化療引起的惡心嘔吐的預(yù)防與管理

1、Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy,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

2、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 – develo

3、ps 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 b

4、efore patients receive their chemotherapy, after a prior negative experience with chemotherapyBreakthrough – occurs despite prophylactic treatment and/or requires rescue.Refractory – nausea and emesis during subseque

5、nt 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 Oncology–Version 3. 2008. Antiemesis,Rates of CINV

6、,Adapted from:1. Hickok JT, et al. Cancer. 2003;97:2880-6.2.ashpadvantage/previous_meetings/mcm_2005/cemornings2005/CEM_CINV_handout.pdf,Chemotherapy-Induced Emesis Risk Factors,Patient-related risk factors include:Y

7、ounger 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. 1997.R

8、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

9、. Cancer 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 subs

10、equent nausea.,Adapted from Roscoe et al. Cancer. 2004 101(11):2701-8.,Chemotherapy-Induced Emesis Risk Factors,Treatment-related risk factors include: High drug dose High emetogenicity of chemotherapy drugsOf all th

11、e 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 CINV,In addition to emesis induced by chemot

12、herapy, CINV can be caused by:Partial or complete bowel obstructionVestibular DysfunctionBrain MetastasesElectrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia, uremiaConcomitant drugs, including opiates

13、Gastroparesis 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 Oncology–Version 3

14、. 2008. Antiemesis.,,Consequence of Unresolved CINV,Discontinuation of therapy Serious metabolic derangementsNutritional depletion and anorexiaEsophageal tearsWound dehiscenceDeterioration of patients’ physical and

15、mental statusDegeneration of self-care and functional ability,Adverse sequelae of nausea and vomiting in the cancer patient.,Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.,Poll of the aud

16、ienceAs 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 Nau

17、sea Chemotherapy Registry (ANCHOR) study,The authors determined the incidence of acute and delayed CINV after modern antiemetics.Then they compared the actual incidences of CINV to the predictions made by physicians an

18、d 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 Grunberg et al. Cancer 2004;100:2261-8.,Toxi

19、city 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 ex

20、perience any toxicities.,Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland,Rates of CINV in,N=26,,Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland,Rate of CINV,Adapted from Cancer 2004;100:2261-8.,,N

21、=231,at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland in comparison to the Grunberg data,Health Care Professionals Perception of CINV at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland,A

22、dapted from Cancer 2004;100:2261-8.,CINV—Decreased 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 am

23、ong the most favorable health states, just below perfect health and clinical remission.,Adapted from Support Care Cancer 2005;13:219-27.,CINV—Decreased Quality of Life,Adapted from Support Care Cancer 2005;13:219-27.,Ada

24、pted from Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472.,CINV—Decreased Quality of Life,FLIE QuestionnaireHEC-FLIE > MEC-FLIE P=0.0049FLIE-nausea > FLIE-Vomiting P=0.0097There is a greater negative im

25、pact 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 = moderately

26、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

27、 predicting the level of CINV experienced by our patients.CINV has a enormous impact on our patients quality of life.,Mechanisms of CINV,Central mechanism:Chemotherapeutic agent activates the chemoreceptor trigger zon

28、e (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

29、 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

30、& Wilkins; 2001:2869–2880.,Adapted from N Engl J Med 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:H

31、ighly effective in acute vomiting, less effective for delayed events.Optimal use is with dexamethasone.Primary mechanism of action appears to be peripheral.,Adapted from: Berger AM et al. In: Cancer: Principles and Pr

32、actice 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

33、1998;9:811-19. Endo T et al Toxicology 2000;153:189-201. Hesketh PJ et al Eur J Cancer 2003;39:1074-80.,Substance P and Neurokinin­1 (NK1) Receptor Pathway,High density of substance P/NK1 receptors located in brai

34、n regions implicated 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 antagoni

35、st 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.,,Conceptual Model of Acute & Delayed

36、 CINV,Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds). Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147.,,,,,,,,,5-HT3-sensitive phase,Prokinetic-sensitive phase

37、,Steroid-sensitive phase,Disrupted gut motility,Cell breakdown products,Intensity of emesis,Time (days),0,1,2,3,4,5,,,5HT,,NK1-sensitive phase,,,,,Pharmacogenomics,Quest for individualized therapy.Identification and ch

38、aracterization 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 resp

39、onse.,Pharmacogenomics,Pharmacogenomics - 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 availabl

40、e 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 in different

41、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 population (UM) Ul

42、trarapid 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 f

43、or 2D6 (CYP2D6) on efficacy of ondansetron and tropisetron for CINV.The ultrarapid metabolizer patients experienced significantly more nausea and vomiting after chemotherapy. The impact of genotype on vomiting incide

44、nce 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.,Adapted from: Kaiser R, Sezer O, Papies A, et al: Pati

45、ent-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 ({+/-}

46、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

47、a day (B),Pharmacogenomics in CINV,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

48、. 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 ANTIE

49、METIC 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 A

50、gents -,Adapted from MASCC Antiemetic March 2008 Guideline Update.,MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES,- Committee I (3/5): Emetic Risk Groups - Single IV Agents,Adapted from MASCC Antiemetic March 2008 Guideline

51、 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 Guideline Update.,Principles o

52、f 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 antieme

53、tic 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 bef

54、ore chemotherapy.,Adapted from MASCC Antiemetic March 2008 Guideline Update.,To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen is recommended including single doses of:

55、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 recom

56、mendation: A,Adapted 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 combin

57、ation 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:

58、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 rec

59、ommendation: 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

60、including a combination of anthracycline plus cyclophosphamide:5-HT3 receptor antagonist +Dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course.MASCC level of confidence: Hi

61、ghMASCC level of consensus: HighASCO level of evidence: IASCO grade of recommendation: A,Adapted from MASCC Antiemetic March 2008 Guideline Update.,Guideline for the Prevention of Acute Nausea and Vomiting Following C

62、hemotherapy 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. Retrieved July 21, 2008 from

63、 bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf,ONS Putting Evidence into Practice,Adapted from ONS PEP Nausea Retrieved July 21, 2008 from ons.org/outcomes/volume1/nausea/pdf/

64、nauseaPEPCard.pdf,Adapted from ONS PEP Nausea Retrieved July 21, 2008 from ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf,ONS Putting Evidence into Practice – Cont’d,Cancer Care Ontario - Telephone Nursing Practic

65、e - and Symptom Management Guidelines,Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf,Cancer Care Ontario - Telephone Nursing Practic

66、eand Symptom Management Guidelines,Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf,Common CINV Challenges,Challenges in multiple-day

67、 chemotherapy regimensBreakthrough CINVAnticipatory CINVDelayed CINV,Multiple-Day Chemotherapy Regimens,Challenge – Patients receiving multi-day chemotherapy (chemotherapy administered over several days per cycle)

68、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 ris