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1、Evidence,Challengesand Solutions:Preventing and Managing Chemotherapy-Induced Nausea and Vomiting,Scott Edwards,Pharm DClinical Oncology PharmacistEastern Health,St.Johns,NLNOPS 2008,Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy,Adapted from:1Coates A et al.Eur J Cancer
2、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 Pract 1999;7:59-65.,CINV-Definitions,Acute within a few minutes to several hours after drug administration and commonly resolves within 24 hours.Delayed de
3、velops in patients more than 24 hours after chemotherapy administration.May last up to 6 daysIt commonly occurs with cisplatin,carboplatin,cyclophosphamide and/or anthracyclines.Anticipatory nausea and/or vomiting before patients receive their chemotherapy,after a prior negative experience with chem
4、otherapyBreakthrough occurs despite prophylactic treatment and/or requires rescue.Refractory nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles,Adapted from:ASHP Am J Health Syst Pharm 1999;56:729-764 NCCN Practice Guidelines in Oncolog
5、yVersion 3.2008.Antiemesis,Rates of CINV,Adapted from:1.Hickok JT,et al.Cancer.2003;97:2880-6.,Chemotherapy-Induced Emesis Risk Factors,Patient-related risk factors include:Younger ageFemale genderNo/minimal prior history of alcohol usePrior CINVAnxiety High pretreatment expectation of severe nausea
6、,Adapted from:Gregory RE et al.Drugs.1998.;2.Hesketh PJ et al.J Clin Oncol.1997.Roscoe 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.Can
7、cer 2004;101:2701-2708,Influence of Patient Expectations on CINV,Expectancy 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.,Chemotherapy-Ind
8、uced Emesis Risk Factors,Treatment-related risk factors include:High drug dose High emetogenicity of chemotherapy drugsOf 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.,Causes of
9、 CINV,In addition to emesis induced by chemotherapy,CINV can be caused by:Partial or complete bowel obstructionVestibular DysfunctionBrain MetastasesElectrolyte imbalance:hypercalcemia,hyperglycemia,hyponatremia,uremiaConcomitant drugs,including opiatesGastroparesis induced by a tumor or chemotherap
10、y(such as vincristine)Psychophysiologic factors,including anxiety as well as anticipatory nausea and vomiting,Adapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis.,Consequence of Unresolved CINV,Discontinuation of therapy Serious metabolic derangementsNutritional depletion and
11、anorexiaEsophageal tearsWound dehiscenceDeterioration of patients physical and mental statusDegeneration of self-care and functional ability,Adverse sequelae of nausea and vomiting in the cancer patient.,Adapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis.,Poll of the audience
12、As 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.,Anti Nausea Chemotherapy Registry(ANCHOR)study,The authors determined the incidence of acute and de
13、layed CINV after modern antiemetics.Then 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.,Anchor Study Perception vs Reality Moderately Emetogenic Chemotherapy,Adapted from Gr
14、unberg et al.Cancer 2004;100:2261-8.,Toxicity Assessments,Grade common toxicity effects of adjuvant breast cancer patients.Patients are assessed the day of chemotherapy and again 2-3 days post chemotherapy.Patients also have a number to call back if they experience any toxicities.,Dr.H.Bliss Murphy
15、Cancer Center,St.Johns Newfoundland,Rates of CINV in,N=26,Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland,Rate of CINV,Adapted from Cancer 2004;100:2261-8.,N=231,at the Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland in comparison to the Grunberg data,Health Care Professionals Perception
16、 of CINV at the Dr.H.Bliss Murphy Cancer Center,St.Johns Newfoundland,Adapted from Cancer 2004;100:2261-8.,CINVDecreased Quality of Life,CINV adversely impact patients quality of life.Ovarian cancer patients in a recent study included complete to almost complete control from CINV among the most favo
17、rable health states,just below perfect health and clinical remission.,Adapted from Support Care Cancer 2005;13:219-27.,CINVDecreased Quality of Life,Adapted from Support Care Cancer 2005;13:219-27.,Adapted from Bloechl-Daum B et al.J Clin Oncol.2006;24:4472.,CINVDecreased Quality of Life,FLIE Questi
18、onnaireHEC-FLIE MEC-FLIE P=0.0049FLIE-nausea FLIE-Vomiting P=0.0097There is a greater negative impact onQOL from nausea than there is from vomitingThere is a greater negative impact onQOL from HEC than there is from MEC,FLIE=Functional Living Index-Emesis;HEC=highly emetogenic chemotherapy;MEC=moder
19、ately emetogenic chemotherapy.,Summary of the Importance of Prevention and Treatment of CINV,There still is a high level of anguish for CINV experienced by our patients.As health care professionals,we may not be accurately predicting the level of CINV experienced by our patients.CINV has a enormous
20、impact on our patients quality of life.,Mechanisms of CINV,Central mechanism:Chemotherapeutic agent activates the chemoreceptor trigger zone(CTZ).Activated CTZ invokes release of various neurotransmitters,which stimulate vomiting center.Peripheral mechanism:Chemotherapeutic agent causes irritation a
21、nd damage to gastrointestinal(GI)mucosa,resulting in the release of neurotransmitters.Activated receptors send signals to vomiting center via vagal afferents.,Adapted from:Berger AM et al.In:Cancer:Principles and Practice of Oncology.6th ed.Lippincott Williams 2001:28692880.,Adapted from N Engl J Me
22、d 2008;358:2482-94.,Serotonin and 5-HT3 Receptor Pathway,First recognized with high-dose metoclopramide.Development of 5-HT3 antagonists has had dramatic impact:Highly effective in acute vomiting,less effective for delayed events.Optimal use is with dexamethasone.Primary mechanism of action appears
23、to be peripheral.,Adapted from:Berger AM et al.In:Cancer:Principles and Practice of Oncology.6th ed.Lippincott Williams 39:1074-80.,Substance P and Neurokinin1(NK1)Receptor Pathway,High density of substance P/NK1 receptors located in brain regions implicated in the emetic reflex.Primary mechanism of
24、 NK1 receptor blockade action appears to be central.Effective for both acute and delayed events.Augments 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 Suppor
25、t Care Cancer 2001;9:350-54.,Conceptual Model of Acute&Delayed CINV,Adapted from Andrews 1993:147.,5-HT3-sensitive phase,Prokinetic-sensitive phase,Steroid-sensitive phase,Disrupted gut motility,Cell breakdown products,Intensity of emesis,Time(days),0,1,2,3,4,5,5HT,NK1-sensitive phase,Pharmacogenomi
26、cs,Quest for individualized therapy.Identification 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 response.,Pharmacogenomics,P
27、harmacogenomics-the study of the relationship between specific DNA sequence variations and the actual effect of a drug.CYP2D6 is involved in the metabolism of all of the most commonly available serotonin antagonists,except granisetron,and their efficacy and side effects may therefore be affected by
28、the CYP2D6 polymorphism.As this enzyme is polymorphic,several different alleles may be present in different individuals.,Number of Subjects,Increasing Metabolic Capacity,EM,PM,URM,Pharmacogenomics Polymorphic Distribution,CYP2D6 mutations or deletions,poor metabolizer(PM),occur in 10%of the general
29、population(UM)Ultrarapid metabolizer phenotype is observed in 2%of the general population.EM(extensive metabolizer),which is the normal or usual phenotype.,Pharmacogenomics in CINV,Kaiser studied the impact of patient genotype for 2D6(CYP2D6)on efficacy of ondansetron and tropisetron for CINV.The ul
30、trarapid metabolizer patients experienced significantly more nausea and vomiting after chemotherapy.The impact of genotype on vomiting incidence was observed during both early(hours 0 to 4)and late(hours 5 to 24)observation periods,although delayed nausea and vomiting was not evaluated in this study
31、.,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.,Figure 2.Mean number of episodes of vomiting(+/-standard deviation)experienced 5-24 hour
32、s 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 CINV,Adapted from:Kaiser R,Sezer O,Papies A,et al:Patient-tailored antiemetic treatment with 5-h
33、ydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.J Clin Oncol 20:2805-11,2002.,ANTIEMETIC GUIDELINE CONSENSUS,-Official Process Subscribed to by 9 International Oncology Groups-,Adapted from MASCC Antiemetic March 2008 Guideline Update.,MASCC(PERUGIA)2004 ANTI
34、EMETIC GUIDELINES,ANTIEMETIC TREATMENT GUIDELINES-The Four Emetic Risk Groups-,Adapted from MASCC Antiemetic March 2008 Guideline Update.,MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINES,-Emetic Risk Groups-Single IV Agents-,Adapted from MASCC Antiemetic March 2008 Guideline Update.,MASCC(PERUGIA)2004 ANTIE
35、METIC GUIDELINES,-Committee I(3/5):Emetic Risk Groups-Single IV Agents,Adapted from MASCC Antiemetic March 2008 Guideline Update.,MASCC(PERUGIA)2004 ANTIEMETIC GUIDELINES,ANTIEMETIC TREATMENT GUIDELINES-Committee I(5/5):Emetic Risk Groups-Single Oral Agents-,Adapted from MASCC Antiemetic March 2008
36、Guideline Update.,Principles of Care for Acute Highly andModerately Emetic Settings,UNANIMOUS CONSENSUS:CATEGORY 1 EVIDENCEUse the lowest tested fully effective dose.No schedule is better than a single dose given before chemotherapy.The antiemetic efficacy and adverse effects of serotonin antagonist
37、 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 Antiemetic March 2008 Guideline Update.,To prevent acute vomiting and nausea following chemotherapy o
38、f high emetic risk,a three-drug regimen is recommended including single doses of:5-HT3 antagonistDexamethasoneAprepitant(or fosaprepitant)given before chemotherapy is recommended.MASCC Level of confidence:HighMASCC Level of consensus:HighASCO Level of evidence:IASCO Grade of recommendation:A,Adapted
39、 from slide from MASCC Antiemetic March 2008 Guideline Update.,Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk:,Example-Women receiving a combination of anthracycline+cyclophosphamide represent a situation with a particularly great risk of vomitin
40、g and nausea.To prevent acute vomiting and nausea in these women,a three-drug regimen including single doses of:5-HT3 antagonistDexamethasoneAprepitant(or fosaprepitant)given before chemotherapy is recommended.MASCC Level of confidence:ModerateMASCC Level of consensus:HighASCO Level of evidence:IIAS
41、CO Grade of recommendation:A,Adapted from MASCC Antiemetic March 2008 Guideline Update.,Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk(MEC):,In patients who receive MEC,not including a combination of anthracycline plus cyclophosphamide:5-HT3
42、receptor antagonist+Dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course.MASCC level of confidence:HighMASCC level of consensus:HighASCO level of evidence:IASCO grade of recommendation:A,Adapted from MASCC Antiemetic March 2008 Guideline Update.,Guideline for
43、 the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk(MEC):,B.C.Cancer Agency Antiemetic regimens,Adapted from:Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults.,ONS Putting Evidence into Practice,Adapted from ONS PEP
44、Nausea Retrieved July 21,2008 from,Adapted from ONS PEP Nausea Retrieved July 21,2008 from,ONS Putting Evidence into Practice Contd,Cancer Care Ontario-Telephone Nursing Practice-and Symptom Management Guidelines,Adapted from CCO Telephone Assessments.Retrieved July 21,2008 from,Cancer Care Ontario-
45、Telephone Nursing Practiceand Symptom Management Guidelines,Adapted from CCO Telephone Assessments.Retrieved July 21,2008 from,Common CINV Challenges,Challenges in multiple-day chemotherapy regimensBreakthrough CINVAnticipatory CINVDelayed CINV,Multiple-Day Chemotherapy Regimens,Challenge Patients r
46、eceiving multi-day chemotherapy(chemotherapy administered over several days per cycle)are at risk for both acute and delayed nausea and vomiting.It is difficult to recommend appropriate antiemetics for each day since acute and delayed may overlap after the initial day of chemotherapy.The period of r
47、isk for delayed nausea and vomiting also depends on the emetogenic potential of the last chemotherapy agent administered in the regimen.,Adapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis,Multi-Day Chemotherapy Regimens(continued),A 5-HT3 receptor antagonist should be adminis
48、tered prior to each days 1st dose of moderately or highly-emetogenic chemotherapy.Dexamethasone should be administered once daily either orally or IV for every day of chemotherapy and for 2-3 days post chemotherapy.Aprepitant may be used for multi-day chemotherapy.Aprepitant 125 mg on day 1,then apr
49、epitant 80 mg daily on days 2 and 3 along with dexamethasone.Based on Phase II data,aprepitant may be safely administered on days 4 and 5 after chemotherapy.,Adapted from NCCN Practice Guidelines in OncologyVersion 3.2008.Antiemesis,Breakthrough CINV,Breakthrough emesis refers to vomiting that occur
50、s despite prophylactic treatment and/or requires rescue.Refractory emesis refers to emesis that occurs during subsequent treatment cycles when antiemetic prophylaxis and/or rescue have failed in earlier cycles.Challenge-Breakthrough nausea and vomiting represents a difficult situation as ongoing ref
