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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,化疗引起的恶心呕吐的预防与管理,1,Evidence, Challengesand Solut,Patient Perceptions of the Most Severe Side Effects of Cancer C
2、hemotherapy,Adapted 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 Pract 1999;7:59-65.,化疗引起的恶心呕吐的预防与管理,2,Patient Perceptions of the Mos,CINV - Definitions,Acute
3、within a few minutes to several hours after drug administration and commonly resolves within 24 hours.Delayed develops in patients more than 24 hours after chemotherapy administration. May last up to 6 daysIt commonly occurs with cisplatin, carboplatin, cyclophosphamide and/or anthracyclines.Anticip
4、atory nausea and/or vomiting before patients receive their chemotherapy, after a prior negative experience with chemotherapyBreakthrough occurs despite prophylactic treatment and/or requires rescue.Refractory nausea and emesis during subsequent cycles when antiemetic prophylaxis and/or rescue have f
5、ailed in earlier cycles,Adapted from: ASHP Am J Health Syst Pharm 1999;56:729-764 NCCN Practice Guidelines in OncologyVersion 3. 2008. Antiemesis,化疗引起的恶心呕吐的预防与管理,3,CINV - Definitions Acute wit,Rates of CINV,Adapted from:1. Hickok JT, et al. Cancer. 2003;97:2880-6.2.,化疗引起的恶心呕吐的预防与管理,4,Rates of CINVAd
6、apted from:化疗引起,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,Adapted from:Gregory RE et al. Drugs. 1998.; 2. Hesketh PJ et al. J Clin Oncol
7、. 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. Cancer 2004;101:2701-2708,化疗引起的恶心呕吐的预防与管理,5,Chemotherapy-Induced Emesi
8、s R,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.,化疗引起的恶心呕吐的预防与管理,6,Influence of Pa
9、tient Expectati,Chemotherapy-Induced 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 Sy
10、st Pharm 1999;56:729-64.,化疗引起的恶心呕吐的预防与管理,7,Chemotherapy-Induced Emesis Ri,Causes of CINV,In addition to emesis induced by chemotherapy, CINV can be caused by:Partial or complete bowel obstructionVestibular DysfunctionBrain MetastasesElectrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia,
11、uremiaConcomitant drugs, including opiatesGastroparesis induced by a tumor or chemotherapy (such as vincristine)Psychophysiologic factors, including anxiety as well as anticipatory nausea and vomiting,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,8,Cau
12、ses of CINVIn addition to e,Consequence of Unresolved CINV,Discontinuation of therapy Serious metabolic derangementsNutritional depletion and anorexiaEsophageal tearsWound dehiscenceDeterioration of patients physical and mental statusDegeneration of self-care and functional ability,Adverse sequelae
13、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,9,Consequence of Unresolved CINV,Poll of the audienceAs Health care professionals we often :,A. Accurately recognize the incidence of acute and delayed CINV in
14、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,10,Poll of the audienceAs Health,Anti Nausea Chemotherapy Registry (ANCHOR) study,The authors determined the incidence of acute and delayed CINV after modern antiemetics.Then they compare
15、d 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,11,Anti Nausea Chemotherapy Regis,Anchor Study Perception vs Reality Moderately Emetogenic Chemotherapy,Adapted from Grun
16、berg et al. Cancer 2004;100:2261-8.,化疗引起的恶心呕吐的预防与管理,12,Anchor Study Perception vs Rea,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 t
17、hey 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,13,Toxicity AssessmentsGrade comm,Rates of CINV in,N=26,Dr. H. Bliss Murphy Cancer Center, St. Johns Newfoundland,化疗引起的恶心呕吐的预防与管理,14,Rates of CINV in N=26Dr. H. Bl,Rate of CINV,Adapted from Cance
18、r 2004;100:2261-8.,N=231,at the Dr. H. Bliss Murphy Cancer Center, St. Johns Newfoundland in comparison to the Grunberg data,化疗引起的恶心呕吐的预防与管理,15,Rate of CINVAdapted from Cance,Health Care Professionals Perception of CINV at the Dr. H. Bliss Murphy Cancer Center, St. Johns Newfoundland,Adapted from Ca
19、ncer 2004;100:2261-8.,化疗引起的恶心呕吐的预防与管理,16,Health Care Professionals Perc,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 favorable health states, just below per
20、fect 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 Lif,CINVDecreased Quality of Life,Adapted from Support Care Cancer 2005;13:219-27.,化疗引起的恶心呕吐的预防与管理,18,CINVDecreased Quality of Lif,Adapted from Bloechl-Daum B et al. J Cli
21、n Oncol. 2006;24:4472.,CINVDecreased Quality of Life,FLIE QuestionnaireHEC-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 = Functiona
22、l 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,19,Adapted from Bloechl-Daum B et,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
23、 care professionals, we may not be accurately predicting the level of CINV experienced by our patients.CINV 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,20,Summary of the Importance of,Mechanisms of CINV,Central mechanism:Chemotherapeutic agent activates the chemoreceptor t
24、rigger zone (CTZ). Activated CTZ invokes release of various neurotransmitters, which stimulate vomiting center.Peripheral mechanism:Chemotherapeutic agent causes irritation and damage to gastrointestinal (GI) mucosa, resulting in the release of neurotransmitters.Activated receptors send signals to v
25、omiting center via vagal afferents.,Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams 2001:28692880.,化疗引起的恶心呕吐的预防与管理,21,Mechanisms of CINVCentral mech,Adapted from N Engl J Med 2008;358:2482-94.,化疗引起的恶心呕吐的预防与管理,22,Adapted from N Engl J Med 20
26、08,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 to be peripheral
27、.,Adapted from: Berger AM et al. In: Cancer: Principles and Practice of Oncology. 6th ed. Lippincott Williams 39:1074-80.,化疗引起的恶心呕吐的预防与管理,23,Serotonin and 5-HT3 Receptor P,Substance P and Neurokinin1 (NK1) Receptor Pathway,High density of substance P/NK1 receptors located in brain regions implicated
28、 in the emetic reflex.Primary mechanism of 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
29、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,24,Substance P and Neurokinin1 (,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 brea
30、kdown products,Intensity of emesis,Time (days),0,1,2,3,4,5,5HT,NK1-sensitive phase,化疗引起的恶心呕吐的预防与管理,25,Conceptual Model of Acute & De,Pharmacogenomics,Quest for individualized therapy.Identification and characterization of a large number of genetic polymorphisms(biomarkers) in drug metabolizing enzym
31、es and drug transporters may provide substantial knowledge about the mechanisms of inter-individual differences in drug response.,化疗引起的恶心呕吐的预防与管理,26,PharmacogenomicsQuest for indi,Pharmacogenomics,Pharmacogenomics - the study of the relationship between specific DNA sequence variations and the actua
32、l 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 the CYP2D6 polymorphism. As this enzyme is polymorphic, several different alleles may be present i
33、n different individuals.,化疗引起的恶心呕吐的预防与管理,27,PharmacogenomicsPharmacogenomi,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 population (UM) Ultrarapid metabolizer phe
34、notype 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,28,Number of SubjectsIncreasing M,Pharmacogenomics in CINV,Kaiser studied the impact of patient genotype for 2D6 (CYP2D6) on efficacy of ondansetron and tropisetron
35、 for CINV.The ultrarapid 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 e
36、valuated 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,29,Pharmacogenomics in CINVKaiser,Figure 2
37、. 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 CINV,Ad
38、apted 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,30,Figure 2. Mean number of episo,ANTIEMETIC GUIDELINE CONSENSUS,- Of
39、ficial Process Subscribed to by 9 International Oncology Groups -,Adapted from MASCC Antiemetic March 2008 Guideline Update.,化疗引起的恶心呕吐的预防与管理,31,ANTIEMETIC GUIDELINE CONSENSUS,MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES,ANTIEMETIC TREATMENT GUIDELINES - The Four Emetic Risk Groups -,Adapted from MASCC
40、 Antiemetic March 2008 Guideline Update.,化疗引起的恶心呕吐的预防与管理,32,MASCC (PERUGIA) 2004 ANTIEMETI,MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES,- Emetic Risk Groups - Single IV Agents -,Adapted from MASCC Antiemetic March 2008 Guideline Update.,化疗引起的恶心呕吐的预防与管理,33,MASCC (PERUGIA) 2004 ANTIEMETI,MASCC (PERUGIA)
41、 2004 ANTIEMETIC GUIDELINES,- Committee I (3/5): Emetic Risk Groups - Single IV Agents,Adapted from MASCC Antiemetic March 2008 Guideline Update.,化疗引起的恶心呕吐的预防与管理,34,MASCC (PERUGIA) 2004 ANTIEMETI,MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES,ANTIEMETIC TREATMENT GUIDELINES - Committee I (5/5): Emetic R
42、isk 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,35,MASCC (PERUGIA) 2004 ANTIEMETI,Principles of Care for Acute Highly andModerately Emetic Settings,UNANIMOUS CONSENSUS: CATEGORY 1 EVIDENCEUse the lowest tested fully effective dose.No sched
43、ule is better than a single dose given before chemotherapy.The 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 chemothe
44、rapy.,Adapted from MASCC Antiemetic March 2008 Guideline Update.,化疗引起的恶心呕吐的预防与管理,36,Principles of Care for Acute H,To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen is recommended including single doses of:5-HT3 antagonistDexamethasoneAprepitant (o
45、r fosaprepitant)given before chemotherapy is recommended.MASCC Level of confidence : HighMASCC Level of consensus: HighASCO Level of evidence: IASCO Grade of recommendation: A,Adapted from slide from MASCC Antiemetic March 2008 Guideline Update.,Guideline for the Prevention of Acute Nausea and Vomit
46、ing Following Chemotherapy of High Emetic Risk:,化疗引起的恶心呕吐的预防与管理,37,To prevent acute vomiting and,Example - Women 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 wome
47、n, 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: IIASCO Grade of recommendation: A,Adapted from MASCC Antiemeti
48、c 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,38,Example - Women receiving a co,In patients who receive MEC, not including a combination of anthracycline plus cyclophosphamide:5-HT3 recep
49、tor 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
50、 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,39,In patients who receive MEC, n,B.C. Cancer Agency Antiemetic regimens,Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Ret
