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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
use of a roller pump through a heat exchanger. By circulating the heated saline, an intraabdominal temperature of 40°C (104°F) is maintained. Perfusion with cisplatin for 90
minutesistheninitiated.Attheendoftheperfusion,drainsareusedtoemptytheabdominal
cavityascompletelyas possible. Findings of a recent study suggested that the addition of
HIPEC after complete or optimal interval cytoreductive surgery resulted in longer median
recurrence-free and overall survival, than following surgery alone. However, HIPEC
remains controversial for ovarian cancer; its role is still being debated and phase 3
trialsareinprogress(36).
Antibody–DrugConjugates
Antibody–drug conjugates (ADCs) represent a very promising new class of cancer
therapeutics that are designed to harness the specificity of antibodies with the
cytotoxicityof chemotherapeutic agents. EmergingclinicaldatawithADCssuggestthat
these new drugs have great potential to become effective and well-tolerated anticancer
therapeutics. The recent approvals of brentuximab vedotin (Adcetris), directed at CD30,
which is expressed in Hodgkin lymphoma and anaplastic large cell lymphoma, and ado-
trastuzumabemtansine(T-DM1,Kadcyla)directedatHER2expressedinbreastcancer,have
prompted the clinical development of other novel ADCs (37,38).ADCsarecomposed of
three well-defined components, the antibody,the linker, and the payload. An optimal
ADC that achieves maximum efficacy with minimal toxicity requires the appropriate
combinationofeachofthesecomponents.ThemajorityofpayloadsutilizedinADCsare
highlypotentcytotoxicagentswithanefficacyinthe lownanomolar orpicomolarrange.
Thisis required because <1% of theinjecteddose of an antibody localizestotheantigenexpressingtumor.ThecytotoxicpayloadsofmostoftheADCsthatarecurrentlyinclinical
trials for gynecologic or breast cancers are auristatins (MMAE, MMAF), maytansinoids
(DM1, DM4), calicheamicin, pyrrolobenzodiazepines or SN-38. Both cleavable and
noncleavable linkers are currently being investigated in clinical trials. Anumber of novel
targetantigensarecurrentlybeingvalidatedinclinicaltrialsincludingfolatereceptoralpha,
mesothelin,CA125,NaPi2b,NOTCH3,proteintyrosinekinase-like7, ephrin-A4, TROP2,
CEACAM5, and LAMP1. For most ADCs currently in clinical development, the doselimiting toxicities appear to be unrelated to the targeted antigen, but are more closely
associatedwiththepayload(39).
ChemotherapyinPregnancy
The risk of congenital abnormalities from chemotherapeutic agents is highest during
the first trimester, especially when antimetabolites (e.g., cytosine arabinoside or
methotrexate)andalkylatingagentsareused(40).Chemotherapyadministeredduringthe
second or third trimesters usually is not associated with an increased risk of fetal
abnormalities,andappearstoberelativelysafealthoughthe numberofpatients studiedis
relativelysmall(seeChapter17).
DrugResistance
Resistancetochemotherapycontinuestobeamajorproblemincancertreatmentand
canbebroadlyclassifiedintoprimaryandacquiredresistance(41).Primaryorintrinsic
resistanceisresistancewhichexistsbeforeanydrugtreatmentisgiven.Itcanbecaused
by(i)preexistinggeneticmutationsthatresultindecreasedresponsivenessofcancercellsto
chemotherapy, or by (ii) heterogeneity of tumors, in which preexisting insensitive
subpopulationsofcellsareselectedbydrugtreatment.These subpopulationsmay bemade
upofcancer stemcells,often quiescentandnot cycling,whichareintrinsicallyresistantto
chemotherapy(28,29).Increasingevidencehas showntheexistenceofintratumoralgenetic
heterogeneity in many cancers (42). Primary resistance is a common feature of such
tumorsasmetastaticuterineleiomyosarcomaandclearcellovariancancer.
Acquiredresistanceoccurs after an initialresponseto chemotherapy.Mostpatientswith
advanced solid tumors will eventually develop acquired resistance. It can result from
newlyemergingdrivergenesormutations,alteredexpressionlevelsofthedrugtargets,
ornewchangesinthetumormicroenvironmentaftertreatment(21,27,28,41).
Both primary and acquired resistance may be caused by alterations in drug metabolism,
includingchangesindruguptake,efflux,anddetoxification.Enhancedeffluxiscausedby
increased expression of P-glycoprotein and multidrug resistance-associated protein 1
(MRP1). P-glycoprotein transports a number of hydrophobic agents, such as doxorubicin,
paclitaxel, and vinca alkaloids, while MRP1 transports topoisomerase inhibitors and
anthracyclines(43).
ChemotherapyResistanceMechanisms
DrugEfflux
Elevated efflux of anticancer agents, which leads to decreased intracellular drug
accumulation,has beenconsideredto bethemajor reasonfor chemotherapeutic resistance.
Theresistancecausedbytheabnormallyhighratesofdrugeffluxmaybeeitherintrinsicor
acquired(44).
DNADamageResponse
Manychemotherapeuticdrugs,suchascisplatinand5-fluorouracil(5-FU),killcancercells
byinducingDNAdamage.TheDNAdamageresponse(DDR)ofaffectedcellsmayresultin
reducedefficacyofthedrugsbyDNAlesionrepairs,leadingtodrugresistance(45).
Senescence
CellularsenescenceisanirreversiblearrestofcellproliferationthatcanbetriggeredbyDNA
damage caused by chemotherapeutic drugs. For example, doxorubicin and cisplatin, by
inducing cell death, can also initiate senescence (46). Escape from therapy-induced
senescence has been recognized as a mechanism for drug resistance and tumor
recurrence/progression. Cancer cells with therapy-induced senescence can gain stem-cell
properties,whichaccountfortheescapefromsenescenceandcancerrelapse(47).
EpigeneticModifications
RecentstudieshavesuggestedthatepigeneticmodificationsthatincludeDNAmethylation,
histone modification, chromatin remodeling, and noncoding RNA-related alterations may
contributetodrugresistance(48,49).
TumorHeterogeneity
Ampleevidencehasshownthatsubpopulationsofcancercellswithvariousgeneticmakeups
coexist in primary tumors such as ovarian cancer (50). However, beyond genomic
heterogeneity,themattermaybemorecomplicated.Recentstudieshavesuggestedthatthere
maybeseverallayersofintratumoralheterogeneityincludingcelltypeheterogeneity(such
as cancer cells, stromal cells, immune cells), metabolic heterogeneity with respect to
oxygen/nutrient distribution, and temporal heterogeneity with respect to dynamic tumor
progression (51). Tumor heterogeneity increases the complexity and difficulty of cancer
treatment,makingitalmostimpossible to kill all cancer cells using one single therapeutic
agent.
TumorMicroenvironment
Recentstudieshavesuggestedthatthetumormicroenvironmentmayalsoplayanimportant
roleinthedevelopmentofchemotherapeuticresistance. Solidtumorscontain varioustypes
of cells and extracellular matrix that work together to contribute to all aspects of the
hallmarksofcancer(52).
Table4.3DrugInteractionsinCancerChemotherapy
EpithelialMesenchymalTransition
Epithelialmesenchymaltransition(EMT)isaprocessduringwhichepithelialcellslosetheir
attachmenttoeachotherandgainthecharacteristicsofmesenchymalstemcells.Increasing
evidencehasshownthatEMTplaysacriticalroleinchemotherapeuticresistance(53).The
mechanismsofEMT-induceddrugresistancearenotfullyunderstoodbutrecentstudieshave
suggested that EMT cells share many similarities in signaling pathways with cancer stem
cells(CSCs),suchasWnt,Notch,andHedgehogpathways(54).
In summary, drug resistance is a serious impediment to the successful treatment of
cancers but the mechanisms involved remain poorly understood. While prevailing
evidencestronglysuggeststhattheresistanceisdrivenbymutations,emergingevidence
suggests that nongenetic/epigenetic mechanisms leading to tolerance and persistence
mayalsobeimportantintheacquisitionofdrugresistance.
Sincedrugresistancewillultimatelyoccurinmostpatients,newclinicaltrialdesignswithindepthcharacterizationof tumor tissue at the timeofprogression may lead to an improved
understandingofclinicallyrelevantresistancemechanisms,and helpinthe developmentof
bettertailoredtreatments.
Excretion
Mostchemotherapeuticagentsareexcretedthroughthekidneyorliver.Overall,kidney
orliver function is critical to normal drug excretion, so it is necessary to modify the
dosageofcertainagentsifeitheroftheseorgansisfunctionallyimpaired.
Certaindrugs (e.g., vincristine, doxorubicin, paclitaxel) are excreted primarily through the
liver,andothers(e.g.,methotrexate)areexcretedalmostentirelybythekidney.Extremecare
should be taken with appropriate dose reduction in patients with impaired renal function.
Most experimental protocols and cooperative group trials contain formulas for dose
modification,ordoseomission,forspecificorganimpairments(55).
DrugInteractions
There are multiple opportunities for clinically important drug interactions to occur during
cancertreatment(56,57).Theseinteractionsmayincreaseordecreasetheantitumoractivity
of an agent, or they may increase or modify its toxicity. Types of drug interactions of
potentialimportanceincludethoselistedinTable4.3.
Importantdruginteractionswithantineoplasticagentsincludethefollowing:
1. Thealkylatingagentsarehighlyreactivecompoundsandmayproducedirectchemicalor
physicalinactivationwhenmultipledrugsaremixed.
2. Intestinalabsorptionofcertainoralchemotherapeuticagentsisalteredbyantibioticsthat
suppress bowel flora (e.g., reduced absorption of oral methotrexate), resulting in
decreasedcirculatinglevels.
3. Drugssuchascisplatinormethotrexatebindtoalbuminorplasmaproteinsandmaybe
displacedfromthatbinding bydrugsthatbindtosimilarsites,suchasaspirin orsulfa,
therebyincreasingthecirculatinglevelofbioavailablecisplatinormethotrexate.
4. Alterationsindrugactivationmayoccur,aswhenmethotrexateincreases5-fluorouracil
activation;conversely,adruginteractionmayantagonizeanantitumoreffect,aswhen5fluorouracilimpairstheantifolateactionofmethotrexate.
5. Nephrotoxicantibioticsfrequentlyaltermethotrexateexcretionandmayalsoincreasethe
renaltoxicityofcisplatin.
CombinationChemotherapy
There is a solid theoretic basis for combination chemotherapy founded on cellular
kinetics,drugmetabolism,drugresistance,andtumorheterogeneity(58).Combination
chemotherapyisthestandardapproachtothemanagementofmanyadultsolidtumors,
includingbreastcancerandgynecologicmalignancies,particularlywhengivenasadjuvantor
first-linetherapy,wheretheaimistoachieveahighresponserateandadurableremission.
There is no evidence that outcomes are improved with combination chemotherapy
comparedtosingleagentswhentheaimoftreatmentispalliation(e.g.,platinum-resistant
ovariancancerormetastaticbreastcancer).
Table4.4ImportantFactorsintheDesignofDrugCombinations
1. Thedrugsusedmustbeactiveassingleagentsagainsttheparticulartumor.
2. Thedrugsshouldhavedifferentmechanismsofactiontominimizeemergenceofdrugresistance.
3. Thecombinationofdrugsshouldhaveadditiveorpreferablysynergisticeffects.
4. Thedrugschosenshouldhaveadifferentspectrumoftoxicitysothattheycanbeusedformaximumcell
killat(ornear)fulldoses.
5. Thedrugschosenshouldbeadministeredintermittentlysothatcellkillisenhancedandprolonged
myelosuppressionisminimized.
Combination chemotherapeutic regimens typically include active chemotherapeutic
agents that act in different phases of the tumor cell cycle. General principles for the
developmentofsuccessfulcombinationsareshowninTable4.4.Theuseofmultipledrugs
ismorelikelyto reducethetumorvolumethan the use of a single chemotherapeutic
agent, and should theoretically decrease the likelihood of developing drug resistance
(58).For instance,ifa cellcycle–nonspecific agentisadministered, producinga 2-log cell
killinatumormasswith109cells,andnofurthertherapyisgiven,aminortumorresponse
willoccur,followed by tumorregrowth,andthere will be no impact on survival. If a cell
cycle–specificagentproducesasimilardegreeofcellkill,onlythosecellscomingintocell
cyclewillbeaffectedbytheagent.Theuseofcombinationsofcellcycle–specificandcell
cycle–nonspecificagentscanenhancelogkillintumors.Combiningdrugsmayachieve
sufficientlogkilltoproduceacureorprolongedremission.
Thisdoesnotnecessarilymeanthatthreeorfourdrugsarebetterthantwodrugsinadvanced
cancerswherecureisunlikely.Thiswasillustratedbythe GOG182study,whichincluded
more than 4,000 women with advanced ovarian cancer. The study demonstrated that
carboplatin and paclitaxel had the same median progression-free and overall survival as
triplet or alternating doublet combinations, which included agents such as liposomal
doxorubicin,gemcitabine,ortopotecan(59).
Although the probability of the emergence of drug-resistant cells in any given
population is reduced if two or more agents with differentmechanisms of action are
used in a tightly sequenced treatment scheme, the majority of advanced cancers
ultimatelydevelopdrugresistance(59).
Druginteractionsmaybeadditive,synergistic,orantagonistic.Combinationsthatresult
inhigherresponseratesthanthoseachievedwitheitherdrugalonearesaidtobesynergistic.
Additive therapies have response rates equivalent to the sum of both agents acting
independently. Some antitumor agents may antagonize each other, producing a lesser
therapeutic effect than when used singly (60). For example, 5-fluorouracil prevents the
antifolateactionofmethotrexatewhenusedbeforemethotrexateadministration.
ClinicalBenefit
Whenatreatmentregimenhasbeenselected,itisnecessarytohaveastandardizedmethodto
evaluatetheresponseandtodeterminewhethertherehasbeenaclinicalbenefit.Theterms
completeresponse,partial response, stable disease, and progressivedisease are widely
acceptedandusedinclinicaltrialsaswellasclinicalpractice.
Complete Response implies the complete disappearance of all objective evidence of
tumor, and theresolutionof allsignsandsymptoms referabletothe tumor.Complete
responseisoftenassociatedwithsignificantprolongationinprogression-freesurvivalbutis
notsynonymouswithcureinpatientswithmostadvancedsolidcancers.
Partial Response is defined as a 30% reduction in the sum of the diameters of all
measurabletargetlesions.Partialresponsesmaybe associatedwith improvedwell-being,
symptombenefit,anddelayedtimetoprogression.
RECISTCriteria
Theresponseevaluationcriteriainsolidtumors(RECIST)isusedinallclinicaltrials.
Thecriteriaweremodifiedin2009,andRECIST1.1isusedinclinicaltrials(Table4.5)(61).
In clinical trials, baseline documentation of “target” and “nontarget” lesions before
treatmentisessential.Allmeasurablelesionsuptoamaximumoftwolesionsperorgan
andfive lesions in total, representativeofall involved organs, should be identified as
targetlesionsandrecordedandmeasuredatbaseline.Targetlesionsshouldbeselectedon
the basis of their size (lesions with the longest diameter [LD]) and their suitability for
accuraterepeatedmeasurementsbyradiologicimaging.
AsumoftheLDforalltargetlesionsshouldbecalculatedandreportedasthebaseline
sumLD andthisshouldbeused asthereferenceforassessing theobjectiveresponse.
All other lesions (or sites of disease) should be identified as nontarget lesions and
recordedatbaseline. Measurements of theselesionsare not required, butthepresence or
absenceofeachshouldbenotedthroughoutfollow-up.
DoseAdjustment
Patients vary in their tolerance to chemotherapy, and tailoring the treatment is necessary,
particularlywhentreatmentisadministeredwithpalliativeintent.Allclinicaltrialprotocols
stipulatedosemodificationanddosereductionsbasedontoxicities,particularlygrade3
or4toxicities.Itisbeyondthescopeofthischaptertodetailthedosemodifications,butall
cancercenters haveprotocolsand guidelinesto ensure thesafe administrationoftreatment
(55).
Table4.5RECIST1.1DefinitionsofResponse
Completeresponse(CR) Disappearanceofalltargetlesions
Partialresponse(PR) Atleasta30%decreaseinthesumofthelongestdiameter(LD)
oftargetlesions,takingasreferencethebaselinesumLD
Progressivedisease(PD) Atleasta20%increaseinthesumoftheLDoftargetlesions,
takingasreferencethesmallestsumLDrecordedsincethe
treatmentstartedortheappearanceofoneormorenewlesions
Stabledisease(SD) NeithersufficientshrinkagetoqualifyforPRnorsufficient
increasetoqualifyforPD,takingasreferencethesmallestsum
LDsincethetreatmentstarted
CarboplatinDoseCalculation
Carboplatin-basedchemotherapyremainsthemainstayoftreatmentformanypatients
withgynecologicmalignancies.Itisclearedrenally,andseveremarrowtoxicitymayoccur
inpatientswithimpairedrenalfunction;hence,thedoseisbasedonrenalfunction.Typically,
the carboplatin dose is calculated using an estimated creatinine clearance or glomerular
filtrationrate (GFR), whichisderived from formulas thatuse the patient’screatinine,age,
and weight. The Cockcroft–Gault equation for estimating creatinine clearance is most
commonlyused,buttheJellifeformula,whichdoesnotusethepatient’sweight,isalsoused
(62,63).
TheCalvertformulaisusedtocalculatethecarboplatindoseaccuratelyinordertoobtaina
targetAreaUndertheCurve(AUC)byusingonlytheGFR(63).Theformulais:
Dose(mg)=targetAUC(mg/mL×min)×[GFR(mL/min)+25(mL/min)]
ThetargetAUCiscommonly4to5mg/mLforpreviouslytreatedpatientsand5to6
mg/mLforthosepreviouslyuntreated.
The switch to the isotope dilution mass spectrometry (IDMS) method to measure serum
creatinine has resulted in creatinine values that are 10–20% lower than older non-IDMS
values.Inpatientswitharelativelylowserumcreatinine,theIDMSmethodwillresultina
lower creatinine and an overestimation of creatinine clearance, with a potentially higher
calculated carboplatin dose. In view of this, NCI/CTEP has recommended that the GFR
used in the Calvert formula should not exceed 125 mL/min, and that the maximum
carboplatindosebasedontheAUCshouldbecapped.Forexample,ifthetargetAUCis
6,thedoseshouldnotexceed900mg;forAUC5,itshouldnotexceed750mg,andfor
AUC4,itshouldnotexceed600mg(64).
TheCockcroft–Gaultequationisunreliableinpatientswhoareobese,cachectic,orhavean
abnormallylowserumcreatinine.Ideally,these patientsshouldhave anEDTAclearanceto
moreaccuratelymeasureGFR,butifthisisnot possible,guidelines areavailable fromthe
GOG(65).
ToxicitiesandTheirManagement
Antineoplastic drugs have many potential side effects with predictable and at times
unpredictable toxicities. In almost all instances, chemotherapeutic agents are used in
dosesthatproducesomedegreeoftoxicitytonormaltissues.
Severedebility,advancedage,poornutritionalstatus,orimpairedorganfunctioncan result
in severe side effects. Idiosyncratic drug reactions can have severe and unexpected
consequences.Asaresult,carefulmonitoringofpatientsreceivingchemotherapyisamajor
responsibilityofthetreatingphysician.
HematologicToxicity
The proliferating cells of the erythroid, myeloid, and megakaryocytic series of the bone
marrow are highly susceptible to damage by many of the commonly used antineoplastic
agents. Granulocytopenia and thrombocytopenia are predictable side effects of most
antitumor agents, and are seen with all effective regimens of combination
chemotherapy.The severityand durationofthesesideeffectsare variable,anddependon
the drugs, the dose, the schedule, and the patient’s previous exposure to radiation or
chemotherapy.
In general, acute granulocytopenia occurs 6 to 12 days after administration of most
myelosuppressive chemotherapeutic agents, and recovery occurs within 21 days;
platelet suppression occurs 4 to 5 days later, with recovery after white cell count
recovery (66). Several agents are unique in producing delayed bone marrow suppression,
among them mitomycin C and the nitrosoureas. Marrow suppression from these drugs
commonlyoccursat28to42days,withrecovery40to60daysaftertreatment.
Neutropenia
Patientswithanabsoluteneutrophilcountoflessthan500/mm3for5daysorlongerare
athighriskoffebrileneutropenia,whichcanberapidlyfatal.Itiscriticaltorecognize
neutropenicfeverearly.Thewidespreaduseofempiric,broad-spectrumantibioticsin
cancer patients with febrile neutropenia significantly decreases the likelihood of lifethreateningtoxicity(66,67).
If systemic antineoplastic therapy adversely affects myelopoiesis and the integrity of the
gastrointestinalmucosa, cancer patients areat risk for invasiveinfectiondue to colonizing
bacteria and/or fungi translocating across the damaged intestinal mucosa. Since the
magnitude of the neutrophil-mediated component of the inflammatory response may be
mutedinneutropenicpatients,afevermaybetheonlysignofinfection(68).
Althoughthesignsandsymptomsofinfectionmaybesignificantlymuted, anearlypartof
the clinical assessment should include an examination for evidence of a systemic
inflammatoryresponsesyndromeandadeterminationofthecriteriaforsepsis,severesepsis,
or septic shock. Fever in a neutropenic patient should be considered a medical
emergency. Antibiotics are usually administered empirically but should always include
appropriatecoverageforsuspectedorknowninfections.Evenwhenthepathogenisknown,
the antibiotic regimen should provide broad-spectrum empiric coverage for the
possibility of co-pathogens, unlike the treatment strategy adopted in many
immunocompetenthosts.Initialantibioticselectionshouldbeguidedbythepatient’shistory,
allergies,symptoms,signs,recentorconcurrentantibioticuseandculturedata,togetherwith
an awareness of the susceptibility patterns of institutional nosocomial pathogens (67,68).
Colony-stimulating factors (CSFs), also known as myeloid growth factors or
hematopoieticgrowthfactorssuchasgranulocyteandgranulocyte-macrophagecolonystimulating factors (G-CSF and GM-CSF), are generally not recommended for the
managementofpatientswithestablishedfeverandneutropenia,withsomeexceptions
(66).
RecommendationsfromexpertgroupsforuseoftherapeuticCSFs inestablished feverand
neutropenia differ: Guidelines from American Society of Clinical Oncology (ASCO)
recommend against routine use of CSFs in this setting, but they suggest that CSFs
shouldbe“considered”forpatientsat highrisk forinfection-associatedcomplications
orwhohaveprognosticfactorsthatarepredictiveofapoorclinicaloutcome(66).These
featuresincludeexpectedprolonged(>10days)orprofound(<100cells/μL)neutropenia,age
olderthan65years,pneumoniaorotherclinicallydocumentedinfections,sepsissyndrome,
invasivefungalinfection,priorepisode of febrile neutropenia, or being hospitalized at the
timeofthedevelopmentofthefever.
The National Comprehensive Cancer Network (NCCN) has recommended that
granulocyteCSFbecontinuedinpatientswhowerereceivingprophylacticCSFsatthe
time of presentation (67). They have also suggested “consideration” of CSFs in patients