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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
who had not received prophylactic CSFs and in whom there were risk factors for an
infection-relatedcomplication,similartothoseoutlinedintheASCOguidelines.
The likelihood of developing neutropenic fever in patients treated with a given
chemotherapeutic regimen is the primary factor determining whether or not
prophylacticCSFsshouldbegiven.Theincidenceofneutropenicfeverfollowingtreatment
is influenced by the intensity of chemotherapy, the presence and degree of injury to the
gastrointestinal mucosa, the presence of underlying damage to the patient’s hematopoietic
stemcells,theconcurrentuseofradiation,andtheoverallclinicalstatusofthepatient(i.e.,
ageandcomorbidconditions).
PrimaryProphylaxis
Primary prophylaxis refers to the initiation of G-CSFs during the first cycle of
myelosuppressivechemotherapy,withthegoalofpreventingneutropeniccomplications
throughoutthe chemotherapycycles(66). Primary prophylaxis may be used to decrease
theincidenceofneutropenicfeverandtheneedforhospitalization.Primaryprophylaxismay
also be used to maintain dose-dense or dose-intense chemotherapeutic strategies that have
survivalbenefits,orifitisknownthatreductionsinthedose-intensityordose-densityofthe
chemotherapywillbeassociatedwithaworseprognosis.
Indications,Benefits,andGuidelines
Theupdated2015guidelinesfromtheAmericanSocietyofClinicalOncology(ASCO),
theupdated2016guidelinesfromtheEuropeanSocietyforMedicalOncology(ESMO),
and consensus-based guidelines from the National Comprehensive Cancer Network
(NCCN) all recommend primary prophylaxis should be used when the anticipated
incidenceofneutropenicfeverisapproximately20%orhigherwithanygivenregimen
(66–68).
Thrombocytopenia
Patientswithsustainedthrombocytopenia,whohaveplateletcountsbelow10,000/mm3,
are at risk of spontaneous hemorrhage, particularly gastrointestinal or intracranial,
andplatelettransfusionssignificantlyreducetherisk.Forpatientswhoarecriticallyill
with fever, sepsis, or coagulopathy, the platelet count should be maintained above
20,000/mm3.Patientswithplateletcountsexceeding50,000/mm3donotusuallyexperience
severebleeding.Transfusionatthislevelisonlyindicatedifthepatientisactivelybleeding
orabouttoundergoanurgentsurgicalprocedure(67).
Aposttransfusionplateletcountperformed1hourafterplateletadministrationshould
showanappropriateincrementalincrease.If noplatelet increaseoccurs, itislikely that
therehasbeenprevioussensitizationtorandomdonorplatelets,andthepatientmayrequire
single-donorhumanleukocyteantigen-matchedplateletsforfuturetransfusions(67).
NauseaandEmesis
Fewsideeffectsofcancertreatmentaremorefearedbythepatientthannauseaandvomiting.
Althoughnauseaandemesis(vomitingand/orretching)canresultfromsurgeryorradiation
therapy,chemotherapy-inducednausea andvomiting(CINV) ispotentiallythe mostsevere
andmostdistressing. Significant progress has beenmade,butCINV remains animportant
adverseeffectoftreatment(69).
Three distinct types of CINV have been defined, with important implications for both
preventionandmanagement(69,70):
Acuteemesis, which most commonly begins within 1 to 2 hours of chemotherapy and
usuallypeaksin4to6hours
Delayedemesis,whichoccursmorethan24hoursafterchemotherapy
Anticipatory emesis, which occurs prior to treatment as a conditioned response in
patientswho have developedsignificantnausea and vomitingduring previous cyclesof
chemotherapy
Theobjectiveofantiemetictherapyisthecompletepreventionofnauseaandvomiting,
andthisshouldbeachievableinthemajorityofpatientsreceivingchemotherapy,even
withhighlyemeticagents(69,70).
Table4.6ChemotherapyandTargetedTherapy:FrequencyofEmesis
Level
FrequencyofEmesis
(%) ChemotherapeuticDrugandDose
High >90 Cisplatin
Anthracyclineandcyclophosphamide
Cyclophosphamide≥1,500mg/m
2
Moderate 30to90 Azacytidine
Carboplatin
Cyclophosphamide<1,500mg/m
2
Doxorubicin
Epirubicin
Ifosfamide
Irinotecan,liposomalirinotecan
Oxaliplatin
Temozolomide
Thiotepa
Trabectedin
Low 10to30 Docetaxel
Eribulin
Etoposide
Fluorouracil
Gemcitabine
Ixabepilone
Methotrexate
Mitomycin
Paclitaxelandnab-paclitaxel
Pegylatedliposomaldoxorubicin
Pemetrexed
Temsirolimus
Topotecan
Ado-trastuzumabemtansine
Minimal <10 Bevacizumab
Bleomycin
Nivolumab
Pembrolizumab
Trastuzumab
Vinblastine
Vincristine
Vinorelbine
FromRoilaF,MolassiotisA,HerrstedtJ,etal.2016MASCCandESMOguidelineupdateforthepreventionof
chemotherapy-andradiotherapy-inducednauseaandvomitingandofnauseaandvomitinginadvancedcancer
patients.AnnOncol2016;27:v119.Copyright©2016TheAuthor.ReproducedbypermissionofOxfordUniversity
Press.HeskethP,KrisMG,BaschE,etal.Antiemetics:AmericanSocietyofClinicalOncologyClinicalPractice
GuidelineUpdate.JClinOncol2017;35:3240.
Chemotherapeuticagentsaredividedintofourcategoriesbasedupontheriskofemesis
intheabsenceofantiemeticprophylaxis(Table4.6):
Highlyemetic—>90%riskofemesis
Moderatelyemetic—>30to90%riskofemesis
Lowemetogenicity—10to30%riskofemesis
Minimallyemetic—<10%riskofemesis
ChemotherapeuticsandFrequencyofEmesis
Thethreecategoriesofdrugswiththehighesttherapeuticindexforthemanagementof
CINV are the type three 5-hydroxytryptamine (5-HT3) receptor antagonists, the
neurokinin-1 receptor (NK1R) antagonists, and glucocorticoids (especially
dexamethasone) (69,70). In addition, more recent data have demonstrated substantial
antiemetic activity for the antipsychotic medication olanzapine when used in combination
withotherantiemetics.
Theseagentsareusedaloneandinspecificcombinations,dependingontheemetogenicityof
thespecificchemotherapeutic regimen being administered and its tendencytoproduce not
only acute but also delayed emesis. The recommended antiemetic prophylaxis for
intravenouslyadministeredchemotherapyinadultsispresentedinTable4.7(69–71).
Forpatientswhodonotachieveadequatecontrolofchemotherapy-inducednauseaand
vomiting with their initial antiemetic regimen, the patient’s management should be
reviewedtoensurethattherearenootherfactorsresponsibleforcontinuedemesisand
that adequate antiemetic therapy actually was administered for the given
chemotherapeuticregimen.Olanzapine,5or10mgdailyfor3days,canbeconsideredas
rescue therapy for patients with breakthrough nausea and vomiting who did not receive
olanzapineinitially.Forpatientsalreadyreceivingolanzapine,anagentshouldbetriedfrom
adifferent classthanwas used forinitialprophylaxis (e.g., prochlorperazine).The modest
antiemetic activity of cannabinoids and their unfavorable side effect profile, especially in
older patients, limit their clinical utility for treatment of refractory chemotherapy-induced
nausea and vomiting. Nevertheless, guidelines from NCCN and ASCO state that
cannabinoids can be considered for refractory nausea and vomiting, and as a rescue
antiemetic(67,70).
Table4.7RecommendedAntiemeticProphylaxisforIntravenouslyAdministeredChemotherapyin
Adults
RiskCategory Agent
DosingonDayof
Chemotherapy
DosingonSubsequent
Days
Highemeticrisk
a
NK1Rantagonist(oneofthefollowing):
(>90%)
Option1
•Aprepitant 125mgoral 80mgoraldailyondays
2and3.
•Fosaprepitant 150mgIV
•Rolapitant 180mgoralor166.5mgIV
PLUS
5-HT3antagonist(oneofthefollowing):
•Granisetron 2mgoral;1mgor0.01
mg/kgIV;10mg
subcutaneous
•Ondansetron 8mgoral;8mgIV
•Palonosetron 0.5mgoral;0.25mgIV
•Dolasetron 100mgoralONLY
•Tropisetron 5mgoral;5mgIV
•Ramosetron 0.3mgIV
PLUS
Glucocorticoid:
•Dexamethasone 12mgoralorIV(20mg
orallyifusingrolapitant)
Ifaprepitantisused:8
mgoralorIVdailyon
days2to4b.
Iffosaprepitantisused:
8mgoralorIVonday2;
8mgoralorIVtwice
dailyondays3to4b.
Ifrolapitantisused:8
mgoralorIVtwicedaily
ondays2to4b.
PLUS
•Olanzapine
5to10mg
c
5to10mgdailyondays
2to4c.
Highemeticrisk
a
(>90%)
Option2
NEPA(netupitantplus
palonosetron,capsule)
Once
OR
Fosnetupitantplus
palonosetron(injection)
Once
PLUS
Glucocorticoid:
•Dexamethasone 12mgoralorIV 8mgoraloncedailyon
days2to4(cisplatin
onlyd).
PLUS
•Olanzapine
5to10mg
c
5to10mgdailyondays
2to4c.
Moderateemeticriske,
f
(30–90%)
Non-carboplatin
5-HT3antagonist(oneofthefollowing):
•Referaboveforoptions
forhighemeticrisk
option1
PLUS
Glucocorticoid:
•Dexamethasone 8mgoralorIV 8mgoralorIVdailyon
days2and3.
Moderateemeticriske,
f
(30–90%)
Carboplatinbased
NK1Rantagonist(oneofthefollowing):
Referaboveforoptionsforhighemeticriskoption1
PLUS
5-HT3antagonist(oneofthefollowing):
•Referaboveforoptionsforhighemeticriskoption1
PLUS
Glucocorticoid:
•Dexamethasone 12mgoralorIV(20mg
orallyifusingrolapitant)
Lowemeticrisk
(10–30%)
Glucocorticoid:
•Dexamethasone 4to8mgoralorIV
OR
5-HT3antagonist(oneofthefollowing):
•Referaboveforoptionsforhighemeticriskoption1
OR
Phenothiazine-typedrug(e.g.,prochlorperazineorlevomepromazine)
Minimalemeticrisk
(<10%)
None None None
NK1R,neurokinin1receptor;IV,intravenous;5-HT3,type35-hydroxytryptamine.
a
Includesthecombinationofananthracyclineandcyclophosphamide.Rolapitant,aprepitant,andfosaprepitant
allinterferewithdexamethasonemetabolism,leadingtohigherexposureforanyspecificdose.Whengivenasa
singledoseonday1,fosaprepitantimpairsdexamethasonemetabolismondays1and2only.Ifpatientsdonot
receiveanNK1Rantagonist,thedexamethasonedoseshouldbeadjustedto20mgonday1and16mgdailyon
days2to4.
b
Forpatientsreceivinganthracycline/cyclophosphamideforbreastcanceroracarboplatin-containingregimen,
deletedays2to4ofdexamethasone.
c
5mgdoseofolanzapineispreferredformostpatientsbecauseoflesssedation.
d
WhenNEPAisusedonday1,multidayadministrationofglucocorticoidsisonlyusedinthedelayedphase
periodwithcisplatin.Foranthracycline/cyclophosphamidecombinations,administerglucocorticoidsonday1
only.Ifafirst-generation5-HT3antagonistisusedonday1ratherthanpalonosetron,treatmentwithafirstgeneration5-HT3antagonistaloneondays2and3isanacceptablealternative.
e
ClinicianswhochoosetouseanNK1Rantagonistforamoderate-riskregimenshouldfollowthe
recommendationsforhigh-riskchemotherapyregimens.Importantly,acorticosteroidisonlygivenonday1;the
dexamethasonedoseislower(12mg)unlessrolapitantisemployed(20mg).
f
Alsoappropriateforanthracycline/cyclophosphamide-containingchemotherapyindiseasesotherthanbreast
cancer.
ModifiedfromRoilaF,MolassiotisA,HerrstedtJ,etal.2016MASCCandESMOguidelineupdateforthe
preventionofchemotherapy-andradiotherapy-inducednauseaandvomitingandofnauseaandvomitingin
advancedcancerpatients.AnnOncol2016;27:v119;HeskethP,KrisMG,BaschE,etal.Antiemetics:
AmericanSocietyofClinicalOncologyClinicalPracticeGuidelineUpdate.JClinOncol2017;35:3240.
GastrointestinalToxicity
Mucositis, caused by a direct effect on the rapidly dividing epithelial mucosal cells, is
commonandconcomitantneutropeniamayallowtheinjuredmucosatobecomeinfectedand
serve as a portal of entry for bacteria and fungi into the bloodstream. Impaired cellular
immunitybecauseofunderlyingdiseaseorcorticosteroidtherapycancontributetoextensive
infection of the gastrointestinal tract (72). Other side effectsrelated to the gastrointestinal
tractincludeimpairedintestinalmotility,resultingfromtheautonomicneuropathic effect
ofvincaalkaloids(vincristineandvinblastine),andnauseaandvomiting,inducedbymany
anticancerdrugs(72).
UpperGastrointestinal
Theonset ofmucositisisfrequently3to5 daysearlierthanthat ofmyelosuppression
(72). Lesions of the mouth and pharynx are difficult to distinguish from candidiasis and
herpes simplex infection. Esophagitis resulting from direct drug toxicity can be confused
withradiationesophagitisorinfectionswithbacteria,fungi,orherpessimplexbecausethey
allproducedysphagiaandretrosternalburningpain.Mildoralcandidiasis(thrush)responds
toseveraloralagents.Moreintensivetherapywillberequiredforesophagealorsevereoral
candidiasis or herpes simplex infections. Symptomatic management of painful upper
gastrointestinal inflammation includes warm saline mouth rinses and topical anesthetics
suchasviscouslidocaine.Intravenousfluidsmay beindicated,and hyperalimentationmay
rarelyberequired(72).
LowerGastrointestinal
Mucositis in the lower gastrointestinal tract is invariably associated with diarrhea.
Serious complications include bowel perforation, hemorrhage, and necrotizing
enterocolitis (72). Necrotizing enterocolitis includes a spectrum of severe diarrheal
illnessesthatcanbefatalinaneutropenicpatient.Broad-spectrumantibiotictherapymay
predisposethepatienttonecrotizingenterocolitis,asmaycytotoxicchemotherapy,whichcan
interfere with the integrity of the bowel wall. This condition is more common in patients
receivingintensivechemotherapy (e.g., patients with leukemia), but it can also occur with
treatment of gynecologic malignancies. The most commonly involved organism is
Pseudomonas aeruginosa. Symptoms of necrotizing enterocolitis include watery or
bloody diarrhea, abdominal pain, sore throat, nausea, vomiting, and fever. Physical
examination usually reveals abdominal tenderness and distention. The performance of an
abdominal or pelvic computed tomographic scan or ultrasound will be helpful in the
evaluation of this constellation of signs and symptoms. Treatment includes the
administration of broad-spectrum antibiotics with specific activity against aerobic
gram-negativeorganisms and anaerobes.Nasogastricdecompression, intravenous fluids,
andbowelrestmayberequired.Intheneutropenicpatient,recoveryofnormalbloodcounts
isessentialforimprovementofthecondition.Surgicalinterventionisoccasionallynecessary.
Immunosuppression
Mostanticancerdrugsarecapableofproducingsuppressionofcellularand,toalesser
extent, humoral immunity. The magnitude and duration of the immunosuppression
vary with the dose and schedule of drug administration and are inadequately
characterized for most chemotherapeutic agents (66,67). Most of the acute
immunosuppressive side effects do not persist after the completion of drug treatment.
Laboratory studies suggest a decrease in host defenses during treatment associated with a
rebound to complete or nearly complete restoration 2 to 3 days after treatment has been
completed.Thisshort-termimmunosuppressiveeffecthasledtoincreaseduseofintermittent
chemotherapy regimens to allow immunologic recovery. Individuals with cancer who
undergocertaincytotoxicorimmunosuppressivetherapiesandhavehepatitisBvirus(HBV)
infection or prior exposure to HBV may be at elevated risk of liver failure from HBV
reactivation (73). HBV screening requires clinical judgment but should be considered in
patientswhomaybeatpotentialrisk.WhenevidenceforchronicHBVinfectionisfound,
antiviraltherapybeforeandthroughoutthecourseofchemotherapymaybeconsidered
toreducetheriskofHBVreactivation.
DermatologicReactions
Severalimportantdrugtoxicitiesinvolveskinreactions.Skinnecrosisandsloughingmay
resultfromextravasationofcertainirritatingchemotherapeuticagents,suchasdoxorubicin,
actinomycin D, mitomycin C, vinblastine, vincristine,andnitrogenmustard. The extent of
necrosisdependson thequantityof drugextravasatedand canvaryfromlocalerythemato
chroniculcerativenecrosis(74).Allcancercentershaveguidelinesandprotocolsinplaceto
deal with extravasation incidents, and the approach is dependent on the agent. Long-term
monitoringoftheaffectedareaisrequired,andsurgicaldebridementandfull-thicknessskin
graftingmaybenecessaryinselectedpatients.
Alopeciaisaverycommonsideeffectofmanychemotherapeuticagentsandmayhave
significantemotionalconsequencesforpatients.Agentscommonlyassociatedwithsevere
hairloss include theanthracyclineantibiotics and taxanes,suchas paclitaxel or docetaxel.
Mostcommonly useddrug combinationsproduce variabledegreesof alopecia.Alopecia is
reversible,andregrowthusuallybeginsseveralweeks after treatment has been completed.
Attemptstominimizealopeciabyusingavarietyofmethodssuchascalpcoolinghavebeen
triedwithvaryingdegreesofsuccess,dependingonthechemotherapeutic agents involved
(75).
Generalized allergic skin reactions can occur with chemotherapeutic agents and can
sometimes be severe. Other skin reactions occasionally seen include increased skin
pigmentation (bleomycin), photosensitivity reactions, transverse banding or nail loss,
folliculitis(actinomycinD,methotrexate),andradiationrecallreactions(doxorubicin).
Liposomal doxorubicin can produce a painful dermatologic syndrome characterized by
desquamationoftheskin,mostofteninvolvingthehandsandfeet(76).Blistering,focalor
disseminated,maybeobserved.
HepaticToxicity
Modest elevations in aminotransferase, alkaline phosphatase, and bilirubin levels are
frequentlyseenwithmanyanticanceragents,buttheyusuallyresolvequickly(77).More
severereactionsmayoccur,andlong-termadministrationofmethotrexatecaninducehepatic
fibrosis that can progress to cirrhosis. The cirrhosis and drug-induced hepatitis should be
managedbywithdrawalofthetoxicagent,withthesamesupportivemeasuresthatareused
for hepatitis or cirrhosis of any cause. Preexisting liver disease or exposure to other
hepatotoxinsmayincreasetherisk.
PulmonaryComplications
Respiratorycompromiseresultingfromlungmetastases,pulmonaryemboli,radiation
pneumonitis, and pneumonia may be significant complications associated with an
underlyingmalignancy,butdirectpulmonarytoxicityfromcommonlyusedanticancer
drugsissometimesseen(78).Interstitialpneumonitiswith pulmonaryfibrosisisthe usual
pattern of lung damage associated with cytotoxic drugs. Likely agents include bleomycin,
alkylating agents, gemcitabine, and the nitrosoureas. The physical and chest radiologic
findingsare not easilydistinguishablefrom those ofinterstitial pneumonitis resultingfrom
infectious agents or lymphangitic spread of cancer. Management of drug-induced
interstitialpneumonitisincludesdiscontinuationofthesuspectedagentandsupportive
care.Steroidsmaybeofsymptomaticbenefitinsomepatients.
CardiacToxicity
Cardiac toxicity is seen with several important cancer chemotherapeutic agents.
Althoughthemyocardium consists of largelynondividingcells,drugs of the anthracycline
antibioticclass,specifically,doxorubicinanddaunomycin,cancauseseverecardiomyopathy
(79).
Theriskofcardiactoxicityincreaseswiththetotalcumulativedoseofdoxorubicin.Forthis
reason,acumulativedoseof450to500mg/m2ofidealbodysurfaceareaisnowwidely
used as the maximum tolerable dose. With careful and frequent monitoring of left
ventricularfunctionbymeansofejectionfractionstudies,therapycanbecontinuedtohigher
doses if no satisfactory alternative exists. Occasionally, anthracyclines and paclitaxel can
causeacutearrhythmiasthatarenotrelatedtototaldrugdose.Anthracyclinecardiactoxicity
is potentiated by radiation. Discontinuation of the drug at the first indication of
decreasing left ventricular function minimizes the risk of cardiovascular
decompensation(79).
Rarely,cyclophosphamide mayproducecardiotoxicity, particularly inthemassivedoses
used in conjunction with bone marrow transplantation. With conventional doses of
cyclophosphamide, this complication is unlikely. Busulfan and mitomycin C may cause
endocardialfibrosisandmyocardialfibrosis,respectively.Rarely,5-fluorouracilmaycause
symptomsofanginapectorisduetocoronaryarteryspasm.
Cardiac toxicity is an important side effect of trastuzumab, a targeted therapy (HER2