1、化疗引起的恶心呕吐的预防与管理1Patient Perceptions of the Most Severe Side Effects of Cancer ChemotherapyRank198311993219953199941.VomitingNauseaNauseaNausea2.NauseaConstantly tiredLoss of hairLoss of hair3.Loss of hairLoss of hairVomitingConstantly tired 4.Thought of coming for treatmentEffect on familyConstantly
2、 tiredVomiting5.Length of time treatment takesVomitingHaving to have an injectionChanges in the way things tasteAdapted from:1Coates A et al.Eur J Cancer Clin Oncol.1983;19:203-8.2Griffin AM et al.Ann Oncol.1996;7:189-95.3De Boer-Dennert M et al.Br J Cancer.1997;76:1055-61.4 Lindley C et al.Cancer P
3、ract 1999;7:59-65.化疗引起的恶心呕吐的预防与管理2CINV-Definitions nAcute within a few minutes to several hours after drug administration and commonly resolves within 24 hours.nDelayed develops in patients more than 24 hours after chemotherapy administration.nMay last up to 6 daysnIt commonly occurs with cisplatin,
4、carboplatin,cyclophosphamide and/or anthracyclines.nAnticipatory nausea and/or vomiting before patients receive their chemotherapy,after a prior negative experience with chemotherapynBreakthrough occurs despite prophylactic treatment and/or requires rescue.nRefractory nausea and emesis during subseq
5、uent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cyclesAdapted from:1.ASHP Am J Health Syst Pharm 1999;56:729-7642.NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis化疗引起的恶心呕吐的预防与管理3Rates of CINVAdapted from:1.Hickok JT,et al.Cancer.2003;97:2880-6.2.化疗引起的恶心呕吐的预防
6、与管理4Chemotherapy-Induced Emesis Risk FactorsnPatient-related risk factors include:nYounger agenFemale gendernNo/minimal prior history of alcohol usenPrior CINVnAnxiety nHigh pretreatment expectation of severe nausea Adapted from:1.Gregory RE et al.Drugs.1998.;2.Hesketh PJ et al.J Clin Oncol.1997.2.R
7、oscoe JA,Bushunnow P,Morrow GR,et al.Patient experience is a strong predictor of severe nausea after chemotherapy:a University of Rochester Community Clinical Oncology Program study of patients with breast carcinoma.Cancer 2004;101:2701-2708 化疗引起的恶心呕吐的预防与管理5Influence of Patient Expectations on CINV
8、nExpectancy of nausea assessed before patients received their first doxorubicin-based chemotherapy treatment was found to be a strong predictor of subsequent nausea.Adapted from Roscoe et al.Cancer.2004 101(11):2701-8.化疗引起的恶心呕吐的预防与管理6Chemotherapy-Induced Emesis Risk FactorsnTreatment-related risk fa
9、ctors include:nHigh drug dose nHigh emetogenicity of chemotherapy drugsnOf all the known predictive factors,the emetogenicity of a given chemotherapeutic agent is the predominant factor.Adapted from ASHP Am J Health Syst Pharm 1999;56:729-64.化疗引起的恶心呕吐的预防与管理7Causes of CINVIn addition to emesis induce
10、d by chemotherapy,CINV can be caused by:nPartial or complete bowel obstructionnVestibular DysfunctionnBrain MetastasesnElectrolyte imbalance:hypercalcemia,hyperglycemia,hyponatremia,uremianConcomitant drugs,including opiatesnGastroparesis induced by a tumor or chemotherapy(such as vincristine)nPsych
11、ophysiologic factors,including anxiety as well as anticipatory nausea and vomitingAdapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis.化疗引起的恶心呕吐的预防与管理8Consequence of Unresolved CINVnDiscontinuation of therapy nSerious metabolic derangementsnNutritional depletion and anorexianEs
12、ophageal tearsnWound dehiscencenDeterioration of patients physical and mental statusnDegeneration of self-care and functional abilityAdverse sequelae of nausea and vomiting in the cancer patient.Adapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis.化疗引起的恶心呕吐的预防与管理9Poll of the au
13、dienceAs Health care professionals we often:A.Accurately recognize the incidence of acute and delayed CINV in our own practices.B.Underestimate the incidence of acute and delayed CINV in our own practices.化疗引起的恶心呕吐的预防与管理10Anti Nausea Chemotherapy Registry(ANCHOR)study nThe authors determined the inc
14、idence of acute and delayed CINV after modern antiemetics.nThen they compared the actual incidences of CINV to the predictions made by physicians and nurses regarding these patients.Adapted from Grunberg SM et al.Cancer 2004;100:2261-8.化疗引起的恶心呕吐的预防与管理11Anchor Study Perception vs Reality Moderately E
15、metogenic ChemotherapyAdapted from Grunberg et al.Cancer 2004;100:2261-8.化疗引起的恶心呕吐的预防与管理12Toxicity AssessmentsnGrade common toxicity effects of adjuvant breast cancer patients.nPatients are assessed the day of chemotherapy and again 2-3 days post chemotherapy.nPatients also have a number to call bac
16、k if they experience any toxicities.Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland 化疗引起的恶心呕吐的预防与管理13Rates of CINV in N=26Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland 化疗引起的恶心呕吐的预防与管理14Rate of CINVAdapted from Cancer 2004;100:2261-8.N=231at the Dr.H.Bliss Murphy Cancer Center,St.Johns
17、Newfoundland in comparison to the Grunberg data化疗引起的恶心呕吐的预防与管理15Health Care Professionals Perception of CINV at the Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland Adapted from Cancer 2004;100:2261-8.化疗引起的恶心呕吐的预防与管理16 CINVDecreased Quality of LifenCINV adversely impact patients quality of life
18、.nOvarian cancer patients in a recent study included complete to almost complete control from CINV among the most favorable health states,just below perfect health and clinical remission.Adapted from Support Care Cancer 2005;13:219-27.化疗引起的恶心呕吐的预防与管理17 CINVDecreased Quality of LifeAdapted from Suppo
19、rt Care Cancer 2005;13:219-27.化疗引起的恶心呕吐的预防与管理18Adapted from Bloechl-Daum B et al.J Clin Oncol.2006;24:4472.CINVDecreased Quality of LifenFLIE QuestionnairenHEC-FLIE MEC-FLIE P=0.0049nFLIE-nausea FLIE-Vomiting P=0.0097nThere is a greater negative impact onQOL from nausea than there is from vomitingnT
20、here is a greater negative impact onQOL from HEC than there is from MECFLIE=Functional Living Index-Emesis;HEC=highly emetogenic chemotherapy;MEC=moderately emetogenic chemotherapy.化疗引起的恶心呕吐的预防与管理19Summary of the Importance of Prevention and Treatment of CINVnThere still is a high level of anguish f
21、or CINV experienced by our patients.nAs health care professionals,we may not be accurately predicting the level of CINV experienced by our patients.nCINV has a enormous impact on our patients quality of life.化疗引起的恶心呕吐的预防与管理20Mechanisms of CINVnCentral mechanism:nChemotherapeutic agent activates the
22、chemoreceptor trigger zone(CTZ).nActivated CTZ invokes release of various neurotransmitters,which stimulate vomiting center.nPeripheral mechanism:nChemotherapeutic agent causes irritation and damage to gastrointestinal(GI)mucosa,resulting in the release of neurotransmitters.nActivated receptors send
23、 signals to vomiting center via vagal afferents.Adapted from:Berger AM et al.In:Cancer:Principles and Practice of Oncology.6th ed.Lippincott Williams&Wilkins;2001:28692880.化疗引起的恶心呕吐的预防与管理21Adapted from N Engl J Med 2008;358:2482-94.化疗引起的恶心呕吐的预防与管理22Serotonin and 5-HT3 Receptor PathwaynFirst recogniz
24、ed with high-dose metoclopramide.nDevelopment of 5-HT3 antagonists has had dramatic impact:nHighly effective in acute vomiting,less effective for delayed events.nOptimal use is with dexamethasone.nPrimary mechanism of action appears to be peripheral.Adapted from:Berger AM et al.In:Cancer:Principles
25、and Practice of Oncology.6th ed.Lippincott Williams&Wilkins;2001:2869-80.Gralla RJ et al J Clin Oncol 1999;17:2971-94.Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer.Ann Oncol 1998;9:811-19.Endo T et al Toxicology 2000;153:189-201.Hesketh PJ et al Eur J Cancer 2
26、003;39:1074-80.化疗引起的恶心呕吐的预防与管理23Substance P and Neurokinin-1(NK1)Receptor Pathway nHigh density of substance P/NK1 receptors located in brain regions implicated in the emetic reflex.nPrimary mechanism of NK1 receptor blockade action appears to be central.nEffective for both acute and delayed events.
27、nAugments antiemetic activity of a 5-HT3 receptor antagonist and corticosteroid.Adapted from:Hargreaves R J Clin Psychiatry 2002;63(suppl 11):18-24.Saria A Eur J Pharmacol 1999;375:51-60.Hesketh PJ Support Care Cancer 2001;9:350-54.化疗引起的恶心呕吐的预防与管理24Conceptual Model of Acute&Delayed CINVAdapted from
28、Andrews&Davis.In:Andrews PLR&Sanger GJ(Eds).Emesis in Anti-Cancer Therapy:Mechanisms and Treatment.London:Arnold;1993:147.5-HT3-sensitive phaseProkinetic-sensitive phaseSteroid-sensitive phaseDisrupted gut motilityCell breakdown productsIntensity of emesisTime(days)0123455HTNK1-sensitive phase化疗引起的恶
29、心呕吐的预防与管理25PharmacogenomicsnQuest for individualized therapy.nIdentification and characterization of a large number of genetic polymorphisms(biomarkers)in drug metabolizing enzymes and drug transporters may provide substantial knowledge about the mechanisms of inter-individual differences in drug re
30、sponse.化疗引起的恶心呕吐的预防与管理26PharmacogenomicsnPharmacogenomics-the study of the relationship between specific DNA sequence variations and the actual effect of a drug.nCYP2D6 is involved in the metabolism of all of the most commonly available serotonin antagonists,except granisetron,and their efficacy and
31、 side effects may therefore be affected by the CYP2D6 polymorphism.As this enzyme is polymorphic,several different alleles may be present in different individuals.化疗引起的恶心呕吐的预防与管理27Number of SubjectsIncreasing Metabolic CapacityEMPMURMPharmacogenomics Polymorphic Distribution CYP2D6 mutations or dele
32、tions,poor metabolizer(PM),occur in 10%of the general population (UM)Ultrarapid metabolizer phenotype is observed in 2%of the general population.EM(extensive metabolizer),which is the normal or usual phenotype.化疗引起的恶心呕吐的预防与管理28Pharmacogenomics in CINVnKaiser studied the impact of patient genotype fo
33、r 2D6(CYP2D6)on efficacy of ondansetron and tropisetron for CINV.nThe ultrarapid metabolizer patients experienced significantly more nausea and vomiting after chemotherapy.n The impact of genotype on vomiting incidence was observed during both early(hours 0 to 4)and late(hours 5 to 24)observation pe
34、riods,although delayed nausea and vomiting was not evaluated in this study.Adapted from:Kaiser R,Sezer O,Papies A,et al:Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.J Clin Oncol 20:2805-11,2002.化疗引起的恶心呕吐的预防与管理2
35、9Figure 2.Mean number of episodes of vomiting(+/-standard deviation)experienced 5-24 hours after chemotherapy as a function of the number of active cytochrome P450 CYP2D6 enzyme genes in patients receiving tropisetron,5 mg once a day(A),and ondansetron,8 mg twice a day(B)Pharmacogenomics in CINVAdap
36、ted from:Kaiser R,Sezer O,Papies A,et al:Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.J Clin Oncol 20:2805-11,2002.化疗引起的恶心呕吐的预防与管理30ANTIEMETIC GUIDELINE CONSENSUS-Official Process Subscribed to by 9 Internation
37、al Oncology Groups-International:MASCCNorth America:-U.S.ASCO,NCCN -CanadaCCOEurope:ESMO,EONSAfrica:SASMOAustralia:COSAAdapted from MASCC Antiemetic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理31MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINESANTIEMETIC TREATMENT GUIDELINES-The Four Emetic Risk Groups-Adapte
38、d from MASCC Antiemetic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理32MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINES-Emetic Risk Groups-Single IV Agents-HIGHCisplatinMechlorethamineStreptozocinCyclophosphamide 1500 mg/m2CarmustineDacarbazineMODERATEOxaliplatinCytarabine 1 gm/m2CarboplatinIfosfamideCyclopho
39、sphamide 1500 mg/m2DoxorubicinDaunorubicinEpirubicinIdarubicinIrinotecanAdapted from MASCC Antiemetic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理33MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINES-Committee I(3/5):Emetic Risk Groups-Single IV Agents LOWPaclitaxelDocetaxelMitoxantroneTopotecanEtoposidePemetre
40、xedMethotrexateDoxorubicin HCL liposome injectionMitomycinGemcitabineCytarabine 100 mg/m25-FluorouracilBortezomibCetuximabTrastuzumabAdapted from MASCC Antiemetic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理34MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINESANTIEMETIC TREATMENT GUIDELINES-Committee I(5/5):Eme
41、tic Risk Groups-Single Oral Agents-Adapted from MASCC Antiemetic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理35Principles of Care for Acute Highly andModerately Emetic SettingsUNANIMOUS CONSENSUS:CATEGORY 1 EVIDENCEnUse the lowest tested fully effective dose.nNo schedule is better than a single dose
42、given before chemotherapy.nThe antiemetic efficacy and adverse effects of serotonin antagonist agents are comparable in controlled trials.-Intravenous and oral formulations are equally effective and safe.-Always give dexamethasone with a 5-HT3 antagonist before chemotherapy.Adapted from MASCC Antiem
43、etic March 2008 Guideline Update.化疗引起的恶心呕吐的预防与管理36To prevent acute vomiting and nausea following chemotherapy of high emetic risk,a three-drug regimen is recommended including single doses of:5-HT3 antagonistDexamethasoneAprepitant(or fosaprepitant)given before chemotherapy is recommended.MASCC Leve
44、l of confidence:HighMASCC Level of consensus:HighASCO Level of evidence:IASCO Grade of recommendation:AAdapted from slide from MASCC Antiemetic March 2008 Guideline Update.Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk:化疗引起的恶心呕吐的预防与管理37Example-Wo
45、men receiving a combination of anthracycline+cyclophosphamide represent a situation with a particularly great risk of vomiting and nausea.To prevent acute vomiting and nausea in these women,a three-drug regimen including single doses of:n5-HT3 antagonistnDexamethasonenAprepitant(or fosaprepitant)giv
46、en before chemotherapy is recommended.MASCC Level of confidence:ModerateMASCC Level of consensus:HighASCO Level of evidence:IIASCO Grade of recommendation:AAdapted from MASCC Antiemetic March 2008 Guideline Update.Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Mo
47、derate Emetic Risk(MEC):化疗引起的恶心呕吐的预防与管理38In patients who receive MEC,not including a combination of anthracycline plus cyclophosphamide:n5-HT3 receptor antagonist+nDexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course.MASCC level of confidence:HighMASCC level
48、of consensus:HighASCO level of evidence:IASCO grade of recommendation:AAdapted from MASCC Antiemetic March 2008 Guideline Update.Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk(MEC):化疗引起的恶心呕吐的预防与管理39B.C.Cancer Agency Antiemetic regimensAdapted
49、 from:Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults.Retrieved July 21,2008 from 化疗引起的恶心呕吐的预防与管理40ONS Putting Evidence into PracticeAdapted from ONS PEP Nausea Retrieved July 21,2008 from 化疗引起的恶心呕吐的预防与管理41Adapted from ONS PEP Nausea Retrieved July 21,20
50、08 from ONS Putting Evidence into Practice Contd化疗引起的恶心呕吐的预防与管理42Cancer Care Ontario-Telephone Nursing Practice-and Symptom Management GuidelinesAdapted from CCO Telephone Assessments.Retrieved July 21,2008 from 化疗引起的恶心呕吐的预防与管理43Cancer Care Ontario-Telephone Nursing Practiceand Symptom Management Gu
