmentrecommendationsandchoiceofdrugsaredeterminedbytheknownefficacy
andpotentialtoxicitiesofchemotherapeuticagentsandtheclinicalcontextinwhichthe
treatmentisoffered.Withfirst-linetreatment,theaimiscure,whereaswithtreatment
for recurrent disease after one or more lines of prior therapy, the aim is usually
palliation and prolongation of survival. Most antineoplastic agents have a relatively
narrow therapeutic index, and treatment decisions are based on multiple factors, including
age, performance status, medical comorbidities, organ function, tumor type, previous
chemotherapy,objectivesoftherapy,andthepredictedlikelihoodofbenefit,whichshouldbe
communicated clearly to the patient and her family (Table4.1). The extent of previous
therapyandthepatient’sage,generalhealth,andotherrelevantmedicalcomorbidities
(e.g.,neuropathyfromlong-standingdiabetesorpriorchemotherapywithtaxanes)shouldall
be taken into consideration when deciding on the choice of treatment. The patient’s
emotional,social, and financialstatusmust also berespected.It isessentialto clearly
communicate the aims and objectives of therapy, that is, cure or palliation, the
likelihoodofbenefit,andthesideeffectsoftreatment,sothatthepatientcanmakean
informeddecisionregardingchemotherapy.
Itisimportanttoconsiderthe natural history and biology of the cancer being treated. For
example,low-grade serous cancersor granulosa celltumorsare typically slowgrowing, in
contrast to undifferentiated sarcomas, which are rapidly progressive. This may influence
decisionsregarding initiationof treatment,particularly whenchemotherapyis administered
with palliative intent. It may be appropriate to withhold or delay chemotherapy in
asymptomaticpatientswithrelativelyindolentmetastaticorlowvolumedisease.
Itisafundamentalprinciplethatchemotherapyshouldbeadministeredonlytopatients
in whom the diagnosis of cancer has been confirmed with a biopsy. Cytology may
provideacceptableconfirmation,dependingontheclinicalcontext.Forexample,inapatient
withalargevolumeofascites,multipleperitonealnodules,anadnexalmass,andanelevated
CA125 level, it would be acceptable to give neoadjuvant chemotherapy if the cytology
showedmalignant cells and wasconsistent with a primaryovarian cancer,although a core
biopsywouldbeideal.
Response to chemotherapy in gynecologic cancers can be grouped into the following
threecategories,basedonthelikelihoodofresponseandtreatmentbenefit:
1. Highlychemosensitivetumors—treatmentadministeredwithcurativeintent.Thisgroup
includes ovarian germ cell tumors and gestational trophoblastic tumors, where
chemotherapy is curative for most patients. Toxicityis acceptable if the probability of
cure is high, but every effort should be made to limit toxicity and reduce side effects
withoutcompromisingthechanceofcurebyinappropriatedosereductionsorprolonged
delaysbetweencycles.
2. Chemosensitive, but cure is uncommon. This group includes advanced high-grade
serous epithelial ovarian cancers treated in the frontline setting, where response rates
rangefrom70–90%.Chemotherapyincreasesprogression-freeandoverallsurvival, but
themajorityofpatientswillrelapseanddieofdisease.
3. Response to chemotherapy is relatively low. This group includes platinum-resistant
ovarianor endometrial cancers andcervicalcancer following previouschemotherapies,
wheretheimpactoftreatmentonoverallsurvivalisunclear.Inthissetting,itisimportant
to consider the patient’s performance status, other medical comorbidities, extent of
disease,rateofprogression,andsymptomswhendiscussingtherelativerisksandbenefits
ofcytotoxicdrugtherapy.
Table4.1IssuestobeTakenintoAccountWhenConsideringCancerChemotherapy
1.NaturalHistoryoftheMalignancy
a. Diagnosisofamalignancymadebybiopsyorcytology
b. Rateofdiseaseprogression
c. Extentofdiseasespread
2.PatientFactors
a. Age,generalhealth,medicalcomorbidities,performancestatus
b. Extentofprevioustreatment
c. Availabilityoffacilitiestoevaluate,monitor,andtreatpotentialdrugtoxicities
d. Theemotional,social,andfinancialsituationofthepatient
3.LikelihoodofAchievingaClinicalBenefit
a. Cancersinwhichchemotherapyiscurative(e.g.,ovariangermcelltumorsandgestationaltrophoblastic
tumors)
b. Cancersinwhichchemotherapyhasdemonstratedimprovementinsurvival(e.g.,epithelialovarian
cancer)
c. Cancersthatrespondtotreatmentbutinwhichimprovedsurvivalhasnotbeenclearlydemonstrated
(e.g.,metastaticleiomyosarcoma)
d. Cancerswithmarginalornoresponsetochemotherapy(e.g.,platinum-refractoryovariancancer)
DifferentialSensitivity
Mostchemotherapeuticagentsareadministeredusingdosesthatarecloseto,orat,the
maximumtolerateddose(MTD),whichisthehighestdoseofadrugortreatmentthat
doesnotcauseunacceptablesideeffects.Combinationsofchemotherapyarebasedonthe
conceptthatacombinationofdrugswithnooverlappingmechanismsofactionadministered
atfull dosemay preventor delaythe emergenceof drug-resistanttumor cellsand resultin
greater cell kill. Importantly, the therapeutic window between antitumor effect and
normaltissuetoxicitymaybenarrow,becausetherearemanysimilaritiesbetweennormal
cellsand malignant cells, particularly those normalcellpopulations in which constant cell
proliferationis common(e.g.,bone marrow, gastrointestinalepithelium, and hairfollicles).
Asa result,the differentialeffectof antineoplasticdrugs ontumors comparedwithnormal
tissues is quantitative rather than qualitative. Some degree of injury to normal tissue
occurswithallchemotherapeuticagents(1).Thenormaltissuetoxicityproducedbymost
chemotherapeuticagentscorrelateswiththeintrinsicrateofcellularproliferationinthetarget
tissue, which explains why blood count suppression, mucosal injury, and alopecia are
commonwithmanychemotherapeuticregimens.
TherapeuticIndex
Foranychemotherapeuticagent,theneteffectonthepatientisreferredtoasthedrug’s
therapeutic index (i.e., a ratio of the doses at which therapeutic effect and toxicity
occur).Themechanismofactiondoesnotdistinguishbetweennormalcellsandproliferating
cancercells,sothereisanarrowtherapeuticwindowbetweenantitumoreffectandtoxicity
(1).Cancerchemotherapyrequiresabalanceoftherapeuticeffectandtoxicitytooptimizethe
therapeuticindex,whichmaybeinfluencedbypharmacologicandbiologicfactors,including
pharmacogenomicsinanindividualpatient.
BriefHistoryofChemotherapy
Theuseofchemotherapytotreatcancerbeganintheearly20thcenturywithattemptsto
narrowthelargenumberofchemicalsthatmightaffectthediseasebydevelopingmethodsto
screenchemicalsusingtransplantabletumorsinrodents(2).InWorldWarII,agreatdeal
ofresearchwasdoneonvesicantwargases.Althoughgaseswerenotusedinthewar,the
effects of an accidental spill of sulfur mustards on troops from a bombed ship in Bari
Harbor, Italy, led to the observation that both bone marrow and lymph nodes were
markedlydepletedinthosemenexposedtothemustardgas.Theseinitialobservations
further led to the development and testing of several related alkylating compounds,
includingoralderivativessuchaschlorambucilandultimatelycyclophosphamide,whichwas
usedinlymphomapatientsinthelate1940sandearly1950s(3).
NutritionalresearchbeforeandduringWorldWarIIhadidentifiedfolicacidasbeing
importantforbonemarrowfunction.Furtherresearchinthelate1940sidentifiedfolate
antagonists, such a as methotrexate, that were subsequently tested in children with
leukemiaand,in1948,showedthefirstindisputableremissions(4).Choriocarcinomawas
thefirstcancertobereportedlycuredbythechemotherapeuticagent methotrexatein
1958 (5). It was not until the mid-1950s that the fluoropyrimidine 5-fluorouracil was
developedasa drugforthe treatmentofnonhematologic cancers.Thisagent wasfoundto
have activity against a range of solid tumors and, to this day, remains the cornerstone of
treatmentforcolorectalcancer(6).
In the early to mid-1960s, a major breakthrough occurred for both leukemia and
Hodgkin disease with the discovery of the activity of the vinca alkaloids (7) and
procarbazine(8).Finally,combinationsofdrugswereshowntobesuperiortosingleagents
in children with leukemia. Vincristine, amethopterin, 6-mercaptopurine, and prednisone
(VAMP) was the first of a series of cyclically administered combination treatments that
increasedtheremissionrateanddurationofresponse bytheendof thedecade.Halfofthe
remissions lasted for years and were compatible with cure (9,10). By 1970, advanced
Hodgkindiseasewasalsoregardedascurablewithdrugsandprovidedthefirstexample
of an advanced cancer of a major organ system in adults which could be cured by
chemotherapy(11).Investigatorsbegantousecombinationchemotherapyinadvancedbreast
cancerintheearly1970swithsomeencouragingresults.
A combination of cyclophosphamide, methotrexate, and 5-fluorouracil was explored in
patients with advanced breast cancer and results were, for the time, impressive, with an
overallresponserateofover50%,andabout20%ofpatientsattainingacompleteremission
(12).Duringtheseyears,mostdrugdevelopmentwascenteredontheNationalCancer
Institute(NCI)andaverylimitednumberofcancercentersweredoingclinicaltrials.In
the 1970s, the NCI was screening over 40,000 compounds a year before some of the
workloadwastransferredtothepharmaceuticalindustry,asthey beganto seean emerging
marketforeffectivecancer drugs. During this time, clinical testingofnewdrugsand new
chemotherapeutic regimens was markedly expanded through the creation of NCI backed
collaborative clinical trial groups, such as the Gynecologic Oncology Group (GOG).
Thesegroupswereabletoenrolllargenumbersofpatientsquicklyandconductstudiestotest
novelapproachessuchasadjuvantchemotherapyorcombinedmodalitytherapy.
Thedemonstrationthatcombinationchemotherapycouldcuresometypesofadvanced
hematologicmalignanciesgavehopethatthesameresultscouldbeachievedunderideal
circumstances for more common solid tumors. The latter observation opened up the
opportunity to apply drugs in conjunction with surgery and/or radiation treatments to deal
withtheissueofmicrometastases.Thiswasexaminedinitiallyinbreastcancerpatients,and
thefieldofadjuvantchemotherapywasborn. Thefirstagentstobestudiedintheadjuvant
setting in primary breast cancer were L-phenylalanine mustard (L-PAM) alone, and the
cyclophosphamide,methotrexate,5-fluorouracil(CMF)regimen(13,14).Both studies were
positive,andtheresultssetoffacascadeofadjuvantstudiesinbreastcancerandothertumor
typesincludinggynecologicmalignancies.
Much of the data used for defining standard of care chemotherapy in gynecologic
oncologywasgeneratedinthelast2decadesandisstillevolving.Therehavebeenmany
trials beginning in the late 1980s that established the role of platinum agents as first-line
therapy for patients with ovarian cancer,but it wasn’t until results of the GOG 111 study
werepublishedin1996thatcisplatinandpaclitaxelwereshowntobesuperiortocisplatin
and cyclophosphamide in patients with ovarian cancer (15). In 2003, two trials were
published that solidified carboplatin and paclitaxel as the cornerstone of treatment for
ovariancancer(16,17).
For cervical cancer, one of the most significant advances has been the concurrent
administrationofradiation-sensitizingchemotherapy(cisplatin)withradiationtherapy.
Inrandomizedtrialsinbothearlyandadvancedcervicalcancer,theriskofdeathwasreduced
by 30–50%. These studies changed the paradigm for the treatment of cervical cancer
(18–20). Importantly, chemotherapy has now transitioned to the age of “targeted therapy.”
Severalofthemostactivechemotherapeuticregimensarenowcombinedwithnoveltargeted
therapies(seeChapter3).
BiologicFactorsInfluencingTreatment
CellKineticConcepts
Thegrowthcapacity of normal andmalignantcellsis closely regulated byacomplex
processof signaling and inhibitory pathways. The increased or selective cytotoxicity of
chemotherapy in chemosensitive cancers was previously thought to result from the
differentialratesof proliferationinnormalandmalignantcells.Itwasbelievedthatcancer
cellssimply grew fasterthan normal cells,whichcaused their sensitivityto chemotherapy.
However,theefficacyofchemotherapycannotbeexplainedbythisreductionisttheory(1).
Cancers are characterized by continuous dysregulated cellular proliferation, greater
sensitivityto cytotoxicchemotherapythan normalcells, limitedabilityto repairDNA
damage,andcelldeaththroughapoptosis(21).Forexample,ovariancancersthatoccur
in patients with germline BRCA mutations appear to be much more sensitive to
platinum-based chemotherapeutic agents because of a deficiency in homologous
recombinationrepair,an inabilitytorepairDNAdouble-strandbreaks(DSBs),rather
thanbecauseofmorerapidproliferation.
PatternsofNormalGrowth
Allnormal tissueshave thecapacityforcellulardivisionandgrowth.Therearethree
generaltypesofnormaltissuegrowth:static,expanding,andrenewing.
1. The static population comprises relatively well-differentiated cells that, after initial
proliferativeactivityintheembryonicandneonatalperiod,rarelyundergocelldivision.
Typicalexamplesarestriatedmuscleandneurons.
2. Theexpandingpopulationofcellsischaracterizedbythecapacitytoproliferateunder
special stimuli (e.g., tissue injury). Under those circumstances, the normally quiescent
tissue(e.g.,liverorkidney)undergoesasurgeofproliferationwithregrowth.
3. Therenewingpopulationofcellsisconstantlyinaproliferativestate.Thereisconstant
celldivision,a highdegree ofcellturnover,andconstantcellloss.Thisoccurs inbone
marrow,epidermis,andgastrointestinalmucosa.
Normal tissues with a static pattern of growth are rarely seriously injured by drug
therapy, whereas renewing cell populations such as bone marrow, gastrointestinal
mucosa, and spermatozoa are commonly injured, which explains many of the side
effectsofchemotherapy.
CancerCellGrowth
CellCycle
Thecellcycleiscontrolledbyacomplexsystemwithmultipleoverlappingcheckpoints
thatregulateprogressionthroughthecycle(22).Lossof normalcell cyclecontroland
disabledcheckpointsareahallmarkofcancer,withsomaticeventspromotingentryand
progression through the cell cycle. Cyclins and their associated cyclin-dependent
kinases(CDKs)arethe key drivers of the cell cycle, and specific transitions in the cell
cycle are controlled by specific CDKs (22,23). Cell-cycle progression is controlled by
successivechangesincyclin–CDKactivity.Severalcheckpointscanstallthecellcyclein
responseto genotoxic insults. To minimize the possibility of errors, checkpoints exist at
fourdifferentpointsinthecellcycle,G1/S,intra-S,G2/M,andatmetaphasetoanaphase.The
TP53-dependentG1/ScheckpointblocksinitiationofDNAreplication.Theintra-Sphase
checkpointis initiatedby ATR-CHK1, whichstabilizes stalledreplication forksandblocks
replication.TheG2/Mcheckpointinhibitsmitoticentry,andthespindleassemblycheckpoint
inhibits anaphase until there is bipolar attachment of chromosomes to microtubules of the
mitoticspindle(22,23).Thecomplexcellcycleanditscontrolsaresimplifiedbytheclassic
cellcyclemodelshowninFigure2.1(Chapter2).
1. G1phase(postmitoticphase).CyclinD–CDK4/6promotesentryintothecellcycleat
therestrictionpointandistheinitialdriveroftheG1phase.Thisisaperiodofvariable
durationwhenenzymesnecessaryforthesynthesisofDNA,RNA,andotherproteinsare
producedinpreparationforcelldivision.
2. S phase (DNA synthetic phase) is the period in which new DNA replication occurs.
CyclinE–CDK2 activityincreases during lateG1andpeaks in S phase, andcyclinA–
CDK2complexesareactiveinSandG2phases.
3. G2phase(postsyntheticphase)istheperiodduringwhichthecellhasadiploidnumber
ofchromosomesandtwicetheDNAcontentofthenormalcell.Thecellremainsinthis
phaseforarelativelyshorttimebeforeitreentersthemitoticphase.CyclinB–CDK1is
essentialforG2–Mtransitionandmitosis.PLKandAuroraAarecriticalforcentrosome
maturation, formation of the mitotic spindle, and also play a role in chromosomal
segregationandcytokinesis.
4. Mphase(mitoticphase)ofthecellcycleisthephaseofcelldivision.
5. G0phase(theresting phase) is the time during which cells are quiescent and do not
divide.CellsmaymoveinandoutoftheG0phase.
TheG1phasecanvarygreatlydependingonexternalconditionsandextracellularsignals.If
extracellular conditions are unfavorable, cells delay progress through G1 and may enter a
resting state known as G0, in which they can remain for long periods before resuming
proliferation(24).
These cell cycle events have important implications for cancer therapy.Tumorsconsist of
poolsofproliferatingandnonproliferatingorquiescentcells.Dividingcancercellsthatare
activelytraversingthecellcyclearemoresensitivetochemotherapeuticagents.Cellsin
a resting state (G0) are relatively insensitive to chemotherapeutic agents. These may
include cancer stem cells and a hypoxic cell population, which are relatively drug
resistant(25).
CellKinetics
In cell kinetic studies performed on human tumors, the duration of the S phase (DNA
synthesis phase) is about 8 hours for most tumors while the M phase is about 1 hour. In
mammaliancells,thelengthoftheG2phaseisabout2hours.ThelengthoftheG1phaseis
highlyvariableandcanrangefromabout6hourstoseveraldaysorlonger(26).Thelength
ofthecellcycleinhumantumorsvariesfromslightlymorethanhalfadaytoperhaps5days.
With cell cycle times in the range of 24 hours and tumor size doubling times in the
rangeof10to1,000days,itisapparentthatonlyasmallproportionoftumorcellsare
inactivecelldivisionatanyonetime.
Twomajorfactors that affect the rate at which tumors groware the growthfraction
andtherateofcelllossfromthepopulationduetoterminaldifferentiationorcelldeath.
Thegrowthfractionisthenumberofcellsinthetumormassthatareactivelydividing.
Thereisamarkedvariationinthegrowthfractionoftumorsinhumans.Inthepast, itwas
thought that human tumors contained billions of cells, all growing slowly. A contrasting
modelisthatthereis asmallfractionofcellsina tumormassthatisrapidlyproliferating,
whiletheremainderofcells,includingastemcellcomponent,areoutofthecellcycleand
quiescent.Cancer “stem cells” represent a small population of cells within the tumor
mass.Theyappeartoberelativelychemoresistant,andarethoughttoberesponsiblefor
thehighrateof recurrenceofmanysolidtumors. For example, studies have shown an
enriched population of cancer stem cells and stem cell pathway mediators in recurrent
ovarian cancers, suggesting that these cells contribute to the development of recurrence
(27,28).Severaldevelopmentalpathways,includingNotch,Wnt,Hedgehog,andTNF beta,
have been shown to be crucial for the regulation and maintenance of ovarian cancer stem
cells,andtheyarepotentiallyamenabletotargetedtherapies(29).
CellCycle–SpecificVersusCellCycle–NonspecificDrugs
Antineoplasticagentshave complexmechanismsofactionand inducedamage tocellsina
wide variety of ways. They may have different sites of action in the cell cycle, and their
activity is a function of the proliferative capacity of the tumor being treated.
Chemotherapeutic agents can be divided into two main classes based on theirsite of
actioninthecellcycle:Cellcycle–nonspecificandcellcycle–specific,althoughthisisan
oversimplificationofhowchemotherapyworks(Table4.2).
Table4.2CellCycleSpecificityofChemotherapeuticAgents
Classification Examples
Cellcycle–specific,proliferationdependent cytarabine
Cellcycle–specific,lessproliferationdependent 5-fluorouracil,methotrexate
Cellcycle–nonspecific,proliferationdependent cyclophosphamide,actinomycinD,
carboplatin,cisplatin
Cellcycle–nonspecific,lessproliferationdependent topotecan
Cell cycle–nonspecific agents kill in all phases of the cell cycle and have limited
dependencyonproliferativeactivity. Theyhave a lineardose response andare active on
cells in either a dividing or resting state. They include alkylating agents, antitumor
antibiotics,andhormonaltherapies.
Cell cycle–specific agents act only at particular phases of the cell cycle, and include
antimetabolites that are S-phase specific, vinca alkaloids and taxanes that are M-phase
dependent,andbleomycin and topotecan that are G2-phase dependent. Between these two
broad classifications, there is a spectrum of drugs with variable degrees of cell cycle and
proliferationdependence.
LogKillHypothesis
Fromknowledgeofbasiccellularkinetics,conceptsofchemotherapyhaveemergedthathave
provenusefulinthedesignofchemotherapeuticcombinationregimens(21).Inexperimental
tumor systems in mouse models, survival is inversely proportional to the number of cells
implanted, or to the size of the tumor at the time treatment is initiated (30). Treatment
immediatelyafter tumorimplantation, orwhen thetumor issubclinical insize,resultsina
higher chance of cure than if the tumor is clinically obvious and large. Skipper’s cell kill
hypothesis,publishedover60yearsago,suggestedthatiftumorsweretreatedatthelevel
of micrometastases rather than larger volume tumors, it was more likely that the
treatment would be effective (30). This is supported by the results of adjuvant
chemotherapyinmanysolidtumors.
Skipper et al. (30) used a murine leukemic model to define the concept of logarithmic
cancer cell growth and specific log cell kill with chemotherapy. They suggested that
chemotherapeutic agents work by first-order kinetics; that is, they kill a constant
fractionofcellsratherthanaconstantnumberofcells. Thisconcept hashad important
implications for the development of chemotherapeutic regimens and adjuvant
chemotherapeutictrials. For instance, a single exposureoftumor cells to an antineoplastic
drugmightbecapableofproducing2to5logsofcellkill.Withtypicalbodytumorburdens
of1012cells(1kg),asingledoseofchemotherapyisunlikelytobecurative.Thisexplains
theneedforintermittentcoursesofchemotherapytoachievethemagnitudeofcellkill
necessary to produce tumor regression and cure. It also provides a rationale for
multiple-drugorcombinationchemotherapy.
PrinciplesofChemotherapy
NeoadjuvantChemotherapy
Neoadjuvantchemotherapy(NACT)is increasinglyusedtotreatwomenwithovarian
cancerfollowingtheresultsoftworandomizedtrialsthat demonstratednoninferioroverall
survival,and lower morbidity and mortality, compared to primary surgeryinpatientswith
advanceddisease(31,32).Intervaldebulkingsurgery(IDS)followingNACThasprovidedan
opportunitytoassesstumorresponsetoantineoplastictreatments.Validatedscoringsystems
haveprovidedprognosticinformationinpatientswithbreast,esophageal,gastric,andrectal
cancers following neoadjuvant treatment, and are used to guide treatment decisions after
surgery(33,34).Recentstudiesalsohavesuggestedthatneoadjuvantchemotherapyfollowed
byradicalsurgerymayofferapromisingalternativetoradicalsurgeryaloneforpatientswith
locallyadvancedcervicalcancer(35).
HyperthermicIntraperitonealChemotherapy
Hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative
intraperitoneal chemotherapy (EPIC) are two treatment methods that are performed at
some institutions to help improve the efficacy of chemotherapy and possibly prolong
survival.In brief,the abdomen isfilled withsalinethat iscirculated continuouslywiththe