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Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

Evidence, Challenges and Solutions: Preventing and Managing Chemotherapy-Induced Nausea and Vomiting. Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008. Patient Perceptions of the Most Severe Side Effects of Cancer Chemotherapy. Adapted from:

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Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

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  1. Evidence, Challenges and Solutions:Preventing and Managing Chemotherapy-Induced Nausea and Vomiting Scott Edwards, Pharm D Clinical Oncology Pharmacist Eastern Health, St. John’s, NL NOPS 2008

  2. 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 J Cancer. 1997;76:1055-61. 4 Lindley C et al. Cancer Pract 1999;7:59-65.

  3. CINV - Definitions • Acute – 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 days • It 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 chemotherapy • Breakthrough – 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 Oncology–Version 3. 2008. Antiemesis

  4. Rates of CINV Adapted from: 1. Hickok JT, et al. Cancer. 2003;97:2880-6. 2.http://www.ashpadvantage.com/previous_meetings/mcm_2005/cemornings2005/CEM_CINV_handout.pdf

  5. Chemotherapy-Induced Emesis Risk Factors • Patient-related risk factors include: • Younger age • Female gender • No/minimal prior history of alcohol use • Prior CINV • Anxiety • High pretreatment expectation of severe nausea • 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. Cancer 2004;101:2701-2708

  6. 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.

  7. Chemotherapy-Induced Emesis Risk Factors • Treatment-related risk factors include: • High drug dose • High emetogenicity of chemotherapy drugs • Of 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.

  8. Causes of CINV In addition to emesis induced by chemotherapy, CINV can be caused by: • Partial or complete bowel obstruction • Vestibular Dysfunction • Brain Metastases • Electrolyte imbalance: hypercalcemia, hyperglycemia, hyponatremia, uremia • Concomitant drugs, including opiates • 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. 2008. Antiemesis.

  9. Consequence of Unresolved CINV Adverse sequelae of nausea and vomiting in the cancer patient. • Discontinuation of therapy • Serious metabolic derangements • Nutritional depletion and anorexia • Esophageal tears • Wound dehiscence • Deterioration of patients’ physical and mental status • Degeneration of self-care and functional ability Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis.

  10. Poll of the audienceAs 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.

  11. Anti Nausea 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 and nurses regarding these patients. Adapted from Grunberg SM et al. Cancer 2004;100:2261-8.

  12. Anchor Study Perception vs RealityModerately Emetogenic Chemotherapy Adapted from Grunberg et al. Cancer 2004;100:2261-8.

  13. Toxicity Assessments Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland • 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.

  14. Rates of CINV in Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland N=26

  15. Rate of CINV at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland in comparison to the Grunberg data N=231 Adapted from Cancer 2004;100:2261-8.

  16. Health Care Professionals Perception of CINV at the Dr. H. Bliss Murphy Cancer Center, St. John’s Newfoundland Adapted from Cancer 2004;100:2261-8.

  17. 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 among the most favorable health states, just below perfect health and clinical remission. Adapted from Support Care Cancer 2005;13:219-27.

  18. CINV—Decreased Quality of Life Adapted from Support Care Cancer 2005;13:219-27.

  19. CINV—Decreased Quality of Life • FLIE Questionnaire • HEC-FLIE > MEC-FLIE P=0.0049 • FLIE-nausea > FLIE-Vomiting P=0.0097 • There is a greater negative impact onQOL from nausea than there is from vomiting • There is a greater negative impact onQOL from HEC than there is from MEC FLIE = Functional Living Index-Emesis; HEC = highly emetogenic chemotherapy; MEC = moderately emetogenic chemotherapy. Adapted from Bloechl-Daum B et al. J Clin Oncol. 2006;24:4472.

  20. 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 impact on our patients quality of life.

  21. 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 and 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 & Wilkins; 2001:2869–2880.

  22. Adapted from N Engl J Med 2008;358:2482-94.

  23. 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. Adapted from: Berger AM et al. In: Cancer: Principles 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 2003;39:1074-80.

  24. 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 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 Support Care Cancer 2001;9:350-54.

  25. Conceptual Model of Acute & Delayed CINV 5-HT3-sensitive phase Prokinetic-sensitive phase NK1-sensitive phase Intensity of emesis Steroid-sensitive phase 5HT Disrupted gut motility Cell breakdown products 0 2 1 3 4 5 Time (days) Adapted from Andrews & Davis. In: Andrews PLR & Sanger GJ (Eds). Emesis in Anti-Cancer Therapy: Mechanisms and Treatment. London: Arnold; 1993:147.

  26. Pharmacogenomics • 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.

  27. 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 available serotonin antagonists, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6polymorphism. As this enzyme is polymorphic, several different alleles may be present in different individuals.

  28. Pharmacogenomics Polymorphic Distribution • CYP2D6 mutations or deletions, 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. Number of Subjects PM EM URM Increasing Metabolic Capacity

  29. Pharmacogenomics in CINV • Kaiser studied the impact of patient genotype for 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 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. 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.

  30. Pharmacogenomics in CINV Figure 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) 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 ClinOncol20:2805-11, 2002.

  31. ANTIEMETIC GUIDELINE CONSENSUS - Official Process Subscribed to by 9 International Oncology Groups - Adapted from MASCC Antiemetic March 2008 Guideline Update.

  32. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES ANTIEMETIC TREATMENT GUIDELINES - The Four Emetic Risk Groups - Adapted from MASCC Antiemetic March 2008 Guideline Update.

  33. MASCC (PERUGIA) 2004 ANTIEMETIC GUIDELINES - Emetic Risk Groups - Single IV Agents - Adapted from MASCC Antiemetic March 2008 Guideline Update.

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

  35. 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.

  36. Principles of Care for Acute Highly andModerately Emetic Settings UNANIMOUS CONSENSUS: CATEGORY 1 EVIDENCE • Use 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 antagonistagents 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.

  37. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of High Emetic Risk: To prevent acute vomiting and nausea following chemotherapy of high emetic risk, a three-drug regimen is recommended including single doses of: • 5-HT3 antagonist • Dexamethasone • Aprepitant (or fosaprepitant) given before chemotherapy is recommended. MASCC Level of confidence : High MASCC Level of consensus: High ASCO Level of evidence: I ASCO Grade of recommendation: A Adapted from slide from MASCC Antiemetic March 2008 Guideline Update.

  38. Guideline for the Prevention of Acute Nausea and Vomiting Following Chemotherapy of Moderate Emetic Risk (MEC): 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 women, a three-drug regimen including single doses of: • 5-HT3 antagonist • Dexamethasone • Aprepitant (or fosaprepitant) given before chemotherapy is recommended. MASCC Level of confidence: Moderate MASCC Level of consensus: High ASCO Level of evidence: II ASCO Grade of recommendation: A Adapted from MASCC Antiemetic March 2008 Guideline Update.

  39. 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 receptor antagonist + • Dexamethasone is recommended for prophylaxis of acute nausea and vomiting in the first course. MASCC level of confidence: High MASCC level of consensus: High ASCO level of evidence: I ASCO grade of recommendation: A Adapted from MASCC Antiemetic March 2008 Guideline Update.

  40. 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 http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

  41. ONS Putting Evidence into Practice Adapted from ONS PEP Nausea Retrieved July 21, 2008 from http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf

  42. ONS Putting Evidence into Practice – Cont’d Adapted from ONS PEP Nausea Retrieved July 21, 2008 from http://www.ons.org/outcomes/volume1/nausea/pdf/nauseaPEPCard.pdf

  43. Cancer Care Ontario - Telephone Nursing Practice - and Symptom Management Guidelines Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

  44. Cancer Care Ontario - Telephone Nursing Practiceand Symptom Management Guidelines Adapted from CCO Telephone Assessments. Retrieved July 21, 2008 from http://www.cancercare.on.ca/documents/NursingTelephonePracticeGuidelines.pdf

  45. Common CINV Challenges • Challenges in multiple-day chemotherapy regimens • Breakthrough CINV • Anticipatory CINV • Delayed CINV

  46. Multiple-Day Chemotherapy Regimens • Challenge – Patients receiving 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 risk 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 Oncology–Version 3. 2008. Antiemesis,

  47. Multi-Day Chemotherapy Regimens (continued) • A 5-HT3 receptor antagonist should be administered 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 aprepitant 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 Oncology–Version 3. 2008. Antiemesis,

  48. Breakthrough CINV • Breakthrough emesis refers to vomiting that occurs 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 refractory nausea is hard to reverse. Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

  49. Breakthrough CINV (continued) • Management Strategies -Give around the clock administration versus prn. • Additional agents should be from a different drug class than initial therapy. No one treatment is better than the other. • Possibilities include: dopamine antagonists, metoclopramide, haloperidol, cannabinoids, corticosteroids, or agents such as lorazepam • If patient has dyspepsia, consider antacid therapy (H2 blocker or Proton Pump Inhibitor). Adapted from NCCN Practice Guidelines in Oncology–Version 3. 2008. Antiemesis,

  50. Breakthrough CINV – Cont’d Adapted from: Guidelines for Prevention and Treatment of Chemotherapy-Induced Nausea and Vomiting in Adults. Retrieved July 21, 2008 from http://www.bccancer.bc.ca/NR/rdonlyres/8E898B5D-3F12-4623-8E32-5B3C429C58F7/28155/SCNAUSEA_1Mar08.pdf

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