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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
receptor)commonlyused inthemanagementofpatientswithHER2positivebreastcancer,
especiallywhentheagentisdeliveredwithdoxorubicin(80).
A common toxicity of the antiangiogenic agent bevacizumab is the development of
hypertension(81).Inapatientwithpreexistingcardiacabnormalities,thishasthepotential
tocausedeteriorationofheartfunction.Thisconcernislikelytoincreaseasuseofthisclass
ofagentbecomesmorestandardintheclinicalmanagementofgynecologicmalignancies.
GenitourinaryToxicity
In patients with cancer, chronic azotemia oracute renalfailuremay be produced by
fluid depletion, infection, tumor infiltration of the kidney, ureteric obstruction by
tumor,radiationdamage,andtumorlysissyndrome(82,83).
Drugsthatcausekidneydamageincludethefollowing:
1. Cisplatin, which produces renal tubular toxicity associated with azotemia and calcium
andmagnesiumwasting(84)
2. Methotrexate, which canprecipitatein the renal tubules,causingoliguric renal failure.
Methotrexate toxicity can be prevented by maintenance of a high urine volume and
alkalinizationoftheurine
3. Nitrosoureas,whichcauseachronicinterstitialnephritiswithchronicrenalfailure
4. Mitomycin C, which causes a systemic microangiopathic hemolysis and acute renal
failure
Metabolites of cyclophosphamide are irritants to the bladder mucosa and rarely cause a
chronic hemorrhagic cystitis, particularly during high-dose or prolonged treatment.
Vigoroushydrationanddiuresiscanreducetheriskofthiscomplication.
N-acetylcysteine or mesna (sodium mercaptoethane sulfonate) has been used in
conjunctionwithveryhighdosesofcyclophosphamideorifosfamidetopreventbladder
toxicityby inactivating the toxicmetabolite(acrolein).Persistent hemorrhagic cystitis that
does not respond to conservative management may be treated with epsilon-aminocaproic
acid.
Neurotoxicity
Many antineoplastic drugs are associated with some central or peripheral neurotoxicity.
Theseneurologicsideeffectsusuallyaremild,butoccasionallymaybesevere(85,86).
VincaAlkaloids
Thevincaalkaloids(vincristine,vinblastine,andvindesine)arecommonlyassociatedwith
peripheralmotor,sensory,andautonomicneuropathies,whicharethemajorsideeffects
ofvincristine.Toxicityfirst appearsaslossofdeeptendonreflexeswithdistalparesthesia.
Cranialnervescanbeaffected,andtheautonomicneuropathycanappearasadynamicileus,
urinary bladder atony with retention, or postural hypotension. All of these neurologic
toxicitiesfromthevincaalkaloidsmaybeslowlyreversibleaftercessationofthedrug.
Cisplatin
Cisplatinproducesototoxicity,peripheralneuropathy,and,rarely,retrobulbarneuritis
andblindness. High doses of cisplatinareparticularly likely to producea progressive
and somewhat delayed peripheral neuropathy. This defect is characterized by sensory
impairment and loss of proprioception, whereas motor strength usually is preserved.
Progressionofthisneuropathy1to2monthsaftercessationofhigh-dosecisplatinhasbeen
reported(87,88).
Paclitaxel
Paclitaxelis associatedwiththe developmentofa peripheralsensoryneuropathy. The
incidenceandseverityofsymptomsrelatetothepeaklevelsoftheagentintheplasma(89).
The combination of paclitaxel and cisplatin (or carboplatin) has the potential to be more
neurotoxicthaneitheragentusedalone.
OtherDrugs
Rarely, 5-fluorouracil can be associated with an acute cerebellar toxicity, apparently
relatedto its metabolism to fluorocitrate, aneurotoxicmetabolite of the parent compound.
Hexamethylmelamine has also been reported to produce peripheral neuropathy and
encephalopathy(90).
VascularandHypersensitivityReactions
Occasionally,severehypersensitivityreactionsintheformofanaphylaxisdevelopwith
chemotherapeutic agents (91). In rare cases, this has been associated with
cyclophosphamide, doxorubicin, cisplatin, intravenous melphalan, and high-dose
methotrexate.Bleomycinadministrationmaybeassociatedwithmarkedfebrilereactionsor
anaphylaxis. The same reactions have been reported with procarbazine, etoposide, and
teniposide.
Hypersensitivityreactionsaresometimesseenwithpaclitaxelandarebelievedtoresultfrom
hypersensitivity to the cremophor vehicle. They can be ameliorated with the use of
dexamethasone,diphenhydramine,andcimetidinebeforepaclitaxelisadministered.
Carboplatin and cisplatin may be associated with a significant risk of hypersensitivity
reactionsinpatientswhohavebeentreatedwithmorethansixcoursesofaplatinumagent
(92).
SecondMalignancies
Manyantineoplasticagentsaremutagenicandteratogenic.Thepotentialfortheseagents
to induce second malignancies appears to vary with the class of agent (93). Alkylating
agents(especiallymelphalan),procarbazine,andthenitrosoureasseemtobethemajor
offenders. Prolonged use of etoposide has been associated with the development of
leukemia.
The cumulative 7-year risk of developing acute nonlymphocytic leukemia in patients
treatedprimarily with oral melphalan for ovarian cancer has been reported to be as
highas9.6%inpatientsreceivingtherapyformorethan1year(94).Althoughcisplatin
hasbeenassociatedwiththedevelopmentofacuteleukemia,theriskislowerthanwiththe
alkylatingagents(95).
Evidencefromlong-termstudiesofHodgkindiseasesuggestsamajorriskwithcombined
chemotherapy and radiation therapy (96,97). In such patients, there is a risk of acute
leukemiaand anincreasedincidence ofsolid tumors, seenparticularly withintheradiation
fields. The long-term follow-up of women cured of choriocarcinoma, primarily with
antimetabolitetherapy,hasrevealednoincreasedriskofasecondmalignancy.
Radiation alone appears to produce a relatively low risk of late leukemia, as do
chemotherapeutic regimens alone, particularly those without alkylating agents or
procarbazine. Combination chemotherapy (including cisplatin-based treatment of ovarian
cancer)andlimited-fieldradiationtherapyonlyslightlyincreasetherisk.
Patientsatincreasedriskincludethosewhohavereceivedthefollowing:
1. Extensiveradiationtherapypluscombinationchemotherapy
2. Prolongedalkylatingagenttherapy(longerthan1year)
3. Highdosesofcertaindrugssuchasetoposide
GonadalDysfunction
Manycancerchemotherapeuticagents haveprofoundandlastingeffects ontesticular
and ovarian function. Chemotherapeutic agents, particularly alkylating agents, can cause
azoospermiaandamenorrhea.Secondarysexualcharacteristicsrelatedtohormonalfunction
are usually less disturbed. Prolonged intensive combination chemotherapy commonly
producesazoospermiainmen,andrecoveryisuncommon.
Theonset of amenorrhea and ovarianfailureis accompanied by anelevationof the serum
follicle-stimulatinghormone(FSH) andluteinizinghormone (LH)levels,andadecrease in
theserumestradiollevel.
When short-term intensive chemotherapy is used, particularly with antimetabolites, vinca
alkaloids, or antitumor antibiotics, injury to the reproductive system is less common. For
example,mentreatedfortesticularcancer,childrenwithacuteleukemia,andwomencured
ofgestationaltrophoblastic diseaseorovarian germ cellmalignanciesusuallyrecover
reproductivecapacityaftertherapy(98–100).
AntineoplasticDrugs
AlkylatingAgents
Thisclassofantineoplasticagentacts primarily by chemically interacting with DNA.
Thesedrugsformextremelyunstablealkylgroupsthatreactwithnucleophilic(electron-rich)
sitesonmanyimportantorganiccompoundssuchasnucleicacids,proteins,andaminoacids.
Theseinteractionsproducetheprimarycytotoxiceffects.
Mechanism
Alkylating agents impair cell function by transferring alkyl groups to amino, carboxyl,
sulfhydryl, or phosphate groups of biologically important molecules. Most importantly,
nucleicacids(DNAandRNA)andproteinsarealkylated.Alkylationofguanineresultsin
abnormal nucleotide sequences, miscoding of messenger RNA, cross-linked DNA strands
thatcannotreplicate,breakageof DNAstrands, and other damage to the transcription and
translationofgeneticmaterial.Theprimarymodeofactionformostalkylatingagentsis
by means of cross-linking of DNA strands leading to breaks of DNA. Such abnormal
DNA is not able to complete the replication cycle and that leads to cytotoxicity. Tumor
resistancetothesedrugsappearstoberelatedtothecapacityofcellstorepairnucleicacid
damage and to inactivate the drugs by conjugation with glutathione. There are many
alkylating agents; those most commonly used include cyclophosphamide and ifosfamide
(Table4.8).Inaddition,severalotherantineoplasticagentsofdifferenttypesareusuallyalso
classifiedas alkylating-like agents andincludethe platinum analogscisplatin,carboplatin,
andoxaliplatin(Table4.9).
Table4.8AlkylatingAgentsUsedforGynecologicCancer
Drug
Routeof
Administration CommonToxicities DiseasesTreated
Cyclophosphamide PO,IV Myelosuppression,cystitis±
bladderfibrosis,alopecia,
hepatitis,amenorrhea,
azoospermia
Breast,ovariancancer,soft
tissuesarcomas
Ifosfamide IV Myelosuppression,bladder
toxicity,centralnervous
systemdysfunction,renal
toxicity
Cervical,ovariancancer
Temozolomide PO Myelosuppression Melanoma
Thiotepa IT,intracavitary Myelosuppression,cystitis Malignanteffusions,
leptomeningealdisease
PO,oral;IV,intravenous;IM,intramuscular;IT,intrathecal.
Drugs
Cyclophosphamide
Cyclophosphamideisusedinawidevarietyofconditions.Amongthemanyindicationsare
Hodgkindisease,lymphoma,leukemia,ovariancancer,orbreastcancer.The nativedrugis
inactive and requires activation by the liver p450 microsomal oxidase system. Active and
inactive metabolites are excreted in the urine. Degraded products are responsible for
hemorrhagic cystitis which can be prevented by maintaining a high urine output.
Hemorrhagiccystitiscanoccur whenhigherdosesareused.Commonsideeffectsinclude
alopecia and stomatitis. Nausea and vomiting are common after doses of 700 mg/m2 or
more(101).
Ifosfamide
Ifosfamideisusedforthetreatmentoflymphomas,sarcomas,andrelapsedtesticulartumors.
Ifosfamide leads to the formation of DNA–DNA cross-links. The drug undergoes hepatic
activationandthemetaboliteistoxicfortheurothelialmucosa.Themetabolitemayalsobe
responsible for much of the neurotoxic effects. Dose-limiting toxicities are
myelosuppression, hemorrhagic cystitis, and encephalopathy. Common side effects
includealopecia,nausea,andvomiting(102).
Thiotepa
Thiotepais usedforintracavitary therapyof malignanteffusions,isgivenas intravesicular
therapy for urinary bladder cancers and as intrathecal therapy for leptomeningeal disease.
Thiotepa alkylates guanine which causes DNA cross-linking. Dose-limiting toxicity is
myelosuppression(103).
Cisplatin
Cisplatin is used for the treatment of a variety of malignancies. Platin-analogs covalently
bindtoproteins,RNA,andespeciallyDNA,formingplatinum-basedcross-links.Resistance
tocisplatininvolvesalterationsintransmembranetransporterproteins,intracellularlevelsof
glutathione,andthe capacityto repaircisplatinDNAlesions.It iswidelydistributedinthe
body except for the CNS. Cisplatin,carboplatin, and oxaliplatin are considered to be cell
cycle–nonspecificbifunctional alkylatingagents. Asopposed toclassicalalkylating agents,
theypredominantlybindtoDNAtocauseintrastrandcross-linksandadductsthatchangethe
conformationofDNAandaffectDNAreplication(104).
Table4.9Alkylating-likeAgentsUsedforGynecologicCancer
Drug
Routeof
Administration CommonToxicities DiseasesTreated
Cisplatin IV Nephrotoxicity,tinnitusand
hearingloss,nauseaand
vomiting,myelosuppression,
peripheralneuropathy
Ovarianandgermcell
carcinomas,cervical,
endometrialcancer
Carboplatin IV Lessneuropathy,ototoxicity,
andnephrotoxicitythan
cisplatin;morehematopoietic
toxicity,especially
thrombocytopenia,than
cisplatin
Ovariancarcinomas,
endometrialandcervical
cancer
Oxaliplatin IV Acutedysesthesias,
neuropathy,myelosuppression
Colorectal,pancreatic,gastric
cancers
Trabectedin IV Rhabdomyolysis,
cardiomyopathy
Liposarcoma,leiomyosarcoma
IV,intravenous.
Dose-limitingtoxicitiesare:
Cumulativerenalinsufficiency.The incidence of renalinsufficiencyis about 5% with
adequatehydrationmeasuresbutcanriseto25–40%withoutproperhydrationmeasures.
Peripheral sensory neuropathy. This develops after the administration of 200 mg/m
2
andcanbecomedose-limitingwhenthecumulativecisplatindoseexceeds400mg/m2.
Ototoxicitywithtinnitusandhigh-frequencyhearingloss.Thisoccursin5%ofpatients,
and is more common in patients receiving doses of more than 100 mg/m2 by rapid
infusion,orhighcumulativedoses.
Common side effects include severe nausea and vomiting (both acute and delayed),
hypomagnesemia and mild myelosuppression. Alopecia can occasionally occur. In
addition,patientsoftenreportlossoftasteorametallictaste.
Carboplatin
Carboplatinisaheavymetalalkylating-likeagentwithmechanismsofactionverysimilarto
cisplatinbut with a differenttoxicityprofile. Dose-limiting toxicity is myelosuppression.
Commonsideeffectsincludenauseaandvomiting,nephrotoxicity(butlesssevereandless
commonthanwithcisplatin).Occasionaltoxicitiesincludehypersensitivityreactionsand
peripheralneuropathy.Raresideeffectsincludealopecia,skinrash,andototoxicity(105).
Patients may develop hypersensitivity reactions to carboplatin especially when being reexposedtothedrugfortreatmentofrecurrentdisease.
Oxaliplatin
Oxaliplatinisusedforthetreatmentofcolorectal,pancreatic,andgastriccancers.Oxaliplatin
causes DNA intrastrand and interstrand cross-links. Oxaliplatin undergoes extensive
nonenzymaticconversiontoitsactivemetabolite.Thedrugispredominantlyclearedthrough
the kidneys. Dose-limiting toxicities include acute dysesthesia to the hands, feet and
perioral area, and peripheral sensory neuropathy. In contrast to cisplatin, ototoxicity
occursrarely.Commonsideeffectsincludenauseaandvomiting,diarrhea,fatigue,and
mild-to-moderatemyelosuppression. Occasional side effects include mild nephrotoxicity,
stomatitis,andtastealterations(106).
Trabectedin
Trabectedinisusedforthetreatmentofliposarcomaorleiomyosarcomaafteranthracyclinecontaining regimens. In Europe, it is also approved for the treatment of ovarian cancer.
Trabectedinbinds to guanine residues in the minor groove of DNAforming adducts, and
resultinginabendingoftheDNAhelixtowardthemajorgroove.Trabectedinaffectsbinding
of transcription factors and DNA repair. It is mainly metabolized in the liver and only a
negligible amount is excreted in urine. The drug is delivered as a 24-hour continuous
infusion. Dose-limiting toxicities have been rhabdomyolysis (the level of creatinine
phosphokinaseshouldbemonitoredbeforeeachdose),severecardiomyopathy(abaseline
echocardiogramshouldbeobtainedandrepeatedevery2to3monthswhileontherapy)and
neutropenia. Common side effects include thrombocytopenia, anemia, nausea, fatigue,
vomiting,anddiarrhea(107).
Thecharacteristics ofthe commonlyused alkylatingagentsarelistedin Table4.8, andthe
alkylating-likeagentsarelistedinTable4.9.
AntitumorAntibioticsandTopoisomeraseInhibitors
Antitumor antibiotics generally are drugs derived from bacteria which in nature provide
defense against other hostile microorganisms. They act by a variety of mechanisms.
Topoisomerase inhibitors are natural or semisynthetic products. DNA topoisomerase is an
enzymethataltersDNAtopologybycausingandresealingDNAstrandbreaks.
Mechanism
SeveralofthesedrugsinterferewithDNAthroughintercalation,areactionwherebythedrug
inserts itself between DNAbase pairs. Intercalation prevents DNAreplication and mRNA
production.Other drugs haveotheractions. These naturalproducts usually haveextremely
complex and different chemical structures, although they generally function by forming
complexes with DNA. This class of antineoplastic agents is thought to be cell cycle–
nonspecific.TopoisomerasesbindtoDNA domains, forming a “cleavablecomplex”which
allowsDNAtounwindinpreparationforcelldivision.TopoisomeraseIrelaxessupercoiled
DNA. Topoisomerase II catalyzes the double-stranded breaking and resealing of DNA,
therebyallowingthepassageofonedoublehelicalsegmentofDNAthroughanother.
Drugs
ActinomycinD
ActinomycinD(Table4.10)isusedforthe treatmentoftrophoblasticneoplasms,sarcomas,
testicularcarcinoma,andWilmstumor.ActinomycinDintercalatesbetweenDNAbasepairs
andinhibitstopoisomerase II.It extensivelybindstotissues,resulting inalonghalf-lifein
plasma and tissue. Dose-limiting toxicity is myelosuppression. Common side effects
includenausea, vomiting,andalopecia. The drug isa vesicant and cancause necrosis if
extravasationoccurs.Occasionaltoxicitiesincludestomatitis,glossitis,diarrhea,andelevated
liverfunctiontests(108).
Bleomycin
Bleomycin is used for the treatment of lymphomas, testicular carcinomas, and germ cell
tumors.Itis a mixture of glycopeptides thatbindto DNAand form complexes with Fe2+.
OxidationofFe2+leadstothecreationofsuperoxideandhydroxylradicals.Bothfreedrug
and metabolic products are excreted into the urine. The main dose-limiting toxicity is
pneumonitis with a dry cough, interstitial radiographic changes, reduced pulmonary
diffusing capacity,and hypoxia. Pulmonary fibrosis occurs in 1% of patients receiving
cumulative doses of less than 200 U/m2, and in 10% of patients receiving larger doses.
Patients should be monitored with pulmonary function tests. Common side effects include
hypersensitivity reactions and dermatologic changes with hyperpigmentation of skin.
Occasionalsideeffectsincludenauseaandvomiting(109).
Table4.10AntitumorAntibioticsandTopoisomeraseInhibitors
Drug
Routeof
Administration CommonToxicities DiseasesTreated
ActinomycinD IV Nauseaandvomiting,
skinnecrosis,mucosal
ulceration,
myelosuppression
Germcellovarian
tumors,
choriocarcinoma,soft
tissuesarcoma
Bleomycin IV,IM Fever,dermatologic
reactions,pulmonary
toxicity,anaphylactic
reactions
Germcellovarian
tumors
Doxorubicin IV Myelosuppression,
alopecia,
cardiotoxicity,local
vesicant,nauseaand
vomiting,mucosal
ulcerations
Ovarian,breast,
endometrialcancer
Liposomaldoxorubicin IV Palmar–plantar
erythrodysesthesia,
myelosuppression,
stomatitis
Ovarianandendometrial
cancers
Epirubicin IV Myelosuppression,
alopecia,
cardiomyopathy,local
vesicant,nauseaand
vomiting,mucosal
ulceration
Ovarian,breast,
endometrialcancer
Topotecan IV Myelosuppression Ovariancancer
Irinotecan IV Myelosuppression,
diarrhea
Cervical,ovariancancer
Etoposide IV/PO Myelosuppression,
alopecia
Ovariangermcell,
choriocarcinoma
Ovariancancer
IV,intravenous;IM,intramuscular;PO,oral.
Doxorubicin
Doxorubicinis ananthracycline antitumorantibiotic.It isused for thetreatment ofalarge
numberoftumors.ItintercalatesbetweenDNAbasepairs,formsfreeradicals,andinduces
topoisomerase II dependent DNA damage. About 70% of the drug is bound to plasma
proteinsandmetabolizedbytheliver.Thereleaseratefromtissuebindingsitesisslow.This
resultsin relatively prolongedplasma levels. Metabolitesand free drugare excreted inthe
bile. Dose-limiting toxicities include myelosuppression and cardiomyopathy with
congestiveheartfailure.Thepatient’scardiacejectionfractionshouldbemonitoredduring
treatment, particularly when the cumulative dose exceeds 300 mg/m2. Risks and benefits
shouldbe consideredat higher cumulativedoses.Commonsideeffectsinclude alopecia,
nausea,vomiting,andstomatitis.Doxorubicinisavesicantandextravasationofthedrug
resultsinsevereulcerationandnecrosis.Occasionalsideeffectsincludediarrhea(110).
LiposomalDoxorubicin
Liposomal doxorubicin is used for the treatment of ovarian cancer, Kaposi sarcoma, and
myeloma.Liposomaldoxorubicinisencapsulatedinlongcirculatingliposomes(microscopic
vesiclescomposedofaphospholipidbilayer).Theplasmaclearanceisslowerthanstandard
doxorubicin. Dose-limiting toxicity is myelosuppression. The risk of cardiomyopathy is
significantlylowerwhencomparedtostandarddoxorubicin.Occasionalcardiomyopathy
has been reported at cumulative doses above 550 mg/m2. Common side effects include
palmar–plantar erythrodysesthesia (hand–foot syndrome) with erythema and
desquamationonthehandsandfeetassociatedwithpainandinflammation(111).
Epirubicin
Epirubicinisthe4′-epimerofdoxorubicinandisasemisyntheticderivativeofdaunorubicin.
It is used for the treatment of breast and gastric cancers. The toxicity is comparable to
doxorubicinbuttheriskofcardiomyopathyissignificantlylower.Theriskmaybeincreased
substantiallyafteratotaldoseof900mg/m2(112).
Etoposide
Etoposide is used for the treatment of gestational trophoblastic disease, germ cell tumors,
testicularcancer,lymphoma,andovariancancer.ItisavailableasanIVmedicationorasan
oraltablet.Itisextractedfromthepodophyllumpeltatumplant.Etoposideisatopoisomerase
II inhibitor. It causes G2 cell cycle arrest. It is highly bound to plasma proteins, mainly
albumin.Decreasedalbuminlevelsresultinpotentiallygreatertoxicity.Fortypercentofthe
drug is excreted in the urine. The main dose-limiting toxicity is myelosuppression.
Commonsideeffectsincludenausea,vomiting,malaise,andametallictasteduringthe
infusion. Occasional side effects include anemia and thrombocytopenia. Rare side effects
includestomatitisanddiarrhea(113).